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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 (APPSWE) and SNCAA53T mutations promote Aß generation and a-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 APPSWE mutation enhanced Aß generation and increased cell susceptibility to Aß oligomer in cholinergic SN56 cells, whereas SNCAA53T mutations promoted aggregates formation and potentiated mutant a-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 APPSWE or SNCAA53T mutation. SDC3 and FGFRL1 proteins were preferentially expressed in the cholinergic nucleus and dopaminergic neurons of APPSWE and SNCAA53T mouse models, respectively. Finally, the knockdown of SDC3 and FGFRL1 attenuated oxidative stress-induced cell death in SN56-APPSWE and MN9D-SNCAA53T cells. The results demonstrate that SDC3 and FGFRL1 mediated the specific effects of APPSWE and SNCAA53T 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. [ABSTRACT FROM AUTHOR]