Effects Of A?_1-42Monomers On Cognitive Function In PS1/2 Conditional Double Knockout Mice

The mutations of Presenilin 1(PS1)and Presenilin 2(PS2)increase the production of A?1-42 and result in AD synptoms.Although PS1/2 conditional double knockout mice(cDKO mice),which are used in the present study,show many AD-like symptoms,such as brain atrophy,ventricles expand and neurofibrillary tangles,there is no Ap deposition.It is suggested that there may be a pathological mechanism which is not dependent on the deposition of Ap in cDKO mice.Thus,combining molecular biological,electrophysiological and behavioral techniques,we have investigated the effects of PS1/2 conditional double knockout on synaptic,cognitive function and the potential mechanisms in mice.The main results are as follows:1)The spatial working memory and contextual fear memory were impaired in 6-month-old cDKO mice;2)The synaptic transmission efficiency at hippocampal CA3-CA1 pathway wereimpaired in 6-month-old cDKO mice;3)The expression of NMDAR and AMPAR and the activation of PI3K-AKTpathway were decreased in 6-month-old cDKO mice;4)The A?1-42 production in hippocampus was decreased in 6-month-old cDKO mice.Although a large number of studies suggest that the exeessive production and deposition of A?1-42 have neurotoxic effects,but more and more studies also have shown that A?1-42 plays an important role in neuroprotection,synaptic plasticity,and memory in physilolgical status.Thus,we speculate that the decrease of A?1-42 level may result in synaptic and cognitive dysfunction in 6-month-old cDKO mice.In order to confirm this hypothesis,we added A?1-42 monomers with the physiological concentration to cDKO mice,and investigated whether it can improve the synaptic and cognitive dysfunction in cDKO mice.The main results are as follows:1)Intracerebroventricular injection of A?1-42 monomers reversed the deficits of spatial working and contextual fear memory in 6-month-old cDKO mice;2)Perfusion of hippocampal slices with A?1-42 monomers reversed the deficits of synaptic plasticity in 6-month-old cDKO mice;3)Perfusion of hippocampal slices with A?1-42 monomers reversed the decreased expression of NDMAR and AMPAR and activation of PI3K-AKT pathway in 6-month-old cDKO in a dose and time dependent manner.The above results have confirmed that the decrease of A?1-42 level in the hippocampus can result in synaptic and cognitive dysfunction in 6-month-old cDKO mice.What is the mechansim?The previous studies have shown that A?1-42 can regulate the activity of ?7-nicotinic acetylcholine receptor(?7-nAChR),and ?7-nAChR and?4?2-nAChR play roles in neuroprotection,synaptic plasticity and memory.Thus,we hypothesize that the decrease of A?1-42 level may impair cognitive function by inhibiting the function of ?7-nAChR and ?4?2-nAChR.In orther words,exogenous A?1-42 may improve the cognitive function by enhancing the ?7-nAChR and ?4?2-nAChR function in 6-month-old cDKO.In order to confirm this hypothesis,we have investigated the influence of ?7-nAChR and ?4?2-nAChR antagonists on the improve effect of exogenous A?1-42 monomers in 6-month-old cDKO mice.The main results are as follows:1)Antagonism of ?7-nAChR and ?4?2-nAChR can inhibit the improve effect of A?1-42 monomers on the impaired spatial working and contextual fear memory in 6-month-old cDKO mice;2)Antagonism of ?7-nAChR and ?4?2-nAChR can inhibit the improve effect of A?1-42 monomers on the impaired synaptic plasticity in 6-month-old cDKO mice;3)Antagonism of ?7-nAChR and ?4?2-nAChR can inhibit the improve effect of A?1-42 monomers on the decreased expression of NDMAR and AMPAR and activation of PI3K-AKT pathway in 6-month-old cDKO mice.Taken together,these results suggest that the decreased A?1-42 level resulted from PS1/2 conditional double knockout can induce synaptic and cognitive dysfunction via decreasing the expression of a7-nAChR and ?4?2-nAChR,and then decreasing the expression of NMDAR and AMPAR as well as the activation of PI3K-AKT pathway.Our study provides a new insight into the mechanism of cognitive dysfunction caused by knockout of PS1 and PS2,and helps to understand the physiological role of A?1-42 and the potential mechanism.