Collusion of [alpha]-Synuclein and A[beta] aggravating co-morbidities in a novel prion-type mouse model

Background The misfolding of host-encoded proteins into pathological prion conformations is a defining characteristic of many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Lewy body dementia. A current area of intense study is the way in which the pat...

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Published inMolecular neurodegeneration Vol. 16; no. 1
Main Authors Lloyd, Grace M, Dhillon, Jess-Karan S, Gorion, Kimberly-Marie M, Riffe, Cara, Fromholt, Susan E, Xia, Yuxing, Giasson, Benoit I, Borchelt, David R
Format Journal Article
LanguageEnglish
Published BioMed Central Ltd 09.09.2021
Subjects
Alzheimer's disease
Analysis
Brain
Genetic engineering
Medical research
Medicine, Experimental
Nervous system diseases
Prions
California
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Summary:Background The misfolding of host-encoded proteins into pathological prion conformations is a defining characteristic of many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Lewy body dementia. A current area of intense study is the way in which the pathological deposition of these proteins might influence each other, as various combinations of co-pathology between prion-capable proteins are associated with exacerbation of disease. A spectrum of pathological, genetic and biochemical evidence provides credence to the notion that amyloid [beta] (A[beta]) accumulation can induce and promote [alpha]-synuclein pathology, driving neurodegeneration. Methods To assess the interplay between [alpha]-synuclein and A[beta] on protein aggregation kinetics, we crossed mice expressing human [alpha]-synuclein (M20) with APPswe/PS1dE9 transgenic mice (L85) to generate M20/L85 mice. We then injected [alpha]-synuclein preformed fibrils (PFFs) unilaterally into the hippocampus of 6-month-old mice, harvesting 2 or 4 months later. Results Immunohistochemical analysis of M20/L85 mice revealed that pre-existing A[beta] plaques exacerbate the spread and deposition of induced [alpha]-synuclein pathology. This process was associated with increased neuroinflammation. Unexpectedly, the injection of [alpha]-synuclein PFFs in L85 mice enhanced the deposition of A[beta]; whereas the level of A[beta] deposition in M20/L85 bigenic mice, injected with [alpha]-synuclein PFFs, did not differ from that of mice injected with PBS. Conclusions These studies reveal novel and unexpected interplays between [alpha]-synuclein pathology, A[beta] and neuroinflammation in mice that recapitulate the pathology of Alzheimer's disease and Lewy body dementia. Keywords: Alzheimer's disease, A[beta], Lewy body dementia, [alpha]-Synuclein, Prion-like propagation
ISSN:1750-1326
1750-1326
DOI:10.1186/s13024-021-00486-9