Hippocampal Reduction of -Synuclein via RNA Interference Improves Neuropathology in Alzheimer's Disease Mice

Background: Alzheimer's disease (AD) cases are often characterized by the pathological accumulation of alpha-synuclein (alpha-syn) in addition to amyloid-beta (A beta) and tau hallmarks. The role of alpha-syn has been extensively studied in synucleinopathy disorders, but less so in AD. Recent studies have shown that alpha-syn may also play a role in AD and its downregulation may be protective against the toxic effects of A beta accumulation. Objective: We hypothesized that selectively knocking down alpha-syn via RNA interference improves the neuropathological and biochemical findings in AD mice. Methods: Here we used amyloid precursor protein transgenic (APP-Tg) mice to model AD and explore pathologic and behavioral phenotypes with knockdown of alpha-syn using RNA interference. We selectively reduced alpha-syn levels by stereotaxic bilateral injection of either LV-shRNA alpha-syn or LV-shRNA-luc (control) into the hippocampus of AD mice. Results: We found that downregulation of alpha-syn results in significant reduction in the number of A beta plaques. In addition, mice treated with LV-shRNA alpha-syn had amelioration of abnormal microglial activation (Iba1) and astrocytosis (GFAP) phenotypes in AD mice. Conclusion: Our data suggests a novel link between A beta and alpha-syn pathology as well as a new therapeutic angle for targeting AD.