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Sökning: WFRF:(Gouras Gunnar)

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1.
  • Agholme, Lotta (författare)
  • The involvement of degradation pathways and neuron-to-neuron transmission in Alzheimer’s disease
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Although the vast majority of Alzheimer’s disease (AD) cases are of the sporadic type, mutations causing the familial form have been the focus of AD research for decades. The disease is pathologically characterised by β-amyloid (Aβ) and tau protein aggregates in neuritic plaques and neurofibrillary tangles. Furthermore, it is known that AD pathology spreads throughout the brain, most often along the same anatomical pattern. However, so far no cause for the sporadic form of the disease has been found. Accumulation of protein aggregates as well as decreased activity of the protein degradation systems, lysosomes and proteasomes, is found in diseased brains. This indicates that defective degradation contributes to sporadic AD.The aim of this thesis was to develop an improved neuronal model, and study the effects of decreased proteasome function on tau phosphorylation and axonal transport. In addition, the effects on Aβ accumulation and generation upon proteasome inhibition were investigated. Finally, the possibility that intracellularly accumulated Aβ oligomers could be transferred from one neuron to another was tested.Differentiation of human SH-SY5Y neuroblastoma cells in an extracellular matrix gel, using a set of neurotrophic factors, resulted in cells with neuronal phenotype, expressing neuron specific markers and all six adult isoforms of tau. Within this neuronal model, we found that reduced proteasome activity inhibited neuritic transport, and caused tau phosphorylation in a c-Jun and ERK 1/2 dependent manner. Using proteasome inhibition in APP overexpressing cells, we found an autophagy dependent intralysosomal Aβ accumulation, together with elevation of intra- and extracellular concentrations of Aβ. Autophagy inhibition protected the cells from the toxicity induced by decreased proteasome activity. Finally, we could, as the first group, show that Aβ can be directly transferred from one neuron to another through connected neurites. Furthermore, accumulation of Aβ in the endo-lysosomal compartment of receiving cells caused toxicity and neurodegeneration.We believe that cells not able to degrade accumulated Aβ, due to increased generation or reduced degradative capacity, instead tries to clear its content through transfer to connected neurons. If not properly degraded in the receiving cell, this can accelerate AD pathology and cause neuritic and neuronal degeneration spreading throughout the brain. Increasing the activity of the degradative systems, or inhibiting transmission of Aβ between neurons could therefore be novel treatments for AD.
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2.
  • Andersson, Emelie, et al. (författare)
  • Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the App NL−F/NL−F knock-in mouse model of Alzheimer’s disease
  • 2023
  • Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Aβ42/Aβ40 ratios in cerebrospinal fluid (CSF) and blood are reduced in preclinical Alzheimer’s disease (AD), but their temporal and correlative relationship with cerebral Aβ pathology at this early disease stage is not well understood. In the present study, we aim to investigate such relationships using App knock-in mouse models of preclinical AD. Methods: CSF, serum, and brain tissue were collected from 3- to 18-month-old AppNL−F/NL−F knock-in mice (n = 48) and 2–18-month-old AppNL/NL knock-in mice (n = 35). The concentrations of Aβ42 and Aβ40 in CSF and serum were measured using Single molecule array (Simoa) immunoassays. Cerebral Aβ plaque burden was assessed in brain tissue sections by immunohistochemistry and thioflavin S staining. Furthermore, the concentrations of Aβ42 in soluble and insoluble fractions prepared from cortical tissue homogenates were measured using an electrochemiluminescence immunoassay. Results: In AppNL−F/NL−F knock-in mice, Aβ42/Aβ40 ratios in CSF and serum were significantly reduced from 12 and 16 months of age, respectively. The initial reduction of these biomarkers coincided with cerebral Aβ pathology, in which a more widespread Aβ plaque burden and increased levels of Aβ42 in the brain were observed from approximately 12 months of age. Accordingly, in the whole study population, Aβ42/Aβ40 ratios in CSF and serum showed a negative hyperbolic association with cerebral Aβ plaque burden as well as the levels of both soluble and insoluble Aβ42 in the brain. These associations tended to be stronger for the measures in CSF compared with serum. In contrast, no alterations in the investigated fluid biomarkers or apparent cerebral Aβ plaque pathology were found in AppNL/NL knock-in mice during the observation time. Conclusions: Our findings suggest a temporal sequence of events in AppNL−F/NL−F knock-in mice, in which initial deposition of Aβ aggregates in the brain is followed by a decline of the Aβ42/Aβ40 ratio in CSF and serum once the cerebral Aβ pathology becomes significant. Our results also indicate that the investigated biomarkers were somewhat more strongly associated with measures of cerebral Aβ pathology when assessed in CSF compared with serum.
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3.
  • Aso, Ester, et al. (författare)
  • Poly(propylene imine) dendrimers with histidine-maltose shell as novel type of nanoparticles for synapse and memory protection.
  • 2019
  • Ingår i: Nanomedicine: Nanotechnology, Biology, and Medicine. - : Elsevier BV. - 1549-9642 .- 1549-9634. ; , s. 198-209
  • Tidskriftsartikel (refereegranskat)abstract
    • Poly(propylene imine) dendrimers have been shown to be promising 3-dimensional polymers for the use in the pharmaceutical and biomedical applications. Our aims of this study were first, to synthesize a novel type of dendrimer with poly(propylene imine) core and maltose-histidine shell (G4HisMal) assessing if maltose-histidine shell can improve the biocompatibility and the ability to cross the blood brain barrier, and second, to investigate the potential of G4HisMal to protect Alzheimer disease transgenic mice from memory impairment. Our data demonstrate that G4HisMal has significantly improved biocompatibility and ability to cross the blood brain barrier in vivo. Therefore, we suggest that a maltose-histidine shell can be used to improve biocompatibility and ability to cross the blood brain barrier of dendrimers. Moreover, G4HisMal demonstrated properties for synapse and memory protection when administered to Alzheimer disease transgenic mice. Therefore, G4HisMal can be considered as a promising drug candidate to prevent Alzheimer disease via synapse protection.
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4.
  • Azevedo, Carla, et al. (författare)
  • Parkinsons disease and multiple system atrophy patient iPSC-derived oligodendrocytes exhibit alpha-synuclein-induced changes in maturation and immune reactive properties
  • 2022
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Limited evidence has shed light on how aSYN proteins affect the oligodendrocyte phenotype and pathogenesis in synucleinopathies that include Parkinsons disease (PD) and multiple system atrophy (MSA). Here, we investigated early transcriptomic changes within PD and MSA O4(+) oligodendrocyte lineage cells (OLCs) generated from patient-induced pluripotent stem cells (iPSCs). We found impaired maturation of PD and MSA O4(+) OLCs compared to controls. This phenotype was associated with changes in the human leukocyte antigen (HLA) genes, the immunoproteasome subunit PSMB9, and the complement component C4b for aSYN p.A53T and MSA O4(+) OLCs, but not in SNCA(trip) O4(+) OLCs despite high levels of aSYN assembly formation. Moreover, SNCA overexpression resulted in the development of O4(+) OLCs, whereas exogenous treatment with aSYN species led to significant toxicity. Notably, transcriptome profiling of genes encoding proteins forming Lewy bodies and glial cytoplasmic inclusions revealed clustering of PD aSYN p.A53T O4(+) OLCs with MSA O4(+) OLCs. Our work identifies early phenotypic and pathogenic changes within human PD and MSA O4(+) OLCs.
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5.
  • Beckelman, Brenna C., et al. (författare)
  • Dysregulation of Elongation Factor 1A Expression is Correlated with Synaptic Plasticity Impairments in Alzheimer's Disease
  • 2016
  • Ingår i: Journal of Alzheimer's Disease. - 1387-2877. ; 54:2, s. 669-678
  • Tidskriftsartikel (refereegranskat)abstract
    • Synaptic dysfunction may represent an early and crucial pathophysiology in Alzheimer's disease (AD). Recent studies implicate a connection between synaptic plasticity deficits and compromised capacity of de novo protein synthesis in AD. The mRNA translational factor eukaryotic elongation factor 1A (eEF1A) is critically involved in several forms of long-lasting synaptic plasticity. By examining postmortem human brain samples, a transgenic mouse model, and application of synthetic human Aβ42 on mouse hippocampal slices, we demonstrated that eEF1A protein levels were significantly decreased in AD, particularly in the hippocampus. In contrast, brain levels of eukaryotic elongation factor 2 were unaltered in AD. Further, upregulation of eEF1A expression by the adenylyl cyclase activator forskolin, which induces long-lasting synaptic plasticity, was blunted in hippocampal slices derived from Tg2576 AD model mice. Finally, Aβ-induced hippocampal long-term potentiation defects were alleviated by upregulation of eEF1A signaling via brain-specific knockdown of the gene encoding tuberous sclerosis 2. In summary, our findings suggest a strong correlation between the dysregulation of eEF1A synthesis and AD-associated synaptic failure. These findings provide insights into the understanding of molecular mechanisms underlying AD etiology and may aid in identification of novel biomarkers and therapeutic targets.
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6.
