Abstract
BackgroundThe 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.MethodsTo 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.ResultsImmunohistochemical 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.ConclusionsThese 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.
Highlights
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
We investigated the impact that pre-existing amyloid β (Aβ) pathology has on the induction of αSyn inclusion pathology by injection of Preformed fibrils (PFF), how αSyn pathology in turn alters Aβ plaque formation, and the interplay of neuroinflammation induced by these pathologies
Antecedent Aβ pathology leads to exacerbation of induced αSyn inclusion formation To investigate the interplay between the formation of αSyn inclusion pathology and Aβ deposition, we crossed M20 transgenic mice [40, 41] with L85 mice [38, 39]
Summary
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. Many proteins can enter an amyloidogenic state, wherein a protein, prompted by the surrounding milieu, cellular signaling, or even another protein, adopts a βsheet structure These β-sheets can stack upon one another into fibrils stabilized by hydrogen bonding [1] and with time, may accumulate progressively into larger aggregates. Two of the most common forms of age-related neurodegenerative disorders, Alzheimer’s disease (AD) and Parkinson’s disease (PD), which canonically exhibit accumulations of amyloid β (Aβ) and α-synuclein (αSyn) respectively, often exhibit co-pathology of these proteins and represent keystone components on the spectrum of neurodegenerative disorders [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18]. ΑSyn inclusions are frequently observed in brains from patients with sporadic and familial AD, where genetic defects in the APP, PSEN1 and PSEN2 genes directly affect biological pathways that promote Aβ deposition [12, 24,25,26,27]
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