# The Role of cAMP/PKA Dysregulation in Aging and the Initial Stages of Alzheimer'sDisease

> **NIH NIH F31** · YALE UNIVERSITY · 2020 · $25,175

## Abstract

Project Summary/Abstract
 Late-onset Alzheimer’s disease (LOAD) is a growing public health crisis that already costs our country
billions of dollars each year. Currently there are no treatments to slow the progression of LOAD. Age is the
largest risk factor for LOAD. There are two key pathological hallmarks of the disease, amyloid beta plaques
and neurofibrillary tangles composed of hyperphosphorylated tau. This project focuses on studying the
molecular mechanisms by which aging contributes to initial stages of LOAD pathology, particularly tau
phosphorylation. To better understand these mechanisms, this project takes advantage of two animal models,
aged rats and macaques. Macaques represent a close approximation of the human aging cortex in regards to
circuitry and LOAD pathology; however, they are technically challenging. Rats on the other hand do not
develop plaques or tangles but do demonstrate age-related cognitive decline and preliminary evidence
suggests they present with early stages of tau phosphorylation. Furthermore, rodents provide a breadth of
molecular tools to investigate the exact mechanisms by which age-related changes contribute to AD pathology.
Previous work from the Nairn and Arnsten labs has demonstrated an increase in cAMP/PKA signaling with age
in both of these models, which correlates with tau phosphorylation and cognitive decline. Thus, the proposed
project examines the molecular drivers of aberrant cAMP/PKA signaling with age. Aim 1a investigates the role
of age-related increases in neuroinflammatory signaling in driving excess cAMP production by removing the
brakes, through dysregulation of phosphodiesterases. Aim 1b focuses on the ways in which increases in
cAMP/PKA signaling generate a deleterious positive-feedback signaling cascade through phosphorylation of
the ryanodine receptor. I plan to investigate how PKA phosphorylation of the ryanodine receptor can increase
calcium release from ryanodine receptors and further drive cAMP production. Both of these sub-aims examine
the effects of aberrant signaling on PKA phosphorylation of tau and their impact on cognitive decline. Aim 2
expands the scope of these studies through the development of a novel mass spectrometry approach to
analyze phosphorylated tau. This novel approach is able to monitor phospho-sites throughout the protein as
well as the enrichment of kinase motifs between conditions; thus, enabling a more complete understanding of
tau modifications, and the signaling pathways underlying them. Combining this new approach with traditional
biochemical assays of tau protein behavior with the use of phosphomimetics, Aim 2 will be able to investigate
the important steps by which age-related changes in cAMP/PKA contribute to LOAD tau pathology. Through
the aims of this project I will receive extensive training in mass spectrometry, biostatistics, and cortical
neurobiology, all of which will prepare me for my desired career in translational neurobiology research. Overall...

## Key facts

- **NIH application ID:** 10056167
- **Project number:** 5F31AG063425-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Shannon Noble Leslie
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $25,175
- **Award type:** 5
- **Project period:** 2019-09-15 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10056167

## Citation

> US National Institutes of Health, RePORTER application 10056167, The Role of cAMP/PKA Dysregulation in Aging and the Initial Stages of Alzheimer'sDisease (5F31AG063425-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10056167. Licensed CC0.

---

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