Amyloid-Beta (A?) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with A? Pathology.

ABSTRACT: Studies have shown an overlap of A? plaques, tau tangles, and ?-synuclein (?-syn) pathologies in the brains of Alzheimer's disease (AD) and Parkinson's disease (PD) with dementia (PDD) patients, with increased pathological burden correlating with severity of cognitive and motor symptoms. Despite the observed co-pathology and concomitance of motor and cognitive phenotypes, the consequences of the primary amyloidogenic protein on the secondary pathologies remain poorly understood. To better define the relationship between ?-syn and A? plaques, we injected ?-syn preformed fibrils (?-syn mpffs) into mice with abundant A? plaques. A? deposits dramatically accelerated ?-syn pathogenesis and spread throughout the brain. Remarkably, hyperphosphorylated tau (p-tau) was induced in ?-syn mpff-injected 5xFAD mice. Finally, ?-syn mpff-injected 5xFAD mice showed neuron loss that correlated with the progressive decline of cognitive and motor performance. Our findings suggest a "feed-forward" mechanism whereby A? plaques enhance endogenous ?-syn seeding and spreading over time post-injection with mpffs.

SUBMITTER: Bassil F 

PROVIDER: S-EPMC6981053 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature