# APP as a mediator of amyloid beta effects on CaMKII synaptic functions

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2024 · $38,434

## Abstract

Project Summary
The proper functioning of learning, memory, and cognition requires the activity-dependent strengthening of
excitatory synapses in the hippocampus via a process known as long-term potentiation (LTP). LTP can be
impaired in ex vivo hippocampal slices by incubation with the peptide amyloid-β (Aβ); increased concentrations
of this peptide are highly associated with early synaptic deficits in Alzheimer’s disease (AD), a progressive
neurodegenerative disease. LTP is known to require the Ca2+/calmodulin-dependent protein kinase II (CaMKII),
and specifically its localization to excitatory synapses, driven by direct binding of CaMKII to the NMDA-type
glutamate receptor GluN2B. This localization of CaMKII to excitatory synapses is impaired by incubation with
Aβ, revealing a potential mechanism underlying Aβ-induced synaptic deficits. Interestingly, the impairments of
LTP and CaMKII movement caused by exogenous Aβ incubation are alleviated by loss of the amyloid precursor
protein (APP). While the proteolytic cleavage that APP undergoes to form Aβ is well-characterized, this apparent
downstream role as a mediator of Aβ-induced impairment remains largely unexplored. Importantly, individuals
with Down syndrome (DS), a genetic developmental disorder, express increased levels of APP due to triplication
of the APP gene. As loss of endogenous APP “desensitizes” neurons to the synaptic deficits caused by Aβ, it
may conversely be true that these increased APP levels “sensitize” neurons to the effects of Aβ. Initial results
indicate that APP is not only necessary to mediate CaMKII impairments caused by exogenous Aβ, but also
sufficient to impair CaMKII-GluN2B binding in heterologous cells, further implicating APP as a direct mediator of
downstream Aβ-induced CaMKII impairments. Thus, this proposal will investigate various aspects of APP’s role
as a mediator of Aβ, including whether neurons expressing higher levels of APP are more sensitive to Aβ-induced
synaptic impairments, which domain(s) of the APP protein are necessary to mediate these impairments, and
which specific mechanism(s) downstream of APP and Aβ are driving impairments in LTP-related CaMKII
movement. To answer these questions, we will be utilizing several different genetic mouse lines, including a
model of DS, various mutant constructs of APP, and a recently developed photoactivatable CaMKII. The results
of the experiments outlined in this proposal will provide valuable insight into the role of APP in driving synaptic
impairment (underlying hippocampal memory deficits) caused by Aβ in both AD and DS.

## Key facts

- **NIH application ID:** 10928133
- **Project number:** 5F31AG084197-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Matthew E Larsen
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $38,434
- **Award type:** 5
- **Project period:** 2023-08-03 → 2026-08-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10928133

## Citation

> US National Institutes of Health, RePORTER application 10928133, APP as a mediator of amyloid beta effects on CaMKII synaptic functions (5F31AG084197-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10928133. Licensed CC0.

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