  • Boza-serrano, Antonio, et al. (författare)
  • Galectin-3 is elevated in CSF and is associated with Aβ deposits and tau aggregates in brain tissue in Alzheimer’s disease
  • 2022
  • Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322.
  • Tidskriftsartikel (refereegranskat)abstract
    • Galectin-3 (Gal-3) is a beta-galactosidase binding protein involved in microglial activation in the central nervous system(CNS). We previously demonstrated the crucial deleterious role of Gal-3 in microglial activation in Alzheimer’s disease(AD). Under AD conditions, Gal-3 is primarily expressed by microglial cells clustered around Aβ plaques in both humanand mouse brain, and knocking out Gal-3 reduces AD pathology in AD-model mice. To further unravel the importance ofGal-3-associated infammation in AD, we aimed to investigate the Gal-3 infammatory response in the AD continuum. First,we measured Gal-3 levels in neocortical and hippocampal tissue from early-onset AD patients, including genetic and sporadiccases. We found that Gal-3 levels were signifcantly higher in both cortex and hippocampus in AD subjects. Immunohistochemistry revealed that Gal-3+microglial cells were associated with amyloid plaques of a larger size and more irregularshape and with neurons containing tau-inclusions. We then analyzed the levels of Gal-3 in cerebrospinal fuid (CSF) fromAD patients (n=119) compared to control individuals (n=36). CSF Gal-3 levels were elevated in AD patients comparedto controls and more strongly correlated with tau (p-Tau181 and t-tau) and synaptic markers (GAP-43 and neurogranin)than with amyloid-β. Lastly, principal component analysis (PCA) of AD biomarkers revealed that CSF Gal-3 clustered andassociated with other CSF neuroinfammatory markers, including sTREM-2, GFAP, and YKL-40. This neuroinfammatory component was more highly expressed in the CSF from amyloid-β positive (A+), CSF p-Tau181 positive (T+), andbiomarker neurodegeneration positive/negative (N+/−) (A+T+N+/−) groups compared to the A+T−N− group. Overall,Gal-3 stands out as a key pathological biomarker of AD pathology that is measurable in CSF and, therefore, a potential targetfor disease-modifying therapies involving the neuroinfammatory response.
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7.
  • Burrinha, Tatiana, et al. (författare)
  • Up-regulation of APP endocytosis by neuronal aging drives amyloid dependent-synapse loss
  • 2021
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 134:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Neuronal aging increases the risk of late-onset Alzheimer's disease. During normal aging, synapses decline, and β-amyloid (Aβ) accumulates intraneuronally. However, little is known about the underlying cell biological mechanisms. We studied normal neuronal aging using normal aged brain and aged mouse primary neurons that accumulate lysosomal lipofuscin and show synapse loss. We identify the up-regulation of amyloid precursor protein (APP) endocytosis as a neuronal aging mechanism that potentiates APP processing and Aβ production in vitro and in vivo. The increased APP endocytosis may contribute to the observed early endosomes enlargement in the aged brain. Mechanistically, we show that clathrin-dependent APP endocytosis requires F-actin and that clathrin and endocytic F-actin increase with neuronal aging. Finally, Aβ production inhibition reverts synaptic decline in aged neurons while Aβ accumulation, promoted by endocytosis up-regulation in younger neurons, recapitulates aging-related synapse decline. Overall, we identify APP endocytosis up-regulation as a potential mechanism of neuronal aging and, thus, a novel target to prevent late-onset Alzheimer's disease.
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8.
  • Byman, Elin, et al. (författare)
  • Neuronal α-amylase is important for neuronal activity and glycogenolysis and reduces in presence of amyloid beta pathology
  • 2021
  • Ingår i: Aging Cell. - : Wiley. - 1474-9726 .- 1474-9718. ; 20:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent studies indicate a crucial role for neuronal glycogen storage and degradation in memory formation. We have previously identified alpha-amylase (α-amylase), a glycogen degradation enzyme, located within synaptic-like structures in CA1 pyramidal neurons and shown that individuals with a high copy number variation of α-amylase perform better on the episodic memory test. We reported that neuronal α-amylase was absent in patients with Alzheimer's disease (AD) and that this loss corresponded to increased AD pathology. In the current study, we verified these findings in a larger patient cohort and determined a similar reduction in α-amylase immunoreactivity in the molecular layer of hippocampus in AD patients. Next, we demonstrated reduced α-amylase concentrations in oligomer amyloid beta 42 (Aβ42 ) stimulated SH-SY5Y cells and neurons derived from human-induced pluripotent stem cells (hiPSC) with PSEN1 mutation. Reduction of α-amylase production and activity, induced by siRNA and α-amylase inhibitor Tendamistat, respectively, was further shown to enhance glycogen load in SH-SY5Y cells. Both oligomer Aβ42 stimulated SH-SY5Y cells and hiPSC neurons with PSEN1 mutation showed, however, reduced load of glycogen. Finally, we demonstrate the presence of α-amylase within synapses of isolated primary neurons and show that inhibition of α-amylase activity with Tendamistat alters neuronal activity measured by calcium imaging. In view of these findings, we hypothesize that α-amylase has a glycogen degrading function within synapses, potentially important in memory formation. Hence, a loss of α-amylase, which can be induced by Aβ pathology, may in part underlie the disrupted memory formation seen in AD patients.
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9.
  • Capetillo-Zarate, Estibaliz, et al. (författare)
  • High-Resolution 3D Reconstruction Reveals Intra-Synaptic Amyloid Fibrils
  • 2011
  • Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 179:5, s. 2551-2558
  • Tidskriftsartikel (refereegranskat)abstract
    • beta-Amyloid (A beta) accumulation and aggregation are hallmarks of Alzheimer's disease (AD). High-resolution three-dimensional (HR-3D) volumetric imaging allows for better analysis of fluorescence confocal microscopy and 3D visualization of All pathology in brain. Early intraneuronal A beta pathology was studied in AD transgenic mouse brains by HR-3D volumetric imaging. To better visualize and analyze the development of A beta pathology, thioflavin S staining and immunofluorescence using antibodies against A beta, fibrillar A beta, and structural and synaptic neuronal proteins were performed in the brain tissue of Tg19959, wild-type, and Tg19959-YFP mice at different ages. Images obtained by confocal microscopy were reconstructed into three-dimensional volumetric datasets. Such volumetric imaging of CA1 hippocampus of AD transgenic mice showed intraneuronal onset of A beta 42 accumulation and fibrillization within cell bodies, neurites, and synapses before plaque formation. Notably, early fibrillar A beta was evident within individual synaptic compartments, where it was associated with abnormal morphology. In dendrites, increasing intraneuronal thioflavin S correlated with decreases in neurofilament marker SMI32. Fibrillar A beta aggregates could be seen piercing the cell membrane. These data support that A beta fibrillization begins within AD vulnerable neurons, leading to disruption of cytoarchitecture and degeneration of spines and neurites. Thus, HR-3D volumetric image analysis allows for better visualization of intraneuronal A beta pathology and provides new insights into plaque formation in AD. (Am J Pathol 2011, 170:2551-2558. DOI: 10.1016/j.ajpath.2011.07.045)
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10.
  • Capetillo-Zarate, Estibaliz, et al. (författare)
  • Intraneuronal A beta Accumulation, Amyloid Plaques, and Synapse Pathology in Alzheimer's Disease
  • 2012
  • Ingår i: Neurodegenerative Diseases. - : S. Karger AG. - 1660-2862 .- 1660-2854. ; 10:1-4, s. 56-59
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: beta-Amyloid (A beta) plaques are a pathological hallmark of Alzheimer's disease (AD) and multiple lines of evidence have linked A beta with AD. However, synapse loss is known as the best pathological correlate of cognitive impairment in AD, and intraneuronal A beta accumulation has been shown to precede plaque pathology. The progression of A beta accumulation to synapse loss and plaque formation remains incomplete. The objective is to investigate the progression of intraneuronal A beta accumulation in the brain. Methods: To visualize and analyze the development of A beta pathology we perform immunohistochemistry and immunofluorescence microscopy using antibodies against different A beta conformations, synaptic proteins and structural neuronal proteins in brain tissue of AD transgenic mouse models. Results: Our results show the intraneuronal onset of A beta 42 accumulation in AD mouse brains with aging. We observe an inverse correlation of A beta and amyloid fibrils with structural proteins within neurites. Images reveal aggregated amyloid within selective pyramidal neurons, neurites and synapses in AD transgenic mice as plaques arise. Conclusion: The data support that A beta 42 accumulation and aggregation begin within AD-vulnerable neurons in the brain. Progressive intraneuronal A beta 42 aggregation disrupts the normal cytoarchitecture of neurites. Copyright (C) 2012 S. Karger AG, Basel
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11.
  • Dunning, Christopher, et al. (författare)
  • Direct High Affinity Interaction between Aβ42 and GSK3α Stimulates Hyperphosphorylation of Tau. A New Molecular Link in Alzheimer's Disease?
