Neuronal AIMP2–α-synuclein synergy drives endogenous tau and amyloid-β pathologies and neurodegeneration in a mechanistic model of Lewy body dementia

Abstract

Lewy body dementia (LBD), encompassing Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), is defined by widespread α-synuclein (αSyn) aggregation and frequently exhibits coexistent tau and amyloid-β (Aβ) pathologies. However, whether αSyn pathology is sufficient to drive endogenous tau and Aβ aggregation has remained unclear due to a lack of in vivo models that recapitulate the full spectrum of LBD-associated proteinopathies and neurodegeneration. AIMP2, a parkin substrate that accumulates in Parkinson’s disease, enhances αSyn aggregation and toxicity, but its role in initiating downstream mixed pathologies across vulnerable brain regions has not been demonstrated in vivo. Here, we generated a conditional, neuron-specific Tet-Off double-transgenic mouse model enabling post-developmental coexpression of AIMP2 and A53T αSyn. This synergistic coexpression induced rapid and widespread αSyn aggregation, detergent-insoluble Lewy-like inclusions, mitochondrial degeneration, synaptic impairment, and neuronal loss, accompanied by marked gliosis. Mice developed key clinical features of LBD, including progressive cognitive impairment, bradykinesia, and olfactory deficits. Notably, without tau or APP overexpression, endogenous tau became hyperphosphorylated through dysregulated kinase signaling, and Aβ accumulated predominantly as TBS-soluble Aβ42 monomers/oligomers without fibrillar plaque deposition, demonstrating that AIMP2–αSyn–driven pathology is sufficient to trigger downstream tauopathy and Aβ pathologies. These mixed pathologies were associated with lysosomal and proteasomal dysfunction, evidenced by p62 and polyubiquitinated protein accumulation. Proteomic analysis identified dysregulation of pathways linked to amyloid processing, synaptic trafficking, and protein quality control. Importantly, temporal suppression of AIMP2 and αSyn expression promoted reduction of pre-existing pathologies and partially restored cognitive function. This study establishes a genetically controlled in vivo model of LBD-like mixed proteinopathy recapitulating αSyn aggregation, tau hyperphosphorylation, Aβ accumulation, neurodegeneration, and behavioral decline. These findings support a mechanistic link between AIMP2-enhanced αSyn toxicity and secondary proteinopathies and position this model as a platform for mechanistic and therapeutic studies in complex α-synucleinopathies.