Synergistic Interactions between Aβ, Tau, and α-Synuclein: Acceleration of Neuropathology and Cognitive Decline

TLDR

Alzheimer’s disease is marked by amyloid‑β plaques and tau tangles, and up to half of cases also display Lewy‑body α‑synuclein pathology, which is linked to a more rapid cognitive decline, suggesting possible synergistic interactions among these proteins. The authors aimed to create a genetic mouse model that simultaneously recapitulates AD and dementia with Lewy bodies. They achieved this by crossing 3xTg‑AD mice with a transgenic line expressing mutant human α‑synuclein. The resulting DLB‑AD mice exhibited accelerated cognitive deterioration accompanied by markedly increased amyloid‑β, tau, and α‑synuclein pathology, and the data demonstrate that α‑synuclein alone can impair cognition, supporting a mutual promotion of aggregation and dysfunction.

Abstract

Alzheimer's disease (AD), the most prevalent age-related neurodegenerative disorder, is characterized pathologically by the accumulation of beta-amyloid (Abeta) plaques and tau-laden neurofibrillary tangles. Interestingly, up to 50% of AD cases exhibit a third prevalent neuropathology: the aggregation of alpha-synuclein into Lewy bodies. Importantly, the presence of Lewy body pathology in AD is associated with a more aggressive disease course and accelerated cognitive dysfunction. Thus, Abeta, tau, and alpha-synuclein may interact synergistically to promote the accumulation of each other. In this study, we used a genetic approach to generate a model that exhibits the combined pathologies of AD and dementia with Lewy bodies (DLB). To achieve this goal, we introduced a mutant human alpha-synuclein transgene into 3xTg-AD mice. As occurs in human disease, transgenic mice that develop both DLB and AD pathologies (DLB-AD mice) exhibit accelerated cognitive decline associated with a dramatic enhancement of Abeta, tau, and alpha-synuclein pathologies. Our findings also provide additional evidence that the accumulation of alpha-synuclein alone can significantly disrupt cognition. Together, our data support the notion that Abeta, tau, and alpha-synuclein interact in vivo to promote the aggregation and accumulation of each other and accelerate cognitive dysfunction.