  • 2016
  • Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 7:2, s. 161-170
  • Tidskriftsartikel (refereegranskat)abstract
    • Amyloid β peptide (Aβ42) assemblies are considered central to the development of Alzheimer's disease, but the mechanism of this toxicity remains unresolved. We screened protein microarrays with on-pathway oligomeric Aβ42 to identify candidate proteins interacting with toxic Aβ42 species. Samples prepared from Alexa546-Aβ42 and Aβ42 monomers at 1:5 molar ratio were incubated with the array during a time window of the amyloid fibril formation reaction during which the maximum number of transient oligomers exist in the reaction flux. A specific interaction was detected between Aβ42 and glycogen synthase kinase 3α (GSK3α), a kinase previously implicated in the disease pathology. This interaction was validated with anti-GSK3α immunoprecipitation assays in neuronal cell lysates. Confocal microscopy studies further identified colocalization of Aβ42 and GSK3α in neurites of mature primary mouse neurons. A high binding affinity (KD = 1 nM) was measured between Alexa488-Aβ42 and GSK3α in solution using thermophoresis. An even lower apparent KD was estimated between GSK3α and dextran-immobilized Aβ42 in surface plasmon resonance experiments. Parallel experiments with GSK3β also identified colocalization and high affinity binding to this isoform. GSK3α-mediated hyperphosphorylation of the protein tau was found to be stimulated by Aβ42 in in vitro phosphorylation assays and identified a functional relationship between the proteins. We uncover a direct and functional molecular link between Aβ42 and GSK3α, which opens an important avenue toward understanding the mechanism of Aβ42-mediated neuronal toxicity in Alzheimer's disease.
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12.
  • Edgar, James R, et al. (författare)
  • ESCRTs regulate amyloid precursor protein sorting in multivesicular bodies and intracellular beta amyloid accumulation.
  • 2015
  • Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 128:14, s. 2520-2528
  • Tidskriftsartikel (refereegranskat)abstract
    • Intracellular beta amyloid (Aβ) accumulation is a key feature of early Alzheimer's disease (AD) and precedes the appearance of Aβ in extracellular plaques. Aβ is generated through proteolytic processing of amyloid precursor protein (APP), but the intracellular site of Aβ production is unclear. APP has been localized to multivesicular endosomes/bodies (MVBs) where sorting of APP onto ILVs could promote amyloidogenic processing or reduce Aβ production/accumulation by sorting APP and processing products to lysosomes for degradation. We show that APP localizes to the ILVs of a subset of MVBs that also traffic EGF receptor (EGFR), and is delivered to lysosomes for degradation. Depletion of the ESCRT components, Hrs or Tsg101, inhibited targeting of APP to ILVs and the subsequent delivery to lysosomes and lead to increased intracellular Aβ accumulation. This was accompanied by dramatically decreased Aβ secretion. Thus, the early ESCRT machinery has a dual role in limiting intracellular Aβ accumulation through targeting of APP and processing products to the lysosome for degradation and promoting Aβ secretion.
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13.
  • Fernández-Calle, Rosalía, et al. (författare)
  • APOE in the bullseye of neurodegenerative diseases : impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases
  • 2022
  • Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 17:1
  • Forskningsöversikt (refereegranskat)abstract
    • ApoE is the major lipid and cholesterol carrier in the CNS. There are three major human polymorphisms, apoE2, apoE3, and apoE4, and the genetic expression of APOE4 is one of the most influential risk factors for the development of late-onset Alzheimer's disease (AD). Neuroinflammation has become the third hallmark of AD, together with Amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated aggregated tau protein. This review aims to broadly and extensively describe the differential aspects concerning apoE. Starting from the evolution of apoE to how APOE's single-nucleotide polymorphisms affect its structure, function, and involvement during health and disease. This review reflects on how APOE's polymorphisms impact critical aspects of AD pathology, such as the neuroinflammatory response, particularly the effect of APOE on astrocytic and microglial function and microglial dynamics, synaptic function, amyloid-β load, tau pathology, autophagy, and cell-cell communication. We discuss influential factors affecting AD pathology combined with the APOE genotype, such as sex, age, diet, physical exercise, current therapies and clinical trials in the AD field. The impact of the APOE genotype in other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies and Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, and multiple sclerosis, is also addressed. Therefore, this review gathers the most relevant findings related to the APOE genotype up to date and its implications on AD and CNS pathologies to provide a deeper understanding of the knowledge in the APOE field.
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14.
  • Folke, Jonas, et al. (författare)
  • DNAJB6b is Downregulated in Synucleinopathies
  • 2021
  • Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 11:4, s. 1791-1803
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: α-synuclein (α-syn) aggregation contributes to the progression of multiple neurodegenerative diseases. We recently found that the isoform b of the co-chaperone DNAJB6 is a strong suppressor of a-syn aggregation in vivo and in vitro. However, nothing is known about the role of the endogenous isoform b of DNAJB6 (DNAJB6b) in health and disease, due to lack of specific antibodies.OBJECTIVE: Here we generated a novel anti-DNAJB6b antibody to analyze the localization and expression this isoform in cells, in tissue and in clinical material.METHODS: To address this we used immunocytochemistry, immunohistochemistry, as well as a novel quantitative DNAJB6 specific ELISA method.RESULTS: The endogenous protein is mainly expressed in the cytoplasm and in neurites in vitro, where it is found more in dendrites than in axons. We further verified in vivo that DNAJB6b is expressed in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), which is a neuronal subpopulation highly sensitive to α-syn aggregation, that degenerate to a large extend in patients with Parkinson's disease (PD) and multiple system atrophy (MSA). When we analyzed the expression levels of DNAJB6b in brain material from PD and MSA patients, we found a downregulation of DNAJB6b by use of ELISA based quantification. Interestingly, this was also true when analyzing tissue from patients with progressive supranuclear palsy, a taupathic atypical parkinsonian disorder. However, the total level of DNAJB6 was upregulated in these three diseases, which may indicate an upregulation of the other major isoform of DNAJB6, DNAJB6a.CONCLUSION: This study shows that DNAJB6b is downregulated in several different neurodegenerative diseases, which makes it an interesting target to further investigate in relation to amyloid protein aggregation and disease progression.
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15.
  • George, Sonia, et al. (författare)
  • Lesion of the subiculum reduces the spread of amyloid beta pathology to interconnected brain regions in a mouse model of Alzheimer's disease.
  • 2014
  • Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 2:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The progressive development of Alzheimer's disease (AD) pathology follows a spatiotemporal pattern in the human brain. In a transgenic (Tg) mouse model of AD expressing amyloid precursor protein (APP) with the arctic (E693G) mutation, pathology spreads along anatomically connected structures. Amyloid-β (Aβ) pathology first appears in the subiculum and is later detected in interconnected brain regions, including the retrosplenial cortex. We investigated whether the spatiotemporal pattern of Aβ pathology in the Tg APP arctic mice to interconnected brain structures can be interrupted by destroying neurons using a neurotoxin and thereby disconnecting the neural circuitry.
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16.
  • George, Sonia, et al. (författare)
  • Nonsteroidal Selective Androgen Receptor Modulators and Selective Estrogen Receptor β Agonists Moderate Cognitive Deficits and Amyloid-β Levels in a Mouse Model of Alzheimer's Disease.
  • 2013
  • Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 4:12, s. 1537-1548
  • Tidskriftsartikel (refereegranskat)abstract
    • Decreases of the sex steroids, testosterone and estrogen, are associated with increased risk of Alzheimer's disease. Testosterone and estrogen supplementation improves cognitive deficits in animal models of Alzheimer's disease. Sex hormones play a role in the regulation of amyloid-β via induction of the amyloid-β degrading enzymes neprilysin and insulin-degrading enzyme. To mimic the effect of dihydrotestosterone (DHT), we administered a selective androgen receptor agonist, ACP-105, alone and in combination with the selective estrogen receptor β (ERβ) agonist AC-186 to male gonadectomized triple transgenic mice. We assessed long-term spatial memory in the Morris water maze, spontaneous locomotion, and anxiety-like behavior in the open field and in the elevated plus maze. We found that ACP-105 given alone decreases anxiety-like behavior. Furthermore, when ACP-105 is administered in combination with AC-186, they increase the amyloid-β degrading enzymes neprilysin and insulin-degrading enzyme and decrease amyloid-β levels in the brain as well as improve cognition. Interestingly, the androgen receptor level in the brain was increased by chronic treatment with the same combination treatment, ACP-105 and AC-186, not seen with DHT or ACP-105 alone. Based on these results, the beneficial effect of the selective ERβ agonist as a potential therapeutic for Alzheimer's disease warrants further investigation.
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17.
  • Gouras, Gunnar (författare)
  • Convergence of Synapses, Endosomes, and Prions in the Biology of Neurodegenerative Diseases.
  • 2013
  • Ingår i: International Journal of Cell Biology. - : Hindawi Limited. - 1687-8876 .- 1687-8884. ; 2013
  • Forskningsöversikt (refereegranskat)abstract
    • Age-related misfolding and aggregation of disease-linked proteins in selective brain regions is a characteristic of neurodegenerative diseases. Although neuropathological aggregates that characterize these various diseases are found at sites other than synapses, increasing evidence supports the idea that synapses are where the pathogenesis begins. Understanding these diseases is hampered by our lack of knowledge of what the normal functions of these proteins are and how they are affected by aging. Evidence has supported the idea that neurodegenerative disease-linked proteins have a common propensity for prion protein-like cell-to-cell propagation. However, it is not thought that the prion-like quality of these proteins/peptides that allows their cell-to-cell transmission implies a role for human-to-human spread in common age-related neurodegenerative diseases. It will be important to better understand the molecular and cellular mechanisms governing the role of these aggregating proteins in neural function, especially at synapses, how their propagation occurs and how pathogenesis is promoted by aging.
