Abstract: 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 of α7-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 by α7nAChR agonist PHA-543613. Taken together, our results indicate that knockout of PS1 and PS2 can disrupt the function of α7nAChR, 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, finally impair hippocampal-dependent memory.

Key words: Alzheimer&rsquo, s disease, presenilin, neuronal apoptosis, synaptic plasticity, memory