Journal
FASEB JOURNAL
Volume 37, Issue 2, Pages -Publisher
WILEY
DOI: 10.1096/fj.202201359R
Keywords
Alzheimer's disease; fibroblast growth factor receptor-like 1; neurodegeneration; Parkinson's disease; syndecan-3
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Alzheimer's disease (AD) and Parkinson's disease (PD) are age-related neurodegenerative disorders that cause specific neuronal loss in the cholinergic and dopaminergic systems, respectively. The mutations in APP(SWE) and SNCA(A53T) have been implicated in the pathology of AD and PD, promoting the generation of A beta and the aggregation of alpha-synuclein, respectively. We found that SDC3 and FGFRL1 genes were differentially expressed in cells carrying these mutations and their knockdown attenuated cell death induced by oxidative stress.
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(SWE)) and SNCA(A53T) mutations promote A beta generation and alpha-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(SWE) mutation enhanced A beta generation and increased cell susceptibility to A beta oligomer in cholinergic SN56 cells, whereas SNCA(A53T) mutations promoted aggregates formation and potentiated mutant alpha-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(SWE) or SNCA(A53T) mutation. SDC3 and FGFRL1 proteins were preferentially expressed in the cholinergic nucleus and dopaminergic neurons of APP(SWE) and SNCA(A53T) mouse models, respectively. Finally, the knockdown of SDC3 and FGFRL1 attenuated oxidative stress-induced cell death in SN56-APP(SWE) and MN9D-SNCAA53T cells. The results demonstrate that SDC3 and FGFRL1 mediated the specific effects of APP(SWE) and SNCA(A53T) 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.
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