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18.
  • Gouras, Gunnar, et al. (författare)
  • Critical role of intraneuronal A beta in Alzheimer's disease: Technical challenges in studying intracellular A beta
  • 2012
  • Ingår i: Life Sciences. - : Elsevier BV. - 1879-0631 .- 0024-3205. ; 91:23-24, s. 1153-1158
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: Multiple lines of evidence have implicated beta-amyloid (A beta) in the pathogenesis of Alzheimer's disease (AD). However, the mechanism(s) whereby A beta is involved in the disease process remains unclear. The dominant hypothesis in AD has been that A beta initiates the disease via toxicity from secreted, extracellular A beta aggregates. More recently, an alternative hypothesis has emerged focusing on a pool of A beta that accumulates early on within AD vulnerable neurons of the brain. Although the topic of intraneuronal A beta has been of major interest in the field, technical difficulties in detecting intraneuronal A beta have also made this topic remarkably controversial. Here we review evidence pointing to the critical role of intraneuronal A beta in AD and provide insights both into challenges faced in detecting intracellular A beta and the prion-like properties of A beta. Main methods: Immunoprecipitation and Western blot are used for A beta detection. Key findings: We highlight that a standard biochemical method can underestimate intraneuronal A beta and that extracellular A beta can up-regulate intracellular A beta. We also show that detergent can remove intraneuronal A beta. Significance: There is a growing awareness that intraneuronal A beta is a key pathogenic pool of A beta involved in causing synapse dysfunction. Difficulties in detecting intraneuronal A beta are an insufficient reason for ignoring this critical pool of A beta. (C) 2012 Elsevier Inc. All rights reserved.
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19.
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20.
  • Gouras, Gunnar K (författare)
  • In memoriam for M. Flint Beal
  • 2021
  • Ingår i: Journal of Alzheimer's disease : JAD. - 1387-2877. ; 83:1, s. 1-2
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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21.
  • Gouras, Gunnar (författare)
  • mTOR: at the crossroads of aging, chaperones, and Alzheimer's disease.
  • 2013
  • Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 124:6, s. 747-748
  • Tidskriftsartikel (refereegranskat)abstract
    • Read the full article 'Over-expression of heat shock factor 1 phenocopies the effect of chronic inhibition of TOR by rapamycin and is sufficient to ameliorate Alzheimer's-like deficits in mice modeling the disease' on doi: 10.1111/jnc.12080.
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22.
  • Gouras, Gunnar, et al. (författare)
  • The Inside-Out Amyloid Hypothesis and Synapse Pathology in Alzheimer's Disease.
  • 2014
  • Ingår i: Neurodegenerative Diseases. - : S. Karger AG. - 1660-2862 .- 1660-2854. ; 13:2-3, s. 142-146
  • Tidskriftsartikel (refereegranskat)abstract
    • Cumulative evidence in brains and cultured neurons of Alzheimer's disease (AD) transgenic mouse models, as well as in human postmortem AD brains, highlights that age-related increases in β-amyloid peptide (Aβ), particularly in endosomes near synapses, are involved in early synapse dysfunction. Our immunoelectron microscopy and high-resolution immunofluorescence microscopy studies show that this early subcellular Aβ accumulation leads to progressive Aβ aggregation and pathology, particularly within dystrophic neurites and synapses. These studies confirm that neuritic/synaptic Aβ accumulation is the nidus of plaque formation. Aβ-dependent synapse pathology in AD models is modulated by synaptic activity and is plaque independent. The amyloid precursor protein (APP) is normally transported down neurites and appears to be preferentially processed to Aβ at synapses. Synapses are sites of early Aβ accumulation and aberrant tau phosphorylation in AD, which alter the synaptic composition at early stages of the disease. Elucidating the normal role of APP, and potentially of Aβ, at synapses should provide important insights into the mechanism(s) of Aβ-induced synapse dysfunction in AD and how to therapeutically mitigate these dysfunctions. © 2013 S. Karger AG, Basel.
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23.
  • Gouras, Gunnar, et al. (författare)
  • β-amyloid Peptides and Amyloid Plaques in Alzheimer's Disease.
  • 2015
  • Ingår i: Neurotherapeutics. - : Springer Science and Business Media LLC. - 1878-7479 .- 1933-7213. ; 12:1, s. 3-11
  • Forskningsöversikt (refereegranskat)abstract
    • Many lines of evidence support that β-amyloid (Aβ) peptides play an important role in Alzheimer's disease (AD), the most common cause of dementia. But despite much effort the molecular mechanisms of how Aβ contributes to AD remain unclear. While Aβ is generated from its precursor protein throughout life, the peptide is best known as the main component of amyloid plaques, the neuropathological hallmark of AD. Reduction in Aβ has been the major target of recent experimental therapies against AD. Unfortunately, human clinical trials targeting Aβ have not shown the hoped-for benefits. Thus, doubts have been growing about the role of Aβ as a therapeutic target. Here we review evidence supporting the involvement of Aβ in AD, highlight the importance of differentiating between various forms of Aβ, and suggest that a better understanding of Aβ's precise pathophysiological role in the disease is important for correctly targeting it for potential future therapy.
  •  
24.
  • Gustavsson, Nadja, et al. (författare)
  • Correlative optical photothermal infrared and X-ray fluorescence for chemical imaging of trace elements and relevant molecular structures directly in neurons
  • 2021
  • Ingår i: Light, science & applications. - : Springer Science and Business Media LLC. - 2047-7538. ; 10, s. 1-10
  • Tidskriftsartikel (refereegranskat)abstract
    • Alzheimer’s disease (AD) is the most common cause of dementia, costing about 1% of the global economy. Failures ofclinical trials targeting amyloid-βprotein (Aβ), a key trigger of AD, have been explained by drug inefficiency regardlessof the mechanisms of amyloid neurotoxicity, which are very difficult to address by available technologies. Here, wecombine two imaging modalities that stand at opposite ends of the electromagnetic spectrum, and therefore, can beused as complementary tools to assess structural and chemical information directly in a single neuron. Combininglabel-free super-resolution microspectroscopy for sub-cellular imaging based on novel optical photothermal infrared(O-PTIR) and synchrotron-based X-rayfluorescence (S-XRF) nano-imaging techniques, we capture elementaldistribution andfibrillary forms of amyloid-βproteins in the same neurons at an unprecedented resolution. Our resultsreveal that in primary AD-like neurons, iron clusters co-localize with elevated amyloidβ-sheet structures and oxidizedlipids. Overall, our O-PTIR/S-XRF results motivate using high-resolution multimodal microspectroscopic approaches tounderstand the role of molecular structures and trace elements within a single neuronal cell.
  •  
25.
  •  
26.
  • Klementieva, Oxana, et al. (författare)
  • Detection of pre-plaque amyloid aggregation using FTIR
  • 2014
  • Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 10:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Alzheimer's disease (AD) is characterized by misfolding and aggregation of naturally occurring beta-amyloid peptides (Aβ). These aggregates are thought to be pathogenic to neurons, although the conformation of the pathogenic Aβ species remains unclear. Biochemical extraction methods and different microscopy techniques (TEM, confocal) can be used to identify pathogenic Aβ species in the brain, although such methods can alter protein conformation or are n ot designed to determine structural details of protein assemblies.
  •  
27.
  • Klementieva, Oxana, et al. (författare)
  • Super‐Resolution Infrared Imaging of Polymorphic Amyloid Aggregates Directly in Neurons
  • 2020
  • Ingår i: Advanced Science. - : Wiley. - 2198-3844.
  • Tidskriftsartikel (refereegranskat)abstract
    • Loss of memory during Alzheimer's disease (AD), a fatal neurodegenerative disorder, is associated with neuronal loss and the aggregation of amyloid proteins into neurotoxic β‐sheet enriched structures. However, the mechanism of amyloid protein aggregation is still not well understood due to many challenges when studying the endogenous amyloid structures in neurons or in brain tissue. Available methods either require chemical processing of the sample or may affect the amyloid protein structure itself. Therefore, new approaches, which allow studying molecular structures directly in neurons, are urgently needed. A novel approach is tested, based on label‐free optical photothermal infrared super‐resolution microspectroscopy, to study AD‐related amyloid protein aggregation directly in the neuron at sub‐micrometer resolution. Using this approach, amyloid protein aggregates are detected at the subcellular level, along the neurites and strikingly, in dendritic spines, which has not been possible until now. Here, a polymorphic nature of amyloid structures that exist in AD transgenic neurons is reported. Based on the findings of this work, it is suggested that structural polymorphism of amyloid proteins that occur already in neurons may trigger different mechanisms of AD progression.
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28.
  • Knafo, Shira, et al. (författare)
  • Pathology of Synapses and Dendritic Spines
  • 2012
  • Ingår i: Journal of Neural Transplantation & Plasticity. - : Hindawi Limited. - 0792-8483.
