Distinct effects of SDC3 and FGFRL1 on selective neurodegeneration in AD and PD.

Alzheimer's disease (AD) and Parkinson's disease (PD) are age-dependent neurodegenerative disorders. There is a profound neuronal loss in the basal forebrain cholinergic system in AD and severe dopaminergic deficiency within the nigrostriatal pathway in PD. Swedish APP (APP ) and SNCA mutations promote Aβ generation and α-synuclein aggregation, respectively, and have been linked to the pathogenesis of AD and PD. However, the mechanisms underlying selective cholinergic and dopaminergic neurodegeneration in AD and PD are still unknown. We demonstrated that APP mutation enhanced Aβ generation and increased cell susceptibility to Aβ oligomer in cholinergic SN56 cells, whereas SNCA mutations promoted aggregates formation and potentiated mutant α-synuclein oligomer-induced cytotoxicity in MN9D cells. Furthermore, syndecan-3 (SDC3) and fibroblast growth factor receptor-like 1 (FGFRL1) genes were differentially expressed in SN56 and MN9D cells carrying APP or SNCA mutation. SDC3 and FGFRL1 proteins were preferentially expressed in the cholinergic nucleus and dopaminergic neurons of APP and SNCA mouse models, respectively. Finally, the knockdown of SDC3 and FGFRL1 attenuated oxidative stress-induced cell death in SN56-APP and MN9D-SNCAA53T cells. The results demonstrate that SDC3 and FGFRL1 mediated the specific effects of APP and SNCA on cholinergic and dopaminergic neurodegeneration in AD and PD, respectively. Our study suggests that SDC3 and FGFRL1 could be potential targets to alleviate the selective neurodegeneration in AD and PD.