| 1. |
- Benitez, D. P., et al.
(författare)
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Knock-in models related to Alzheimer's disease: synaptic transmission, plaques and the role of microglia
- 2021
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Microglia are active modulators of Alzheimer's disease but their role in relation to amyloid plaques and synaptic changes due to rising amyloid beta is unclear. We add novel findings concerning these relationships and investigate which of our previously reported results from transgenic mice can be validated in knock-in mice, in which overexpression and other artefacts of transgenic technology are avoided. Methods App(NL-F) and App(NL-G-F) knock-in mice expressing humanised amyloid beta with mutations in App that cause familial Alzheimer's disease were compared to wild type mice throughout life. In vitro approaches were used to understand microglial alterations at the genetic and protein levels and synaptic function and plasticity in CA1 hippocampal neurones, each in relationship to both age and stage of amyloid beta pathology. The contribution of microglia to neuronal function was further investigated by ablating microglia with CSF1R inhibitor PLX5622. Results Both App knock-in lines showed increased glutamate release probability prior to detection of plaques. Consistent with results in transgenic mice, this persisted throughout life in App(NL-F) mice but was not evident in App(NL-G-F) with sparse plaques. Unlike transgenic mice, loss of spontaneous excitatory activity only occurred at the latest stages, while no change could be detected in spontaneous inhibitory synaptic transmission or magnitude of long-term potentiation. Also, in contrast to transgenic mice, the microglial response in both App knock-in lines was delayed until a moderate plaque load developed. Surviving PLX5266-depleted microglia tended to be CD68-positive. Partial microglial ablation led to aged but not young wild type animals mimicking the increased glutamate release probability in App knock-ins and exacerbated the App knock-in phenotype. Complete ablation was less effective in altering synaptic function, while neither treatment altered plaque load. Conclusions Increased glutamate release probability is similar across knock-in and transgenic mouse models of Alzheimer's disease, likely reflecting acute physiological effects of soluble amyloid beta. Microglia respond later to increased amyloid beta levels by proliferating and upregulating Cd68 and Trem2. Partial depletion of microglia suggests that, in wild type mice, alteration of surviving phagocytic microglia, rather than microglial loss, drives age-dependent effects on glutamate release that become exacerbated in Alzheimer's disease.
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| 2. |
- Michno, Wojciech, 1992, et al.
(författare)
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Chemical traits of cerebral amyloid angiopathy in familial British-, Danish-, and non-Alzheimer 's dementias
- 2022
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 163:3, s. 233-246
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Tidskriftsartikel (refereegranskat)abstract
- Familial British dementia (FBD) and familial Danish dementia (FDD) are autosomal dominant forms of dementia caused by mutations in the integral membrane protein 2B (ITM2B, also known as BRI2) gene. Secretase processing of mutant BRI2 leads to secretion and deposition of BRI2-derived amyloidogenic peptides, ABri and ADan that resemble APP/beta-amyloid (A beta) pathology, which is characteristic of Alzheimer's disease (AD). Amyloid pathology in FBD/FDD manifests itself predominantly in the microvasculature by ABri/ADan containing cerebral amyloid angiopathy (CAA). While ABri and ADan peptide sequences differ only in a few C-terminal amino acids, CAA in FDD is characterized by co-aggregation of ADan with A beta, while in contrast no A beta deposition is observed in FBD. The fact that FDD patients display an earlier and more severe disease onset than FBD suggests a potential role of ADan and A beta co-aggregation that promotes a more rapid disease progression in FDD compared to FBD. It is therefore critical to delineate the chemical signatures of amyloid aggregation in these two vascular dementias. This in turn will increase the knowledge on the pathophysiology of these diseases and the pathogenic role of heterogenous amyloid peptide interactions and deposition, respectively. Herein, we used matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) in combination with hyperspectral, confocal microscopy based on luminescent conjugated oligothiophene probes (LCO) to delineate the structural traits and associated amyloid peptide patterns of single CAA in postmortem brain tissue of patients with FBD, FDD as well as sporadic CAA without AD (CAA+) that show pronounced CAA without parenchymal plaques. The results show that CAA in both FBD and FDD consist of N-terminally truncated- and pyroglutamate-modified amyloid peptide species (ADan and ABri), but that ADan peptides in FDD are also extensively C-terminally truncated as compared to ABri in FBD, which contributes to hydrophobicity of ADan species. Further, CAA in FDD showed co-deposition with A beta x-42 and A beta x-40 species. CAA+ vessels were structurally more mature than FDD/FBD CAA and contained significant amounts of pyroglutamated A beta. When compared with FDD, A beta in CAA+ showed more C-terminal and less N-terminally truncations. In FDD, ADan showed spatial co-localization with A beta 3pE-40 and A beta 3-40 but not with A beta x-42 species. This suggests an increased aggregation propensity of A beta in FDD that promotes co-aggregation of both A beta and ADan. Further, CAA maturity appears to be mainly governed by A beta content based on the significantly higher 500/580 patterns observed in CAA+ than in FDD and FBD, respectively. Together this is the first study of its kind on comprehensive delineation of Bri2 and APP-derived amyloid peptides in single vascular plaques in both FDD/FBD and sporadic CAA that provides new insight in non-AD-related vascular amyloid pathology.
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| 3. |
- Vitanova, K. S., et al.
(författare)
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Dementia associated with disorders of the basal ganglia
- 2019
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547.
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Forskningsöversikt (refereegranskat)abstract
- Dementia is now the leading cause of death in the United Kingdom, accounting for over 12% of all deaths and is the fifth most common cause of death worldwide. As treatments for heart disease and cancers improve and the population ages, the number of sufferers will only increase, with the chance of developing dementia doubling every 5 years after the age of 65. Finding an effective treatment is ever more critical to avert this pandemic health (and economic) crisis. To date, most dementia-related research has focused on cortex and hippocampus; however, with dementia becoming more fully recognized as aspects of diseases historically categorized as motor disorders (e.g., Parkinson's and Huntington's diseases), the role of the basal ganglia in dementia is coming to the fore. Conversely, it is highly likely that neuronal pathways in these structures traditionally considered as spared in Alzheimer's disease are also affected, particularly in later stages of the disease. In this review, we examine some of the limited evidence linking the basal ganglia to dementia.
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| 4. |
- Wood, Jack, 1997, et al.
(författare)
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Plaque contact and unimpaired Trem2 is required for the microglial response to amyloid pathology
- 2022
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 41:8
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Tidskriftsartikel (refereegranskat)abstract
- Using spatial cell-type-enriched transcriptomics, we compare plaque-induced gene (PIG) expression in mi-croglia-touching plaques, neighboring plaques, and far from plaques in an aged Alzheimer's mouse model with late plaque development. In 18-month-old APPNL-F/NL-F knockin mice, with and without the Alzheimer's disease risk mutation Trem2R47H/R47H, we report that expression of 38/55 PIGs have plaque-induced micro-glial upregulation, with a subset only upregulating in microglia directly contacting plaques. For seven PIGs, including Trem2, this upregulation is prevented in APPNL-F/NL-FTrem2R47H/R47H mice. These TREM2-depen-dent genes are all involved in phagocytic and degradative processes that we show correspond to a decrease in phagocytic markers and an increase in the density of small plaques in Trem2-mutated mice. Furthermore, despite the R47H mutation preventing increased Trem2 gene expression, TREM2 protein levels and micro-glial density are still marginally increased on plaques. Hence, both microglial contact with plaques and func-tioning TREM2 are necessary for microglia to respond appropriately to amyloid pathology.
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