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
  •  
29.
  • Kobro-Flatmoen, Asgeir, et al. (författare)
  • Intracellular Amyloid-β in the Normal Rat Brain and Human Subjects and Its relevance for Alzheimer's Disease
  • 2023
  • Ingår i: Journal of Alzheimer's disease : JAD. - 1387-2877. ; 95:2, s. 719-733
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Amyloid-β (Aβ) is a normal product of neuronal activity, including that of the aggregation-prone Aβ42 variant that is thought to cause Alzheimer's disease (AD). Much knowledge about AD comes from studies of transgenic rodents expressing mutated human amyloid-β protein precursor (AβPP) to increase Aβ production or the Aβ42/40 ratio. Yet, little is known about the normal expression of Aβ42 in rodent brains.OBJECTIVE: To characterize the brain-wide expression of Aβ42 throughout the life span of outbred Wistar rats, and to relate these findings to brains of human subjects without neurological disease.METHODS: Aβ42 immunolabeling of 12 Wistar rat brains (3-18 months of age) and brain sections from six human subjects aged 20-88 years.RESULTS: In healthy Wistar rats, we find intracellular Aβ42 (iAβ42) in neurons throughout the brain at all ages, but levels vary greatly between brain regions. The highest levels are in neurons of entorhinal cortex layer II, alongside hippocampal neurons at the CA1/subiculum border. Concerning entorhinal cortex layer II, we find similarly high levels of iAβ42 in the human subjects.CONCLUSION: Expression of iAβ42 in healthy Wistar rats predominates in the same structures where iAβ accumulates and Aβ plaques initially form in the much used, Wistar based McGill-R-Thy1-APP rat model for AD. The difference between wild-type Wistar rats and these AD model rats, with respect to Aβ42, is therefore quantitative rather that qualitative. This, taken together with our human results, indicate that the McGill rat model in fact models the underlying wild-type neuronal population-specific vulnerability to Aβ42 accumulation.
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30.
  • Kobro-Flatmoen, Asgeir, et al. (författare)
  • Lowering levels of reelin in entorhinal cortex layer II-neurons results in lowered levels of intracellular amyloid-β
  • 2023
  • Ingår i: Brain Communications. - 2632-1297. ; 5:2, s. 1-15
  • Tidskriftsartikel (refereegranskat)abstract
    • Projection neurons in the anteriolateral part of entorhinal cortex layer II are the predominant cortical site for hyper-phosphorylation of tau and formation of neurofibrillary tangles in prodromal Alzheimer's disease. A majority of layer II projection neurons in anteriolateral entorhinal cortex are unique among cortical excitatory neurons by expressing the protein reelin. In prodromal Alzheimer's disease, these reelin-expressing neurons are prone to accumulate intracellular amyloid-β, which is mimicked in a rat model that replicates the spatio-temporal cascade of the disease. Two important findings in relation to this are that reelin-signalling downregulates tau phosphorylation, and that oligomeric amyloid-β interferes with reelin-signalling. Taking advantage of this rat model, we used proximity ligation assay to assess whether reelin and intracellular amyloid-β directly interact during early, pre-plaque stages in anteriolateral entorhinal cortex layer II reelin-expressing neurons. We next made a viral vector delivering micro-RNA against reelin, along with a control vector, and infected reelin-expressing anteriolateral entorhinal cortex layer II-neurons to test whether reelin levels affect levels of intracellular amyloid-β and/or amyloid precursor protein. We analysed 25.548 neurons from 24 animals, which results in three important findings. First, in reelin-expressing anteriolateral entorhinal cortex layer II-neurons, reelin and intracellular amyloid-β engage in a direct protein-protein interaction. Second, injecting micro-RNA against reelin lowers reelin levels in these neurons, amounting to an effect size of 1.3-4.5 (Bayesian estimation of Cohen's d effect size, 95% credible interval). This causes a concomitant reduction of intracellular amyloid-β ranging across three levels of aggregation, including a reduction of Aβ42 monomers/dimers amounting to an effect size of 0.5-3.1, a reduction of Aβ prefibrils amounting to an effect size of 1.1-3.5 and a reduction of protofibrils amounting to an effect size of 0.05-2.1. Analysing these data using Bayesian estimation of mutual information furthermore reveals that levels of amyloid-β are dependent on levels of reelin. Third, the reduction of intracellular amyloid-β occurs without any substantial associated changes in levels of amyloid precursor protein. We conclude that reelin and amyloid-β directly interact at the intracellular level in the uniquely reelin-expressing projection neurons in anteriolateral entorhinal cortex layer II, where levels of amyloid-β are dependent on levels of reelin. Since amyloid-β is known to impair reelin-signalling causing upregulated phosphorylation of tau, our findings are likely relevant to the vulnerability for neurofibrillary tangle-formation of this entorhinal neuronal population.
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31.
  • Konings, Sabine C, et al. (författare)
  • Apolipoprotein E intersects with amyloid-β within neurons
  • 2023
  • Ingår i: Life Science Alliance. - 2575-1077. ; 6:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Apolipoprotein E4 (ApoE4) is the most important genetic risk factor for Alzheimer's disease (AD). Among the earliest changes in AD is endosomal enlargement in neurons, which was reported as enhanced in ApoE4 carriers. ApoE is thought to be internalized into endosomes of neurons, whereas β-amyloid (Aβ) accumulates within neuronal endosomes early in AD. However, it remains unknown whether ApoE and Aβ intersect intracellularly. We show that internalized astrocytic ApoE localizes mostly to lysosomes in neuroblastoma cells and astrocytes, whereas in neurons, it preferentially localizes to endosomes-autophagosomes of neurites. In AD transgenic neurons, astrocyte-derived ApoE intersects intracellularly with amyloid precursor protein/Aβ. Moreover, ApoE4 increases the levels of endogenous and internalized Aβ 42 in neurons. Taken together, we demonstrate differential localization of ApoE in neurons, astrocytes, and neuron-like cells, and show that internalized ApoE intersects with amyloid precursor protein/Aβ in neurons, which may be of considerable relevance to AD.
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32.
  • Konings, Sabine C., et al. (författare)
  • Astrocytic and Neuronal Apolipoprotein E Isoforms Differentially Affect Neuronal Excitability
  • 2021
  • Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 15, s. 1-16
  • Tidskriftsartikel (refereegranskat)abstract
    • Synaptic changes and neuronal network dysfunction are among the earliest changes in Alzheimer’s disease (AD). Apolipoprotein E4 (ApoE4), the major genetic risk factor in AD, has been shown to be present at synapses and to induce hyperexcitability in mouse knock-in brain regions vulnerable to AD. ApoE in the brain is mainly generated by astrocytes, however, neurons can also produce ApoE under stress conditions such as aging. The potential synaptic function(s) of ApoE and whether the cellular source of ApoE might affect neuronal excitability remain poorly understood. Therefore, the aim of this study was to elucidate the synaptic localization and effects on neuronal activity of the two main human ApoE isoforms from different cellular sources in control and AD-like in vitro cultured neuron models. In this study ApoE is seen to localize at or near to synaptic terminals. Additionally, we detected a cellular source-specific effect of ApoE isoforms on neuronal activity measured by live cell Ca2+ imaging. Neuronal activity increases after acute but not long-term administration of ApoE4 astrocyte medium. In contrast, ApoE expressed by neurons appears to induce the highest neuronal firing rate in the presence of ApoE3, rather than ApoE4. Moreover, increased neuronal activity in APP/PS1 AD transgenic compared to wild-type neurons is seen in the absence of astrocytic ApoE and the presence of astrocytic ApoE4, but not ApoE3. In summary, ApoE can target synapses and differentially induce changes in neuronal activity depending on whether ApoE is produced by astrocytes or neurons. Astrocytic ApoE induces the strongest neuronal firing with ApoE4, while the most active and efficient neuronal activity induced by neuronal ApoE is caused by ApoE3. ApoE isoforms also differentially affect neuronal activity in AD transgenic compared to wild-type neurons.
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33.
