Research Project
10303598
Many studies have provided evidences that beta-amyloid peptide (A?) triggers synaptic dysfunction and loss of hippocampus-dependent memory in the prodromic stage of Alzheimer?s disease (AD), but the underlying mechanisms remain uncertain. A? can alter neuronal signaling through interactions with nicotinic acetylcholine receptors (nAChRs), which elicits synaptic dysfunction in AD. Indeed, the loss of nAChRs is the prominent AD pathology, thus A?-induced disruptions of nAChR function underlie deficits in hippocampal synapses, leading to memory loss in AD. However, the effect of A? on nAChR physiology is complex - A? can act like an agonist or an antagonist on the receptors. Significantly, most of currently prescribed drugs for AD inhibit the general breakdown of acetylcholine (acetylcholinesterase inhibitors), thus potentially stimulates all types of acetylcholine receptors. Importantly, they have only modest efficacy due to non-selective stimulation of acetylcholine receptors given that nearly 30 subtypes of neuronal nAChRs have been reported in the human brain. This suggests distinct nAChR subtypes are differentially affected in AD. Among the three major nAChR subtypes in the hippocampus, ?7-, ?4?2-, and ?3?4-nAChRs, we identify that A? selectively affects ?7- and ?4?2-nAChRs together, but not ?3?4-receptors, in cultured mouse hippocampal neurons, resulting in neuronal and synaptic dysfunction, an important characteristic in AD. Moreover, we reveal that selective co-activation of ?7- and ?4?2-receptors is sufficient to reverse the A? effects in cultured hippocampal neurons. Therefore, the overall hypothesis of the proposed work is that selective co-activation of ?7 and ?4?2 nAChRs reverses A?-induced synaptic dysfunction and memory loss in AD. However, isolated neurons do not reflect the nature of the organism due to the isolation and lack of contact with other cells. The significance of the proposed work thus is based on the scientific premise that further studies using intact neural circuits are needed in order to investigate nAChR subtype selectivity of A? effects on synaptic function and memory in AD. In the proposed work, we will thus use brain slice electrophysiology and animal behavioral assays to test our hypothesis. Moreover, we will use Tg2576 transgenic mice, one of the most well characterized, and widely used, mouse models of AD. In Aim 1. we will test the hypothesis that selective co-activation of ?7- and ?4?2-nAChRs reverses A?-induced altered synaptic plasticity. In Aim 2, we will determine the hypothesis that selective co-activation of ?7- and ?4?2-nAChRs improves learning and memory in AD model mice. Given that cholinergic deficiency is associated with AD, strategies aiming to restore normal cholinergic function have been developed as therapeutic drugs for AD. Unfortunately, no nAChR compounds have demonstrated disease-modifying properties for AD so far. Therefore, the idea that selective co-activation of ?7- and ?4?2-nAChRs in the hippocampus can reverse A? effects on AD pathology is a fundamental new concept, which may lead to innovative and novel therapeutic strategies.
