Dynein-Dependent Endo-Lysosomal Degradation Drives Lewy Body Disorders Accompanied by Aβ Pathology

Dementia with Lewy bodies (DLB) is a significant cause of dementia. However, the limited availability of animal and cellular models that accurately replicate early DLB pathogenesis hampers the understanding of how Aβ plaques influence α-synuclein (αSyn) pathologies. This study addresses this gap by co-culturing primary neurons with adult hippocampal brain slices from either wild-type or Alzheimer's disease (AD) mice containing abundant Aβ plaques and cytokines. Neurons exposed to AD slices showed impaired dynein-dependent organelle trafficking, reducing endosome–lysosome fusion and causing defective degradation of amyloidogenic αSyn fibrils, thus increasing αSyn inclusions. Notably, an abnormal pre-accumulation of dynein in AD mice suggests that dysfunctional dynein may serve as a nucleation site for αSyn aggregation upon exposure to pathogenic fibrils. Furthermore, Rab7 activation successfully restored endo-lysosomal degradation of αSyn fibrils and reduced inclusion formation in mouse models presenting with both Lewy body and Aβ pathologies. These results highlight the dynein-dependent endo-lysosomal pathway as a promising therapeutic target for mitigating αSyn-related pathologies in co-existing Aβ burden, characteristic of many DLB cases.