摘要：Objective：Presenilin （PS） is one of major causative genes of early onset familial Alzheimer’s disease（ FAD），which accounts for 95% of genetic factors. Presenilin-1（ PS1） is considered as the catalytic subunit of the γ-secretase complex that cleaves type Ⅰ transmembrane proteins，such asamyloid precursor protein （APP），a protein closely related with AD. One conserved aspartate residue（Asp385） in PS1 is thought to constitute the active site of γ-secretase. In vitro，D385A mutation（the aspartate to alanine alteration） leads to the failure of PS1 endoproteolysis and abolishment of γ-secretase activity. To further investigate the role of Asp385 residue in PS1 in vivo，we generated PS1 D385A knockin （KI） mice，in which an Asp385Ala （D385A） alteration was introduced in the genomic Psen1 locus. Method：The gene-editing method of Cre-LoxP has been used to generate PS1 D385A KI mice；southern blot has been used to detect the genomic DNA from both embryonic stem （ES） cells and mouse tails to confi rm its genotype. Northern and western have been used to test the mRNA and protein levels of PS1. Morphology and the proliferation of neural progenitor cells of developing brains has been test by HE staining and BrdU immunohistochemistry. Angiogenesis has been test by both western and immunofl uorescence to target the marker of vascular endothelial cells，CD31. In vitro γ-secretase assay has been used to test the activity of γ-secretase. Results：Homozygous D385A KI （KI/KI） mice display severe developmental deficits，including abnormal skeleton development，perinatal lethality，cerebral hemorrhages，enlarged lateral ventricle and massive loss of neural progenitor cells，which is identical to those of Psen1-null mice. D385A mutation dose not interrupt the level of Psen1 mRNA，but disrupt PS1 endoproteolysis. The N- and C-terminal fragments of PS1 are absent，and PS1 holoprotein accumulates （~18-fold） in KI/KI mice relative to the wild type （WT） controls. In addition，D385A mutation abolishes γ-secretase activity in the brain of D385A KI/KI mice，and the activity is signifi cantly reduced in KI/+ mice. Furthermore，compared with WT mice，the protein level of CD31 is signifi cantly increased in KI/+ mice within development and adulthood. In adult，KI/+ mice also show abnormal angiogenesis in both cortex and hippocampus，and cerebrovascular amyloid plaques have been detected in 10 month age. Conclusion：Collectively，these results demonstrate that the Asp385 of PS1 is indispensable for its function in maintaining normal development，neurogenesis，and γ-secretase activity. Furthermore，D385A mutation causes abnormal angiogenesis and amyloid plaques in vessels in adulthood.