  • Konings, Sabine C., et al. (författare)
  • Neurobiological role of Alzheimer's disease genetic risk factor ApoE on early synaptic changes in Alzheimer-like models
  • 2021
  • Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - 1552-5279. ; 17:S3, s. 1-1
  • Konferensbidrag (refereegranskat)abstract
    • BACKGROUND: The presence of an apolipoprotein E4 (ApoE4) genotype is the major genetic risk factor for Alzheimer's disease (AD). Astrocytes are the main source of ApoE in the brain, however ApoE can also be produced by neurons and microglia. ApoE plays a role in many cell types and processes related to AD, however, it remains unclear which mechanism(s) and cellular source of ApoE are most critical for AD. One of the earliest changes in AD are early cellular changes such as endosomal and synaptic alterations. ApoE4 has been associated with impaired endosomal trafficking and dysregulated synaptic plasticity. Neuronal hyperexcitability has been reported in mice expressing human ApoE4, a dysregulation that is also seen in AD transgenic mice. Although ApoE seems to play a crucial role in neuronal changes linked to early AD, ApoE's synaptic localization and mechanisms remain poorly understood. In this study, the aim is to determine the role of ApoE, in particular ApoE4, on synaptic alterations in AD models. METHOD: Mouse neurons and astrocytes are derived from wild-type, ApoE knock-out (KO), humanized ApoE3 and ApoE4 knock-in mice. Astrocyte-conditioned medium from mouse astrocytes expressing human ApoE and recombinant ApoE are used as a source for human ApoE to treat ApoE KO, wild-type and AD transgenic APP/PS1 neurons. Additionally, ApoE KO and humanized ApoE neurons are treated with synthetic Aβ or vehicle control. Analysis is performed using immunofluorescence, confocal and live cell imaging. RESULT: Exogenously added and endogenously produced human ApoE is shown to be present at neurites and synaptic terminals of cultured neurons. Differences in neuronal activity are observed among different ApoE conditions using Ca2+ live cell microscopy, both in the presence and absence of elevated human Aβ. Added recombinant and endogenous ApoE appear to be present in the endosome-lysosome system of neurons. CONCLUSION: ApoE appears to localize at synapses and endosomes, sites associated with early cellular changes in AD, and seems to play a role in neuronal excitability. Determining the neurobiology of ApoE, in particular in connection with cellular sites vulnerable to early changes in AD, can contribute to a better understanding of the role of ApoE in AD.
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34.
  • Liu, Di, et al. (författare)
  • Differential seeding and propagating efficiency of α-synuclein strains generated in different conditions
  • 2021
  • Ingår i: Translational Neurodegeneration. - : Springer Science and Business Media LLC. - 2047-9158. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Accumulation of alpha-synuclein (α-syn) is a main pathological hallmark of Parkinson’s and related diseases, which are collectively known as synucleinopathies. Growing evidence has supported that the same protein can induce remarkably distinct pathological progresses and disease phenotypes, suggesting the existence of strain difference among α-syn fibrils. Previous studies have shown that α-syn pathology can propagate from the peripheral nervous system (PNS) to the central nervous system (CNS) in a “prion-like” manner. However, the difference of the propagation potency from the periphery to CNS among different α-syn strains remains unknown and the effect of different generation processes of these strains on the potency of seeding and propagation remains to be revealed in more detail. Methods: Three strains of preformed α-syn fibrils (PFFs) were generated in different buffer conditions which varied in pH and ionic concentrations. The α-syn PFFs were intramuscularly (IM) injected into a novel bacterial artificial chromosome (BAC) transgenic mouse line that expresses wild-type human α-syn, and the efficiency of seeding and propagation of these PFFs from the PNS to the CNS was evaluated. Results: The three strains of α-syn PFFs triggered distinct propagation patterns. The fibrils generated in mildly acidic buffer led to the most severe α-syn pathology, degeneration of motor neurons and microgliosis in the spinal cord. Conclusions: The different α-syn conformers generated in different conditions exhibited strain-specific pathology and propagation patterns from the periphery to the CNS, which further supports the view that α-syn strains may be responsible for the heterogeneity of pathological features and disease progresses among synucleinopathies.
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35.
  • Lundgren, Jolanta L, et al. (författare)
  • Activity-independent release of the amyloid β-peptide from rat brain nerve terminals.
  • 2014
  • Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 566:Mar 3, s. 125-130
  • Tidskriftsartikel (refereegranskat)abstract
    • Synaptic degeneration is one of the earliest hallmarks of Alzheimer disease. The molecular mechanism underlying this degeneration is not fully elucidated but one key player appears to be the synaptotoxic amyloid β-peptide (Aβ). The exact localization of the production of Aβ and the mechanisms whereby Aβ is released remain elusive. We have earlier shown that Aβ can be produced in crude synaptic vesicle fractions and it has been reported that increased synaptic activity results in increased secreted but decreased intracellular Aβ levels. Therefore, we considered whether Aβ could be produced in synaptic vesicles and/or released through the same mechanisms as neurotransmitters in synaptic vesicle exocytosis. Small amounts of Aβ were found to be produced in pure synaptic vesicle preparations. We also studied the release of glutamate and Aβ from rat cortical nerve terminals (synaptosomes). We found that large amounts of Aβ were secreted from non-stimulated synaptosomes, from which glutamate was not released. On the contrary, we could not detect any differences in Aβ release between non-stimulated synaptosomes and synaptosomes stimulated with KCl or 4-aminopyridine, whereas glutamate release was readily inducible in this system. To conclude, our results indicate that the major release mechanism of Aβ from isolated nerve terminals differs from the synaptic release of glutamate and that the activity-dependent increase of secreted Aβ, reported by several groups using intact cells, is likely dependent on post-synaptic events, trafficking and/or protein synthesis mechanisms.
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36.
  • Lundgren, Jolanta L, et al. (författare)
  • ADAM10 and BACE1 are localized to synaptic vesicles.
  • 2015
  • Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 135:3, s. 606-615
  • Tidskriftsartikel (refereegranskat)abstract
    • Synaptic degeneration and accumulation of the neurotoxic amyloid β-peptide (Aβ) in the brain are hallmarks of Alzheimer disease. Aβ is produced by sequential cleavage of its precursor protein, APP, by the β-secretase BACE1 and γ-secretase. However, Aβ generation is precluded if APP is cleaved by the α-secretase ADAM10 instead of BACE1. We have previously shown that Aβ can be produced locally at the synapse. To study the synaptic localization of the APP processing enzymes we used western blotting to demonstrate that, compared to total brain homogenate, ADAM10 and BACE1 were greatly enriched in synaptic vesicles isolated from rat brain using controlled-pore glass chromatography, whereas Presenilin1 was the only enriched component of the γ-secretase complex. Moreover, we detected ADAM10 activity in synaptic vesicles and enrichment of the intermediate APP-C-terminal fractions (APP-CTFs). We confirmed the western blotting findings using in situ proximity ligation assay to demonstrate close proximity of ADAM10 and BACE1 with the synaptic vesicle marker synaptophysin in intact mouse primary hippocampal neurons. In contrast, only sparse co-localization of active γ-secretase and synaptophysin was detected. These results indicate that the first step of APP processing occurs in synaptic vesicles whereas the final step is more likely to take place elsewhere. This article is protected by copyright. All rights reserved.
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37.
  • Martinsson, Isak, et al. (författare)
  • APP depletion alters selective pre- and post-synaptic proteins
  • 2019
  • Ingår i: Molecular and Cellular Neuroscience. - : Elsevier BV. - 1044-7431 .- 1095-9327. ; 95, s. 86-95
  • Tidskriftsartikel (refereegranskat)abstract
    • The normal role of Alzheimer's disease (AD)-linked amyloid precursor protein (APP) in the brain remains incompletely understood. Previous studies have reported that lack of APP has detrimental effects on spines and electrophysiological parameters. APP has been described to be important in synaptic pruning during development. The effect of APP knockout on mature synapses is complicated by this role in development. We previously reported on differential changes in synaptic proteins and receptors in APP mutant AD transgenic compared to wild-type neurons, which revealed selective decreases in levels of pre- and post-synaptic proteins, including of surface glutamate receptors. In the present study, we undertook a similar analysis of synaptic composition but now in APP knockout compared to wild-type mouse neurons. Here we demonstrate alterations in levels of selective pre- and post-synaptic proteins and receptors in APP knockout compared to wild-type mouse primary neurons in culture and brains of mice in youth and adulthood. Remarkably, we demonstrate selective increases in levels of synaptic proteins, such as GluA1, in neurons with APP knockout and with RNAi knockdown, which tended to be opposite to the reductions seen in AD transgenic APP mutant compared to wild-type neurons. These data reinforce that APP is important for the normal composition of synapses.
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38.
  • Martinsson, Isak, et al. (författare)
  • Aβ/Amyloid Precursor Protein-Induced Hyperexcitability and Dysregulation of Homeostatic Synaptic Plasticity in Neuron Models of Alzheimer’s Disease
  • 2022
  • Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 14, s. 1-16
  • Tidskriftsartikel (refereegranskat)abstract
    • Alzheimer’s disease (AD) is increasingly seen as a disease of synapses and diverse evidence has implicated the amyloid-β peptide (Aβ) in synapse damage. The molecular and cellular mechanism(s) by which Aβ and/or its precursor protein, the amyloid precursor protein (APP) can affect synapses remains unclear. Interestingly, early hyperexcitability has been described in human AD and mouse models of AD, which precedes later hypoactivity. Here we show that neurons in culture with either elevated levels of Aβ or with human APP mutated to prevent Aβ generation can both induce hyperactivity as detected by elevated calcium transient frequency and amplitude. Since homeostatic synaptic plasticity (HSP) mechanisms normally maintain a setpoint of activity, we examined whether HSP was altered in AD transgenic neurons. Using methods known to induce HSP, we demonstrate that APP protein levels are regulated by chronic modulation of activity and that AD transgenic neurons have an impaired adaptation of calcium transients to global changes in activity. Further, AD transgenic compared to WT neurons failed to adjust the length of their axon initial segments (AIS), an adaptation known to alter excitability. Thus, we show that both APP and Aβ influence neuronal activity and that mechanisms of HSP are disrupted in primary neuron models of AD.
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39.
