Amyloid exacerbates tau and alpha-synuclein pathologies, behavioral impairments, and neuroinflammation in a mixed dementia model.

INTRODUCTION

Neurodegenerative diseases often involve overlapping alpha-synuclein (asyn), amyloid beta, and tau proteinopathies, yet the mechanisms, impact, and directionality of their interactions remain unclear.

METHODS

We induced brain-wide neuronal asyn/tau pathologies via viral expression of wild-type asyn, mutant asynE46K, mutant tauA152T, or both asynE46K/tauA152T in adult amyloidosis knock-in mice and controls, either post-plaque deposition (6 months old) or pre-plaque (3 months old). Open-field behavior was assessed baseline and 3 and 6 months post-transduction, followed by neuropathology and neuroinflammation analyses.

RESULTS

Post-plaque induction in amyloid mice increased asyn/tau total and phosphorylated levels and exacerbated amyloid-related hyperlocomotion/anxiety. Pre-plaque induction produced robust phosphorylated pathologies irrespective of amyloid, while causing similar amyloid-dependent behavioral synergy. Tau pathology drove LGALS3+ inflammatory glial responses in white-matter fibers.

DISCUSSION: Amyloid context gates vulnerability, with certain synergies manifesting across stages. White-matter gliosis is a novel mechanism of tauA152T risk. Together, our data argue for the development of stage-aware, multitarget interventions and biomarkers.