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Collusion of α-Synuclein and Aβ Aggravating Co-morbidities in a Novel Prion-type Mouse Model

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Publisher Biomed Central
Date 2021 Sep 10
PMID 34503546
Citations 12
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Abstract

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 β (Aβ) accumulation can induce and promote α-synuclein pathology, driving neurodegeneration.

Methods: To assess the interplay between α-synuclein and Aβ on protein aggregation kinetics, we crossed mice expressing human α-synuclein (M20) with APPswe/PS1dE9 transgenic mice (L85) to generate M20/L85 mice. We then injected α-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 Aβ plaques exacerbate the spread and deposition of induced α-synuclein pathology. This process was associated with increased neuroinflammation. Unexpectedly, the injection of α-synuclein PFFs in L85 mice enhanced the deposition of Aβ; whereas the level of Aβ deposition in M20/L85 bigenic mice, injected with α-synuclein PFFs, did not differ from that of mice injected with PBS.

Conclusions: These studies reveal novel and unexpected interplays between α-synuclein pathology, Aβ and neuroinflammation in mice that recapitulate the pathology of Alzheimer's disease and Lewy body dementia.

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Correction: Collusion of α-Synuclein and Aβ aggravating co-morbidities in a novel prion-type mouse model.

Lloyd G, Dhillon J, Gorion K, Riffe C, Fromholt S, Xia Y Mol Neurodegener. 2024; 19(1):17.

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References
1.
Rusten T, Stenmark H . p62, an autophagy hero or culprit?. Nat Cell Biol. 2010; 12(3):207-9. DOI: 10.1038/ncb0310-207. View

2.
Smith C, Malek N, Grosset K, Cullen B, Gentleman S, Grosset D . Neuropathology of dementia in patients with Parkinson's disease: a systematic review of autopsy studies. J Neurol Neurosurg Psychiatry. 2019; 90(11):1234-1243. DOI: 10.1136/jnnp-2019-321111. View

3.
Samuel W, Galasko D, Masliah E, Hansen L . Neocortical lewy body counts correlate with dementia in the Lewy body variant of Alzheimer's disease. J Neuropathol Exp Neurol. 1996; 55(1):44-52. DOI: 10.1097/00005072-199601000-00005. View

4.
Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M . beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc Natl Acad Sci U S A. 2001; 98(21):12245-50. PMC: 59799. DOI: 10.1073/pnas.211412398. View

5.
Sorrentino Z, Xia Y, Funk C, Riffe C, Rutherford N, Diaz C . Motor neuron loss and neuroinflammation in a model of α-synuclein-induced neurodegeneration. Neurobiol Dis. 2018; 120:98-106. PMC: 6190709. DOI: 10.1016/j.nbd.2018.09.005. View