  • Nikitidou, Elisabeth, 1987- (författare)
  • Cellular responses to amyloid-beta protofibrils : Focus on astrocytes, extracellular vesicles and antibody treatment
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Knowledge about the cellular mechanisms behind the initiation and propagation of Alzheimer’s disease (AD) is limited. Decades of research have focused on neuronal abnormalities in AD, but recently more attention has been given to the glial cells. Being the most numerous glial cell type in the brain, astrocytes are important for many functions, but their role in AD is poorly understood. The aim with this thesis was to clarify the involvement of astrocytes in AD by using a co-culture system of primary neurons and glia. The co-cultures were exposed to soluble amyloid-beta (Aβ) aggregates, i.e. protofibrils that are known to be particularly harmful.In Paper I, the capacity of astrocytes to ingest and degrade Aβ protofibrils was investigated. We found that astrocytes effectively ingested Aβ, but were ineffective in degrading the material. The intracellular accumulation of Aβ in astrocytes resulted in lysosomal dysfunction, high intracellular load of partly N-terminally truncated Aβ and extracellular vesicle (EV) mediated neuronal cell death.Cells can communicate by releasing cargo into EVs, but the role of EVs in the spreading of Aβ pathology is unclear. In Paper II, the protein content of EVs released specifically following Aβ protofibril exposure was analyzed. We found markedly increased levels of apolipoprotein E (apoE) in EVs from Aβ protofibril exposed co-cultures, suggesting a role for intercellular transfer of apoE in Aβ pathology.Passive immunotherapy has been suggested as a promising therapeutic strategy for AD. In Paper III, we investigated if the Aβ protofibril-selective antibody mAb158 could affect Aβ clearance in the co-culture. The mAb158 treatment reduced Aβ accumulation in astrocytes and rescued neurons from Aβ-induced cell death.In Paper IV, we explored the effect of EVs, isolated from Aβ protofibril exposed co-cultures on cultured neurons. In addition to increased cell death, we found that such EVs had a strong negative impact on the synapses, dendrites and mitochondria of the neurons.Taken together, this thesis contributes with important knowledge about the role of astrocytes in Aβ pathology, the vesicle-mediated spreading of Aβ and the effects of anti-Aβ antibody treatment.
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40.
  • O. Freitas, Raul, et al. (författare)
  • Nano-Infrared Imaging of Primary Neurons
  • 2021
  • Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:10, s. 1-15
  • Tidskriftsartikel (refereegranskat)abstract
    • Alzheimer’s disease (AD) accounts for about 70% of neurodegenerative diseases and is a cause of cognitive decline and death for one-third of seniors. AD is currently underdiagnosed, and it cannot be effectively prevented. Aggregation of amyloid-β (Aβ) proteins has been linked to the development of AD, and it has been established that, under pathological conditions, Aβ proteins undergo structural changes to form β-sheet structures that are considered neurotoxic. Numerous intensive in vitro studies have provided detailed information about amyloid polymorphs; however, little is known on how amyloid β-sheet-enriched aggregates can cause neurotoxicity in relevant settings. We used scattering-type scanning near-field optical microscopy (s-SNOM) to study amyloid structures at the nanoscale, in individual neurons. Specifically, we show that in well-validated systems, s-SNOM can detect amyloid β-sheet structures with nanometer spatial resolution in individual neurons. This is a proof-of-concept study to demonstrate that s-SNOM can be used to detect Aβ-sheet structures on cell surfaces at the nanoscale. Furthermore, this study is intended to raise neurobiologists’ awareness of the potential of s-SNOM as a tool for analyzing amyloid β-sheet structures at the nanoscale in neurons without the need for immunolabeling
  •  
41.
  • Olsson, Tomas T., et al. (författare)
  • Prion-like seeding and nucleation of intracellular amyloid-β
  • 2018
  • Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 113, s. 1-10
  • Tidskriftsartikel (refereegranskat)abstract
    • Alzheimer's disease (AD) brain tissue can act as a seed to accelerate aggregation of amyloid-β (Aβ) into plaques in AD transgenic mice. Aβ seeds have been hypothesized to accelerate plaque formation in a prion-like manner of templated seeding and intercellular propagation. However, the structure(s) and location(s) of the Aβ seeds remain unknown. Moreover, in contrast to tau and α-synuclein, an in vitro system with prion-like Aβ has not been reported. Here we treat human APP expressing N2a cells with AD transgenic mouse brain extracts to induce inclusions of Aβ in a subset of cells. We isolate cells with induced Aβ inclusions and using immunocytochemistry, western blot and infrared spectroscopy show that these cells produce oligomeric Aβ over multiple replicative generations. Further, we demonstrate that cell lysates of clones with induced oligomeric Aβ can induce aggregation in previously untreated N2a APP cells. These data strengthen the case that Aβ acts as a prion-like protein, demonstrate that Aβ seeds can be intracellular oligomers and for the first time provide a cellular model of nucleated seeding of Aβ.
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42.
  • Pagnon de la Vega, María, 1994- (författare)
  • Characterization of the novel “Uppsala mutation” causing a familial form of early onset Alzheimer’s disease
  • 2021
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The Alzheimer’s disease (AD) brain displays extracellular plaques of amyloid-β (Aβ), neurofibrillary tangles of tau and neuronal loss. The 40-42 amino acid Aβ peptide is formed from the amyloid precursor protein (APP) by β-secretase and γ-secretase, while α-secretase prevents Aβ generation. According to the amyloid cascade hypothesis, AD is initiated by increased brain levels of toxic Aβ species. Our laboratory has previously identified two APP mutations, causing early onset AD. Whereas the Swedish mutation results in increased β-secretase cleavage leading to higher Aβ levels, the Arctic mutation leads to a conformational Aβ change that promotes formation of toxic Aβ protofibrils.In this thesis, we have performed a screen for novel disease-causing mutations in 102 patients with early onset dementia disorders, who underwent investigation at the Memory clinic at Uppsala University Hospital. Mainly, we found a new APP mutation, which causes familial dominantly inherited AD with age at symptom onset in the early forties. This Uppsala APP mutation, consists of an intra-Aβ deletion of six consecutive amino acids, which results in Aβ with 34-36 amino acids (AβUppΔ19-24).Affected mutation-carriers develop symptoms typical of AD. As for biomarkers, the patients display expected changes although brain Aβ imaging by [11C]PIB-PET is only slightly pathological and Aβ42-analysis of cerebrospinal fluid yields normal results. By investigating neuropathological, biochemical and structural properties of AβUppΔ19-24 in patient samples, on synthetic peptides and in cell culture models we found evidence that Uppsala APP is pathogenic via three mechanisms: increased β-secretase cleavage, altered α-secretase cleavage and rapid formation of Aβ fibrils into unique polymorphs.To allow for in vivo studies of molecular mechanisms related to the Uppsala APP mutation we generated transgenic mice, expressing human APP with this mutation together with Swedish APP (to increase Aβ levels). In the brain of tg-UppSwe mice, we observed diffuse aggregates of mainly AβUpp42Δ19-24, which, given their normal γ-secretase activity, distinguishes these mice from most transgenic mouse models. In order to study if AβUppΔ19-24 co-aggregates with wild-type Aβ (Aβwt), we crossed tg-UppSwe with tg-Swe. Analyses of brains from such mice indicated that AβUppΔ19-24 may act as seeds for Aβwt by changing its aggregation behavior and thereby increasing its deposition in brain.Taken together, our studies of the Uppsala APP mutation have provided new knowledge of pathogenic molecular mechanisms in AD and of basic Aβ biology. Such insights may in a longer perspective help us to develop new diagnostics and therapeutics for this disorder. 
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43.
  • Paulus, Agnes, et al. (författare)
  • Amyloid Structural Changes Studied by Infrared Microspectroscopy in Bigenic Cellular Models of Alzheimer’s Disease
  • 2021
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 22:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Alzheimer’s disease affects millions of lives worldwide. This terminal disease is characterized by the formation of amyloid aggregates, so-called amyloid oligomers. These oligomers are composed of β-sheet structures, which are believed to be neurotoxic. However, the actual secondary structure that contributes most to neurotoxicity remains unknown. This lack of knowledge is due to the challenging nature of characterizing the secondary structure of amyloids in cells. To overcome this and investigate the molecular changes in proteins directly in cells, we used synchrotron-based infrared microspectroscopy, a label-free and non-destructive technique available for in situ molecular imaging, to detect structural changes in proteins and lipids. Specifically, we evaluated the formation of β-sheet structures in different monogenic and bigenic cellular models of Alzheimer’s disease that we generated for this study. We report on the possibility to discern different amyloid signatures directly in cells using infrared microspectroscopy and demonstrate that bigenic (amyloid-β, α-synuclein) and (amyloid-β, Tau) neuron-like cells display changes in β-sheet load. Altogether, our findings support the notion that different molecular mechanisms of amyloid aggregation, as opposed to a common mechanism, are triggered by the specific cellular environment and, therefore, that various mechanisms lead to the development of Alzheimer’s disease.
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44.
