Investigating the Pathogenic Interplay of Alpha-Synuclein, Tau, and Amyloid Beta in Lewy Body Dementia: Insights from Viral-Mediated Overexpression in Transgenic Mouse Models

Lewy body dementia (LBD) is an often misdiagnosed and mistreated neurodegenerative disorder clinically characterized by the emergence of neuropsychiatric symptoms followed by motor impairment. LBD falls within an undefined range between Alzheimer's disease (AD) and Parkinson's disease (PD) due to the potential pathogenic synergistic effects of tau, beta-amyloid (A beta), and alpha-synuclein (alpha syn). A lack of reliable and relevant animal models hinders the elucidation of the molecular characteristics and phenotypic consequences of these interactions. Here, the goal was to evaluate whether the viral-mediated overexpression of alpha syn in adult hTau and APP/PS1 mice or the overexpression of tau in Line 61 hThy1-alpha syn mice resulted in pathology and behavior resembling LBD. The transgenes were injected intravenously via the tail vein using AAV-PHP.eB in 3-month-old hThy1-alpha syn, hTau, or APP/PS1 mice that were then aged to 6-, 9-, and 12-months-old for subsequent phenotypic and histological characterization. Although we achieved the widespread expression of alpha syn in hTau and tau in hThy1-alpha syn mice, no alpha syn pathology in hTau mice and only mild tau pathology in hThy1-alpha syn mice was observed. Additionally, cognitive, motor, and limbic behavior phenotypes were not affected by overexpression of the transgenes. Furthermore, our APP/PS1 mice experienced premature deaths starting at 3 months post-injection (MPI), therefore precluding further analyses at later time points. An evaluation of the remaining 3-MPI indicated no alpha syn pathology or cognitive and motor behavioral changes. Taken together, we conclude that the overexpression of alpha syn in hTau and APP/PS1 mice and tau in hThy1-alpha syn mice does not recapitulate the behavioral and neuropathological phenotypes observed in LBD.