Wild-type human α-synuclein induces progressive tau pathology in a disease-relevant mouse model of synucleinopathy

Tau pathology plays a critical role in the onset and progression of multiple neurodegenerative diseases. Although synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are primarily defined by α-Synuclein (α-Syn) inclusions, they frequently exhibit substantial tau co-pathology. However, whether wild-type (WT) human α-Syn overexpression influences tau pathology in vivo remains poorly defined. Here, we systematically investigated the temporal and regional progression of tau pathology in hSyn transgenic mice overexpressing WT human α-Syn. Using immunohistochemical, biochemical, and structural approaches, we demonstrate progressive, age-dependent accumulation of hyperphosphorylated tau in cortex, hippocampus, and midbrain. Tau pathology was minimal at 5 months, increased substantially by 10 months, and further intensified by 20 months, validated by both phosphorylation-dependent and conformation-specific antibodies. Regional correlation analysis revealed that coordinated accumulation of tau and α-Syn pathology during disease progression (overall r2 = 0.844), with weak association at 5 months and strong, significant correlations by 10 and 20 months. Electron microscopy revealed fibrillar structures in insoluble fractions, and mass spectrometry confirmed the presence of both α-Syn and tau in these fractions. Notably, these pathologies were absent in WT littermates, indicating they arise as a consequence of WT human α-Syn overexpression rather than normal aging. Our findings support tau-targeted therapeutic approaches as a viable strategy for synucleinopathies.