Intracranial administration of alpha-synuclein fibrils in A30P-synuclein transgenic mice causes robust synucleinopathy and microglial induction

Synucleinopathies are neurodegenerative disorders involving pathological alpha-synuclein (alpha Syn) protein, including dementia with Lewy bodies, multiple system atrophy and Parkinson's disease (PD). Current in vivo models of synucleinopathy include transgenic mice overexpressing alpha Syn variants and methods based on administration of aggregated, exogenous alpha Syn. Combining these techniques offers the ability to study consequences of introducing pathological alpha Syn into primed neuronal environments likely to develop synucleinopathy. Herein, we characterize the impacts pre-formed fibrils (PFFs) of recombinant, human alpha Syn have in mice overexpressing human A3OP alpha Syn, a mutation associated with autosomal dominant PD. A3OP mouse brain contains detergent insoluble alpha Syn biochemically similar to PD brain, and these mice develop Lewy-like synucleinopathy with age. Administration of PFFs in A3OP mice resulted in regionally-specific accumulations of phosphorylated synuclein, microglial induction and a motor phenotype that differed from PFF-induced effects in wildtype mice. Surprisingly, PFF-induced losses of tyrosine hydroxylase were similar in A3OP and wildtype mice. Thus, the PFF-A3OP model recapitulates key aspects of synucleinopathy with induction of microglia, creating an appropriate system for evaluating neurodegenerative therapeutics. (C) 2021 Published by Elsevier Inc.