# Neuronal mechanisms of altered circuit excitability in early Alzheimer's

> **NIH NIH R56** · EMORY UNIVERSITY · 2021 · $385,221

## Abstract

14 million Americans are projected to be living with dementia by 2050. Alzheimer’s disease (AD) is the
most common form of dementia, responsible for ~70% of all cases. A hallmark feature of Alzheimer’s
disease (AD) is progressive synaptic and neuronal pathology- factors that ultimately result in cognitive
decline. While there is increasing confidence that specific biomarkers can predict the occurrence of AD in
individuals, the molecular and cellular mechanisms contributing to the initiation of the disease remain
poorly understood. Gaining a greater understanding of these mechanisms is crucial if we hope to halt
neurodegeneration early enough to preserve memory and cognition. Interestingly, a common
phenomenon has now been observed in both humans with mild cognitive impairment, as well as in
animal models during the early stages of AD. These observations agree that neuronal circuits affected by
AD become more active during the early stages of the disease. In addition, evidence exists that
hyperactive neurons become vulnerable to synaptic degradation- a hallmark feature of AD. Our objective
is to uncover neuronal mechanisms that result in this early-stage circuit dysfunction. Evidence exists that
inhibitory interneurons are vulnerable to changes in activity during early AD. For example, action
potential (AP) firing is modified in interneurons, but less so in other cell types, in prodromic AD mouse
models. AP firing in interneurons is controlled by a unique subset of ion channels, and it has been
suggested that the expression of particular ion channels change in interneurons during AD. However,
what changes in the expression, subcellular trafficking, or biophysical properties of ion channels occur in
early AD remain unclear. Using human APP-expressing mouse models and cutting-edge molecular,
electrophysiological, and 2-photon imaging techniques, we propose to uncover changes in specific ion
channels in these GABAergic interneurons in depth. Based on our preliminary data, we hypothesize that
modification of a particular class of Kv channels in interneurons directly contributes to cortical
hyperexcitability in early AD. Importantly, studies will be performed ex vivo early on in the disease
process (i.e., before plaque formation or synapse loss). Findings from this proposal will help us better
understand the initiating factors of circuit pathology during early AD and could lead directly to the
development of molecular and cellular therapies that halt synaptic and neuronal pathology.

## Key facts

- **NIH application ID:** 10359226
- **Project number:** 1R56AG072473-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Matthew J.M. Rowan
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,221
- **Award type:** 1
- **Project period:** 2021-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359226

## Citation

> US National Institutes of Health, RePORTER application 10359226, Neuronal mechanisms of altered circuit excitability in early Alzheimer's (1R56AG072473-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10359226. Licensed CC0.

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