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

Studies have shown an overlap of A beta plaques, tau tangles, and alpha-synuclein (alpha-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 copathology 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 alpha-syn and A beta plaques, we injected alpha-syn preformed fibrils (alpha-syn mpffs) into mice with abundant A beta plaques. A beta deposits dramatically accelerated alpha-syn pathogenesis and spread throughout the brain. Remarkably, hyperphosphorylated tau (p-tau) was induced in alpha-syn mpff-injected 5xFAD mice. Finally, alpha-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 beta plaques enhance endogenous alpha-syn seeding and spreading over time post-injection with mpffs.