| 1. |
- Mahler, Jasmin, et al.
(författare)
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Endogenous murine A beta increases amyloid deposition in APP23 but not in APPPS1 transgenic mice
- 2015
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 36:7, s. 2241-2247
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Tidskriftsartikel (refereegranskat)abstract
- Endogenous murine amyloid-beta peptide (A beta) is expressed in most A beta precursor protein (APP) transgenic mouse models of Alzheimers disease but its contribution to beta-amyloidosis remains unclear. We demonstrate similar to 35% increased cerebral A beta load in APP23 transgenic mice compared with age-matched APP23 mice on an App-null background. No such difference was found for the much faster A beta-depositing APPPS1 transgenic mouse model between animals with or without the murine App gene. Nevertheless, both APP23 and APPPS1 mice codeposited murine A beta, and immunoelectron microscopy revealed a tight association of murine A beta with human A beta fibrils. Deposition of murine A beta was considerably less efficient compared with the deposition of human A beta indicating a lower amyloidogenic potential of murine A beta in vivo. The amyloid dyes Pittsburgh Compound-B and pentamer formyl thiophene acetic acid did not differentiate between amyloid deposits consisting of human A beta and deposits of mixed human-murine A beta. Our data demonstrate a differential effect of murine A beta on human A beta deposition in different APP transgenic mice. The mechanistically complex interaction of human and mouse A beta may affect pathogenesis of the models and should be considered when models are used for translational preclinical studies.
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| 2. |
- Mao, Haian, et al.
(författare)
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Quantitative organization of the excitatory synapses of the primate cerebellar nuclei : further evidence for a specialized architecture underlying the primate cerebellum
- 2019
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Ingår i: Brain Structure and Function. - : Springer Berlin/Heidelberg. - 1863-2653 .- 1863-2661. ; 224:6, s. 1987-1998
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Tidskriftsartikel (refereegranskat)abstract
- The cerebellar intrinsic connectivity is of remarkable regularity with a similar build repeated many times over. However, several modifications of this basic circuitry occur that can provide important clues to evolutionary adaptations. We have observed differences in the wiring of the cerebellar output structures (the deep cerebellar nuclei, DCN) with higher dendritic length density in the phylogenetically newer DCN. In rats, we showed that an increase in wiring is associated with an increase in the presynaptic vesicular glutamate transporter 1 (vGluT1). In this study, we have extended our analysis to the rhesus monkey and can show similarities and differences between the two species. The similarities confirm a higher density in vGluT1+ boutons in the lateral (LN/dentate) and posterior interpositus nucleus compared to the phylogenetically older DCN. In general, we also observe a lower density of vGluT1 and 2+boutons in the monkey, which however, yields a similar number of excitatory boutons per neuron in both species. The only exception is the vGlut1+boutons in the macaque LN/dentate, which showed a significantly lower number of vGluT1+boutons per neuron. We also detected a higher percentage of co-labelled vGluT1 and 2 boutons in the macaque than we found in the rat. In summary, these results confirm that the hyposcalled dendrites of the monkey LN/dentate also show a lower number of vGluT1+boutons per neuron. These results provide further support of our model relating the dendritic morphology of the LN/dentate neurons to the morphology of the specially enlarged LN/dentate nucleus in primates.
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| 3. |
- Novotny, Renata, et al.
(författare)
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Conversion of Synthetic A beta to In Vivo Active Seeds and Amyloid Plaque Formation in a Hippocampal Slice Culture Model
- 2016
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Ingår i: Journal of Neuroscience. - : SOC NEUROSCIENCE. - 0270-6474 .- 1529-2401. ; 36:18, s. 5084-5093
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Tidskriftsartikel (refereegranskat)abstract
- The aggregation of amyloid-beta peptide (A beta) inbrain is an early event and hallmark of Alzheimers disease (AD). We combined the advantages of in vitro and in vivo approaches to study cerebral beta-amyloidosis by establishing a long-term hippocampal slice culture(HSC) model. While no A beta deposition was noted in untreated HSCs of postnatal A beta precursor protein transgenic (APP tg) mice, A beta deposition emerged in HSCs when cultures were treated once with brain extract from aged APP tg mice and the culture medium was continuously supplemented with synthetic A beta. Seeded A beta deposition was also observed under the same conditions in HSCs derived from wild-type or App-null mice but in no comparable way when HSCs were fixed before cultivation. Both the nature of the brain extract and the synthetic A beta species determined the conformational characteristics of HSCA beta deposition. HSCA beta deposits induced a microglia response, spine loss, and neuritic dystrophy but no obvious neuron loss. Remarkably, in contrast to in vitro aggregated synthetic A beta, homogenates of A beta deposits containing HSCs induced cerebral beta-amyloidosis upon intracerebral inoculation into young APP tg mice. Our results demonstrate that a living cellular environment promotes the seeded conversion of synthetic A beta into a potent in vivo seeding-active form.
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| 4. |
- Tanrioever, Gaye, et al.
