论文部分内容阅读
Down syndrome(DS)patients unanimously develop pathologies of Alzheimer's disease (AD)in their 40s.DS is caused by the existence of an extra copy of chromosome 21.Over-dosage of genes on chromosome 21 has been found to contribute to the pathogenesis of DS and AD as well.One well-supported example is APP gene over-dosage on chromosome 21 which leads to over-production of the neurotoxic β-amyloid(Ab)peptides,the prime culprit in AD pathogenesis.Recently,our group found that SNX27 regulates glutamate receptor's trafficking in a DS mouse model.Here we report a novel function of SNX27 in regulating γ-secretase activity and Aβ generation.Over-expression of SNX27 reduces Aβ production,whereas depletion of SNX27 with RNA interference increases Aβ production in cell cultures.Moreover,over-expression of SNX27 in a transgenic AD mouse model using an adeno-associated viral vector reduces amounts of Aβ40 and Aβ42,whereas genetic deletion of Snx27 increases the production of Aβ40 and Aβ42 in the mouse hippocampi.Mechanistically,SNX27 physically associates with the PS1 subunit of the γ-secretase complex and dissociates PS1/γ-secretase complex,decreasing the catalytic activity of the complex.Our identification of SNX27's function in regulating γ-secretase activity and Aβ generation establishes a new molecular mechanism for pathogenesis of both DS and AD.