Many studies have provided evidences that beta-amyloid peptide (Aß) triggers synaptic dysfunction and
loss of hippocampus-dependent memory in the prodromic stage of Alzheimer’s disease (AD), but the underlying
mechanisms remain uncertain. Aß 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 Aß-induced disruptions of nAChR function underlie deficits in hippocampal synapses, leading to
memory loss in AD. However, the effect of Aß on nAChR physiology is complex - Aß 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,
a7-, a4ß2-, and a3ß4-nAChRs, we identify that Aß selectively affects a7- and a4ß2-nAChRs together, but not
a3ß4-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 a7- and a4ß2-receptors is
sufficient to reverse the Aß effects in cultured hippocampal neurons. Therefore, the overall hypothesis of the
proposed work is that selective co-activation of a7 and a4ß2 nAChRs reverses Aß-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
Aß 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 a7- and a4ß2-nAChRs reverses Aß-induced altered synaptic
plasticity. In Aim 2, we will determine the hypothesis that selective co-activation of a7- and a4ß2-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 a7- and a4ß2-nAChRs in the hippocampus can reverse Aß effects on AD
pathology is a fundamental new concept, which may lead to innovative and novel therapeutic strategies.
