α-Syn Suppression Reverses Synaptic and Memory Defects in a Mouse Model of Dementia with Lewy Bodies

Abnormally accumulated alpha-synuclein (alpha-syn) is a pathological hallmark of Lewy body-related disorders such as Parkinson's disease (PD) and dementia with Lewy body disease (DLB). However, it is not well understood whether and how abnormal accumulation of alpha-syn leads to cognitive impairment or dementia in PD and DLB. Furthermore, it is not known whether targeted removal of alpha-syn pathology can reverse cognitive decline. Here, we found that the distribution of alpha-syn pathology in an inducible alpha-syn transgenic mouse model recapitulates that in human DLB. Abnormal accumulation of alpha-syn in the limbic system, particularly in the hippocampus, correlated with memory impairment and led to structural synaptic deficits. Furthermore, when alpha-syn expression was suppressed, we observed partial clearing of pre-existing alpha-syn pathology and reversal of structural synaptic defects, resulting in an improvement in memory function.