# CaMKII nitrosylation in the age-related decline of synaptic plasticity

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $236,725

## Abstract

Project Summary/Abstract
Many patients with Down Syndrome (DS) develop early onset Alzheimer’s disease (AD), and an obvious
mechanistic link between the two conditions is provided by the β-amyloid (Aβ) precursor protein (APP): Aβ is
a major pathological agent in AD, and patients with DS have an extra copy of the APP gene (as it is localized
on the chromosome 21 that is triplicated in DS) as well as elevated Aβ levels in plasma and cerebrospinal fluid.
Aβ is well known to inhibit hippocampal long-term potentiation (LTP), a form of synaptic plasticity thought to
underly higher brain functions such as learning, memory, and cognition (which are impaired in both AD and
DS, albeit in different ways). Indeed, LTP is impaired in mouse models of both AD and DS. LTP is critically
mediated by the Ca2+/calmodulin-dependent protein kinase II (CaMKII), and we have recently shown that Aβ
interferes with LTP by affecting CaMKII signaling: Normal LTP requires CaMKII movement to excitatory
synapses via regulated binding to the NMDA-receptor, and Aβ suppresses this CaMKII movement. Notably, in
the AD-related impairment of LTP, APP acts not only as an upstream precursor but also as a downstream
effector of Aβ. While the role of APP as Aβ precursor is well established, its role as Aβ effector is just emerging
(and has not been examined at all in context of DS). Additionally, while the APP triplication in DS has been
suggested as cause for the DS-associated early onset AD, a role in the DS-associated impairment of LTP prior
to AD onset remains to be investigated. Here, we will determine the function of APP as Aβ precursor versus
effector in a DS mouse model. As APP knockout prevents the Aβ-induced impairments of CaMKII movement
and LTP, we hypothesize that the APP gene triplication in Down Syndrome sensitizes to the effects of
Aβ on CaMKII movement and LTP (even before the manifestation of early onset AD). We will here determine
if hippocampal neurons from a mouse model of DS are more sensitive to the Aβ-induced impairments of CaMKII
movement, as reflected by a lower threshold for either dose or duration of Aβ exposure. Follow-up studies will
investigate (i) a similar sensitization for Aβ-induced LTP impairments, and (ii) dependence of these effects on
the additional copy of APP (by eliminating one of the APP copies in the DS mouse line).

## Key facts

- **NIH application ID:** 10444721
- **Project number:** 3R01AG067713-02S1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** K. Ulrich Bayer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $236,725
- **Award type:** 3
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444721

## Citation

> US National Institutes of Health, RePORTER application 10444721, CaMKII nitrosylation in the age-related decline of synaptic plasticity (3R01AG067713-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10444721. Licensed CC0.

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