S3A-2 The Effect of PHA-543613 on Memory Disorders in Presenilin1 and Presenilin2 Conditional Double Knockout Mice

The mutation in the amyloid-beta precursor protein(APP)and presenilin genes(PSEN1 and PSEN2)cause autosomal dominant Alzheimer’s diease(ADAD)which is typically associated with early-onset familial Alzheimer’s disease(FAD),however,the mechanism by which presenilin mutations cause memory disorders and neurodegeneration remains poorly understood.In the present study,using Presenilin-1 and Presenilin-2 double knockout mice(cDKO mice),we observed that the impaired spatial reference memory,spatial working memory and contextual fear memory in cDKO mice.Consistently,deficits of basal synaptic transmission and LTP formation,as well as down-regulation of PI3K/Akt signaling pathway at hippocampus in cDKO mice.Furthermore,we found the expression levels ofα7-nicotinic ACh receptors(α7nAChRs),NMDAR and AMPAR composition subunits,which related to synaptic plasticity and memory,were decreased at hippocampus in cDKO mice.Importantly,all above deficits could be reversed byα7nAChR agonist PHA-543613.Taken together,our results indicate that knockout of PS1 and PS2 can disrupt the function ofα7nAChR,thereby down-regulate activation of PI3K/Akt signaling pathway,reduce the synaptic expression levels of NMDAR and AMPAR composition subunits at hippocampus,consequently cause neuronal apoptosis,disrupt basal synaptic transmission and LTP formation at hippocampus,fi nally impair hippocampal-dependent memory.