(författare)
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Prominent microglial inclusions in transgenic mouse models of alpha-synucleinopathy that are distinct from neuronal lesions
- 2020
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Ingår i: Acta neuropathologica communications. - : BMC. - 2051-5960. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Alpha-synucleinopathies are a group of progressive neurodegenerative disorders, characterized by intracellular deposits of aggregated alpha-synuclein (alpha S). The clinical heterogeneity of these diseases is thought to be attributed to conformers (or strains) of alpha S but the contribution of inclusions in various cell types is unclear. The aim of the present work was to study alpha S conformers among different transgenic (TG) mouse models of alpha-synucleinopathies. To this end, four different TG mouse models were studied (Prnp-h[A53T]alpha S; Thy1-h[A53T]alpha S; Thy1-h[A30P]alpha S; Thy1-m alpha S) that overexpress human or murine alpha S and differed in their age-of-symptom onset and subsequent disease progression. Postmortem analysis of end-stage brains revealed robust neuronal alpha S pathology as evidenced by accumulation of alpha S serine 129 (p-alpha S) phosphorylation in the brainstem of all four TG mouse lines. Overall appearance of the pathology was similar and only modest differences were observed among additionally affected brain regions. To study alpha S conformers in these mice, we used pentameric formyl thiophene acetic acid (pFTAA), a fluorescent dye with amyloid conformation-dependent spectral properties. Unexpectedly, besides the neuronal alpha S pathology, we also found abundant pFTAA-positive inclusions in microglia of all four TG mouse lines. These microglial inclusions were also positive for Thioflavin S and showed immunoreactivity with antibodies recognizing the N-terminus of alpha S, but were largely p-alpha S-negative. In all four lines, spectral pFTAA analysis revealed conformational differences between microglia and neuronal inclusions but not among the different mouse models. Concomitant with neuronal lesions, microglial inclusions were already present at presymptomatic stages and could also be induced by seeded alpha S aggregation. Although nature and significance of microglial inclusions for human alpha-synucleinopathies remain to be clarified, the previously overlooked abundance of microglial inclusions in TG mouse models of alpha-synucleinopathy bears importance for mechanistic and preclinical-translational studies.
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| 5. |
- Wagner, Jessica, et al.
(författare)
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Medin co-aggregates with vascular amyloid-beta in Alzheimers disease
- 2022
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Ingår i: Nature. - : Nature Portfolio. - 0028-0836 .- 1476-4687. ; 612, s. 123-131
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Tidskriftsartikel (refereegranskat)abstract
- Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age(1,)(2), making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction(3). Here we demonstrate in amyloid-beta precursor protein (APP) transgenic mice and in patients with Alzheimers disease that medin co-localizes with vascular amyloid-beta deposits, and that in mice, medin deficiency reduces vascular amyloid-beta deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-beta burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimers disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-beta to promote its aggregation, as medin forms heterologous fibrils with amyloid-beta, affects amyloid-beta fibril structure, and cross-seeds amyloid-beta aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-beta deposition in the blood vessels of the brain.
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| 6. |
- Wegenast-Braun, Bettina M., et al.
(författare)
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Spectral Discrimination of Cerebral Amyloid Lesions after Peripheral Application of Luminescent Conjugated Oligothiophenes
- 2012
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Ingår i: American Journal of Pathology. - : Elsevier. - 0002-9440 .- 1525-2191. ; 181:6, s. 1953-1960
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Tidskriftsartikel (refereegranskat)abstract
- In vivo imaging of pathological protein aggregates provides essential knowledge of the kinetics and implications of these lesions in the progression of proteopathies, such as Alzheimer disease. Luminescent conjugated oligothiophenes are amyloid-specific ligands that bind and spectrally distinguish different types of amyloid aggregates. Herein, we report that heptamer formyl thiophene acetic acid (hFTAA) passes the blood-brain barrier after systemic administration and specifically binds to extracellular beta-amyloid deposits in the brain parenchyma (A beta plaques) and in the vasculature (cerebral beta-amyloid angiopathy) of beta-amyloid precursor protein transgenic APP23 mice. Moreover, peripheral application of hFIAA also stained intracellular lesions of hyperphosphorylated Tau protein in P301S Tau transgenic mice. Spectral profiling of all three amyloid types was acquired ex vivo using two-photon excitation. hFTAA revealed a distinct shift in its emission spectra when bound to A beta plaques versus Tau lesions. Furthermore, a spectral shift was observed for A beta plaques versus cerebral beta-amyloid angiopathy, indicating that different amyloid types and structural variances of a specific amyloid type can be distinguished. In conclusion, by adding spectral signatures to amyloid lesions, our results pave the way for a new area of in vivo amyloid imaging, allowing in vivo differentiation of amyloid (sub)types and monitoring changes of their structure/composition over time. (Am J Pathol 2012, 181: 1953-1960 http://dx.doi.org/10.1016/j.ajpath.2012.08.031)
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