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

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $583,165

## Abstract

Project Summary Abstract
Postsynaptic kinase/phosphatase networks in amyloid β-induced synaptic dysfunction
 Alzheimer's disease (AD) is characterized by impaired synaptic function and synapse loss in key
forebrain areas required for learning and memory, including the hippocampus. While the pathologic agent that
causes AD remains contentious (amyloid-beta; Aβ vs. tau) there is strong genetic, biochemical, anatomical and
electrophysiological evidence supporting that Aβ is sufficient to initiate cellular processes leading to severe
synaptic pathology. For example sub-micromolar doses of Aβ acutely (within minutes) inhibit long-term
potentiation (LTP), a form of synaptic plasticity critical for learning and memory. In addition, longer Aβ
exposure (days to weeks) leads to depression and elimination of excitatory synapses through a
process that requires NMDA receptor signaling. However, the downstream signaling networks that drive
acute and chronic Aβ-mediated synaptic pathologies are only beginning to emerge and need to be further
investigated. Strong preliminary data from our labs implicate several postsynaptic ser/thr kinases (CaMKII,
DAPK1, PKA) and a phosphatase (calcineurin (CaN)) as key molecular players responsible for acute Aβ-
induced LTP disruption, possibly through impaired NMDA receptor Ca2+ entry. It remains unclear whether
these same signaling mechanisms mediate chronic Aβ-induced synaptic depression and elimination, but
published and preliminary data presented here indicate that CaN activity is required. Importantly, all of these
kinases and phosphatases interact with one another in a postsynaptic signaling network that integrates
NMDAR activity to promote either LTP or LTD. Indeed, synaptic anchoring of PKA and CaN by the scaffold
protein AKAP79/150 appears to be critical for promoting signaling crosstalk between PKA, CaN, DAPK1 and
CaMKII at synaptic sites to establish normal LTP/LTD balance. In this multi-PI project we will test the
hypothesis that Aβ causes acute (Aims 1 & 2) and chronic (Aims 3 & 4) synaptic dysfunction by perturbing the
balance of this signaling network and its downstream effectors to favor LTD, leading to impaired LTP and
synapse elimination.

## Key facts

- **NIH application ID:** 10207804
- **Project number:** 5R01NS110383-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** K. Ulrich Bayer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $583,165
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207804

## Citation

> US National Institutes of Health, RePORTER application 10207804, Postsynaptic kinase/phosphatase networks in amyloid beta-induced synaptic dysfunction (5R01NS110383-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10207804. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*