# Suppression of CaMKII synaptic targeting and beta-amyloid pathology

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2020 · $35,301

## Abstract

PROJECT SUMMARY:
 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 β-amyloid (Aβ, a major neuropathological agent in AD) exhibit severe LTP impairments. LTP
requires the Ca2+/calmodulin(CaM)-dependent protein kinase II α (CaMKIIα) and its regulated binding to synaptic
NMDA-type glutamate receptors (NMDAR), which results in rapid CaMKIIα accumulation at excitatory synapses.
My preliminary findings indicate that this CaMKIIα synaptic targeting is suppressed by acute Aβ application in a
dose- and time-dependent manner that requires CaMKIIα activity. This suppression of CaMKIIα targeting
suggests a potential disruption in the CaMKIIα/NMDAR interaction. Studies from our lab demonstrate that
CaMKIIα/NMDAR binding can be suppressed by two distinct mechanisms: CaMKIIα 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 CaMKIIα pT305/306 and DAPK1 activation
suppress CaMKIIα accumulation at excitatory synapses during LTD, making them potential candidates for
mediating the Aβ-induced disruption in CaMKIIα targeting during LTP. As CaMKII movement to excitatory
synapses is required for normal LTP, its suppression provides a mechanism for the well-described Aβ-induced
impairment of LTP. Therefore, my proposal will investigate the hypothesis that the Aβ-induced LTP impairment
is mediated by mechanisms that suppress CaMKIIα targeting to excitatory synapses, namely CaMKIIα
pT305/306 and/or DAPK1 activation. Specifically, I will utilize pharmacological inhibition and mutant mouse lines
to determine whether these mechanisms mediate the Aβ-induced suppression of CaMKIIα targeting to excitatory
synapses and/or the Aβ-induced LTP impairment. Notably, this project employs the use of intrabodies to monitor
endogenous CaMKIIα 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 Aβ-induced malfunctions in synaptic plasticity, and potentially contribute to our
understanding of AD-related memory and cognitive impairments.

## Key facts

- **NIH application ID:** 9940669
- **Project number:** 5F31AG062160-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Sarah G Cook
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $35,301
- **Award type:** 5
- **Project period:** 2019-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940669

## Citation

> US National Institutes of Health, RePORTER application 9940669, Suppression of CaMKII synaptic targeting and beta-amyloid pathology (5F31AG062160-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9940669. Licensed CC0.

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