# Postsynaptic kinase/phosphatase networks in amyloid beta-induced synaptic dysfunction

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $775,994

## Abstract

Project Summary/Abstract
Postsynaptic kinase/phosphatase networks in amyloid b-induced synaptic dysfunction
Impaired synaptic function and synapse loss are early hallmarks of Alzheimer’s Disease (AD). There is strong
evidence that amyloid beta (Ab) leads to AD-related synapse dysfunction and cognitive impairment. For example,
long-term potentiation (LTP), a key form of plasticity for learning and memory, is disrupted in mouse models
harboring familial AD-linked mutations that lead to Ab accumulation. Even acute applications of soluble Ab
oligomers block LTP within minutes and lead to synapse loss within days. It is increasingly appreciated that Ab
hijacks normal synaptic signaling pathways involved in plasticity, biasing them toward long-term depression
(LTD), or synapse weakening/elimination. LTP and LTD in the hippocampus are ultimately driven by insertion
and removal of AMPA-type glutamate receptors (AMPAR) from synapses. Central to the signaling pathways
regulating AMPAR trafficking during LTP and LTD is a postsynaptic Ser/Thr kinase/phosphatases signaling
network that is coordinated by the scaffold protein AKAP79/150 and includes CaMKIIa, PKA, and
PP2B/calcineurin (CaN). During the last funding period we made several important discoveries regarding how
Ab engages local, postsynaptic LTD-associated signaling pathways to impair LTP. Central to the current
proposal, we observed that either acute Ab application or prolonged Ab exposure in the 5xFAD mouse model of
AD leads to accumulation of Ca2+-permeable AMPARs (CP-AMPARs) at hippocampal synapses. CP-AMPARs
are normally excluded from synapses but can be trafficked to synapses downstream of AKAP-anchored PKA
signaling to modify synaptic strength during plasticity in the healthy brain. However, in many cases, the
incorporation of CP-AMPARs biases subsequent synaptic signaling toward LTD, consistent with Ab-triggered
synapse depression and elimination. Thus, a new central premise established by the research previously funded
by this multi-PI R01 is that Ca2+ influx through CP-AMPARs plays a previously overlooked, but key role in
mediating Aβ synaptotoxicity. Additional data indicate that Ab may engage AKAP-PKA signaling via G-protein-
coupled b2-adrenergic (b2AR) and/or group I mGluR receptors. During the next funding period we will test the
overall hypothesis that b2AR/mGluR-AKAP-PKA signaling regulates synaptic recruitment of CP-AMPARs to
mediate not only acute impacts of Ab associated with LTP inhibition but also chronic impacts leading to dendritic
spine/excitatory synapse loss, long-term synaptic dysfunction, and cognitive impairments in vivo in 5xFAD mice.

## Key facts

- **NIH application ID:** 10811523
- **Project number:** 2R01NS110383-06
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** MARK L DELL'ACQUA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $775,994
- **Award type:** 2
- **Project period:** 2018-09-30 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811523

## Citation

> US National Institutes of Health, RePORTER application 10811523, Postsynaptic kinase/phosphatase networks in amyloid beta-induced synaptic dysfunction (2R01NS110383-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10811523. Licensed CC0.

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