Mechanisms underlying hippocampal synaptic plasticity, specifically long-term potentiation (LTP) and depression (LTD) of synaptic strength, are thought to underlie learning, memory, and cognition. These functions are disrupted in patients with Alzheimer?s disease (AD), and AD mouse models and acute hippocampal slices treated with ?-amyloid (A?, a major neuropathological agent in AD) exhibit severe LTP impairments. LTP requires the Ca2+/calmodulin(CaM)-dependent protein kinase II ? (CaMKII?) and its regulated binding to synaptic NMDA-type glutamate receptors (NMDAR), which results in rapid CaMKII? accumulation at excitatory synapses. My preliminary findings indicate that this CaMKII? synaptic targeting is suppressed by acute A? application in a dose- and time-dependent manner that requires CaMKII? activity. This suppression of CaMKII? targeting suggests a potential disruption in the CaMKII?/NMDAR interaction. Studies from our lab demonstrate that CaMKII?/NMDAR binding can be suppressed by two distinct mechanisms: CaMKII? T305/306 auto- phosphorylation (pT305/306) and activation of death associated protein kinase 1 (DAPK1). My preliminary results and recent published findings from our lab indicate that CaMKII? pT305/306 and DAPK1 activation suppress CaMKII? accumulation at excitatory synapses during LTD, making them potential candidates for mediating the A?-induced disruption in CaMKII? targeting during LTP. As CaMKII movement to excitatory synapses is required for normal LTP, its suppression provides a mechanism for the well-described A?-induced impairment of LTP. Therefore, my proposal will investigate the hypothesis that the A?-induced LTP impairment is mediated by mechanisms that suppress CaMKII? targeting to excitatory synapses, namely CaMKII? pT305/306 and/or DAPK1 activation. Specifically, I will utilize pharmacological inhibition and mutant mouse lines to determine whether these mechanisms mediate the A?-induced suppression of CaMKII? targeting to excitatory synapses and/or the A?-induced LTP impairment. Notably, this project employs the use of intrabodies to monitor endogenous CaMKII? targeting to excitatory and inhibitory synapses during plasticity. This innovative strategy allows for the simultaneous imaging of multiple endogenous proteins in living cells, without impacting basal localization or cellular function. The results of this proposal will provide insight into the cellular and molecular mechanisms underlying A?-induced malfunctions in synaptic plasticity, and potentially contribute to our understanding of AD-related memory and cognitive impairments.
Alzheimer?s disease (AD) is a terminal neurodegenerative disorder characterized by progressive loss of memory and cognition. AD mouse models demonstrate severe impairments in hippocampal synaptic plasticity, which is fundamental to these brain functions; however, mechanisms underlying these impairments are largely unknown. My proposal will explore this AD-related synaptic disfunction by investigating the contribution of two kinases that mediate synaptic plasticity: CaMKII? and DAPK1.