  • Paulus, Agnes, et al. (författare)
  • Correlative imaging to resolve molecular structures in individual cells: Substrate validation study for super-resolution infrared microspectroscopy
  • 2022
  • Ingår i: Nanomedicine: Nanotechnology, Biology and Medicine. - : Elsevier BV. - 1549-9642 .- 1549-9634. ; 43, s. 102563-102563
  • Tidskriftsartikel (refereegranskat)abstract
    • Light microscopy has been a favorite tool of biological studies for almost a century, recently producing detailed images with exquisite molecular specificity achieving spatial resolution at nanoscale. However, light microscopy is insufficient to provide chemical information as a standalone technique. An increasing amount of evidence demonstrates that optical photothermal infrared microspectroscopy (O-PTIR) is a valuable imaging tool that can extract chemical information to locate molecular structures at submicron resolution. To further investigate the applicability of sub-micron infrared microspectroscopy for biomedical applications, we analyzed the contribution of substrate chemistry to the infrared spectra acquired from individual neurons grown on various imaging substrates. To provide an example of correlative immunofluorescence/O-PTIR imaging, we used immunofluorescence to locate specific organelles for O-PTIR measurement, thus capturing molecular structures at the sub-cellular level directly in cells, which is not possible using traditional infrared microspectroscopy or immunofluorescence microscopy alone.
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45.
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46.
  • Pomeshchik, Yuriy, et al. (författare)
  • Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction and progression of Alzheimer's disease pathogenesis
  • 2023
  • Ingår i: Acta Neuropathologica Communications. - 2051-5960. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • The hippocampus is a primary region affected in Alzheimer's disease (AD). Because AD postmortem brain tissue is not available prior to symptomatic stage, we lack understanding of early cellular pathogenic mechanisms. To address this issue, we examined the cellular origin and progression of AD pathogenesis by comparing patient-based model systems including iPSC-derived brain cells transplanted into the mouse brain hippocampus. Proteomic analysis of the graft enabled the identification of pathways and network dysfunction in AD patient brain cells, associated with increased levels of Aβ-42 and β-sheet structures. Interestingly, the host cells surrounding the AD graft also presented alterations in cellular biological pathways. Furthermore, proteomic analysis across human iPSC-based models and human post-mortem hippocampal tissue projected coherent longitudinal cellular changes indicative of early to end stage AD cellular pathogenesis. Our data showcase patient-based models to study the cell autonomous origin and progression of AD pathogenesis.
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47.
  • Prater, Craig, et al. (författare)
  • Fluorescently Guided Optical Photothermal Infrared Microspectroscopy for Protein-Specific Bioimaging at Subcellular Level
  • 2023
  • Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 66:4, s. 2542-2549
  • Tidskriftsartikel (refereegranskat)abstract
    • Infrared spectroscopic imaging is widely used for the visualization of biomolecule structures, and techniques such as optical photothermal infrared (OPTIR) microspectroscopy can achieve <500 nm spatial resolution. However, these approaches lack specificity for particular cell types and cell components and thus cannot be used as a stand-alone technique to assess their properties. Here, we have developed a novel tool, fluorescently guided optical photothermal infrared microspectroscopy, that simultaneously exploits epifluorescence imaging and OPTIR to perform fluorescently guided IR spectroscopic analysis. This novel approach exceeds the diffraction limit of infrared microscopy and allows structural analysis of specific proteins directly in tissue and single cells. Experiments described herein used epifluorescence to rapidly locate amyloid proteins in tissues or neuronal cultures, thus guiding OPTIR measurements to assess amyloid structures at the subcellular level. We believe that this new approach will be a valuable addition to infrared spectroscopy providing cellular specificity of measurements in complex systems for studies of structurally altered protein aggregates.
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48.
  • Ramakrishna, Sarayu, et al. (författare)
  • APOE4 affects basal and NMDAR mediated protein synthesis in neurons by perturbing calcium homeostasis
  • 2021
  • Ingår i: The Journal of Neuroscience. - 1529-2401. ; 41:42, s. 8686-8709
  • Tidskriftsartikel (refereegranskat)abstract
    • Apolipoprotein E (APOE), one of the primary lipoproteins in the brain has three isoforms in humans - APOE2, APOE3, and APOE4. APOE4 is the most well-established risk factor increasing the pre-disposition for Alzheimer's disease. The presence of the APOE4 allele alone is shown to cause synaptic defects in neurons and recent studies have identified multiple pathways directly influenced by APOE4. However, the mechanisms underlying APOE4 induced synaptic dysfunction remain elusive. Here, we report that the acute exposure of primary cortical neurons or synaptoneurosomes to APOE4 leads to a significant decrease in global protein synthesis. Primary cortical neurons were derived from male and female embryos of Sprague-Dawley rats or C57BL/6J mice. Synaptoneurosomes were prepared from P30 male Sprague-Dawley rats. APOE4 treatment also abrogates the NMDA mediated translation response indicating an alteration of synaptic signaling. Importantly, we demonstrate that both APOE3 and APOE4 generate a distinct translation response which is closely linked to their respective calcium signature. Acute exposure of neurons to APOE3 causes a short burst of calcium through NMDARs leading to an initial decrease in protein synthesis which quickly recovers. Contrarily, APOE4 leads to a sustained increase in calcium levels by activating both NMDARs and L-VGCCs, thereby causing sustained translation inhibition through eEF2 phosphorylation, which in turn disrupts the NMDAR response. Thus, we show that APOE4 affects basal and activity mediated protein synthesis responses in neurons by affecting calcium homeostasis.SIGNIFICANCE STATEMENTDefective protein synthesis has been shown as an early defect in familial Alzheimer's disease. However, this has not been studied in the context of sporadic Alzheimer's disease, which constitutes the majority of cases. In our study, we show that APOE4, the predominant risk factor for Alzheimer's disease, inhibits global protein synthesis in neurons. APOE4 also affects NMDA activity mediated protein synthesis response, thus inhibiting synaptic translation. We also show that the defective protein synthesis mediated by APOE4 is closely linked to the perturbation of calcium homeostasis caused by APOE4 in neurons. Thus, we propose the dysregulation of protein synthesis as one of the possible molecular mechanisms to explain APOE4 mediated synaptic and cognitive defects. Hence, the study not only suggests an explanation for the APOE4 mediated pre-disposition to Alzheimer's disease, it also bridges the gap in understanding APOE4 mediated pathology.
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49.
  • Roos, Tomas T, et al. (författare)
  • Neuronal spreading and plaque induction of intracellular Aβ and its disruption of Aβ homeostasis
  • 2021
  • Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 142:4, s. 669-687
  • Tidskriftsartikel (refereegranskat)abstract
    • The amyloid-beta peptide (Aβ) is thought to have prion-like properties promoting its spread throughout the brain in Alzheimer's disease (AD). However, the cellular mechanism(s) of this spread remains unclear. Here, we show an important role of intracellular Aβ in its prion-like spread. We demonstrate that an intracellular source of Aβ can induce amyloid plaques in vivo via hippocampal injection. We show that hippocampal injection of mouse AD brain homogenate not only induces plaques, but also damages interneurons and affects intracellular Aβ levels in synaptically connected brain areas, paralleling cellular changes seen in AD. Furthermore, in a primary neuron AD model, exposure of picomolar amounts of brain-derived Aβ leads to an apparent redistribution of Aβ from soma to processes and dystrophic neurites. We also observe that such neuritic dystrophies associate with plaque formation in AD-transgenic mice. Finally, using cellular models, we propose a mechanism for how intracellular accumulation of Aβ disturbs homeostatic control of Aβ levels and can contribute to the up to 10,000-fold increase of Aβ in the AD brain. Our data indicate an essential role for intracellular prion-like Aβ and its synaptic spread in the pathogenesis of AD.
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50.
  • Sahlin, Charlotte, et al. (författare)
  • The Arctic Alzheimer mutation favors intracellular amyloid-beta production by making amyloid precursor protein less available to alpha-secretase
  • 2007
  • Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 101:3, s. 854-862
  • Tidskriftsartikel (refereegranskat)abstract
    • Mutations within the amyloid-β (Aβ) domain of the amyloid precursor protein (APP) typically generate hemorrhagic strokes and vascular amyloid angiopathy. In contrast, the Arctic mutation (APP E693G) results in Alzheimer's disease. Little is known about the pathologic mechanisms that result from the Arctic mutation, although increased formation of Aβ protofibrils in vitro and intraneuronal Aβ aggregates in vivo suggest that early steps in the amyloidogenic pathway are facilitated. Here we show that the Arctic mutation favors proamyloidogenic APP processing by increased β-secretase cleavage, as demonstrated by altered levels of N- and C-terminal APP fragments. Although the Arctic mutation is located close to the α-secretase site, APP harboring the Arctic mutation is not an inferior substrate to a disintegrin and metalloprotease-10, a major α-secretase. Instead, the localization of Arctic APP is altered, with reduced levels at the cell surface making Arctic APP less available for α-secretase cleavage. As a result, the extent and subcellular location of Aβ formation is changed, as revealed by increased Aβ levels, especially at intracellular locations. Our findings suggest that the unique clinical symptomatology and neuropathology associated with the Arctic mutation, but not with other intra-Aβ mutations, could relate to altered APP processing with increased steady-state levels of Arctic Aβ, particularly at intracellular locations.
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