Abstract
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.
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This post is Copyright: | July 3, 2026
Neuro-Dementia