# Project 4 - Astrocytic KATP channels in LATE+HS

> **NIH NIH P01** · UNIVERSITY OF KENTUCKY · 2022 · $622,653

## Abstract

PROJECT 4 SUMMARY/ABSTRACT
An astrocyte mechanism will be targeted with the goal of preventing a common subtype of dementia. Limbic-
predominant age-related TDP-43 encephalopathy (LATE) and hippocampal sclerosis (HS) pathology are
present at autopsy in approximately 25% of “Alzheimer’s-type dementia” cases. Notably, a specific ABCC9
gene variant is associated with increased risk of developing LATE+HS. ABCC9 encodes a protein that serves
as a “metabolic sensor” linking brain hypoxia and stress to changes in intracellular calcium and blood flow.
We hypothesize that dysregulation of ABCC9 in astrocytes causes or exacerbates LATE+HS via impaired
cerebrovascular function, hypometabolism (with ionic dyshomeostasis), and neuronal hyperexcitability,
aligning perfectly with themes of this P01. These astrocyte mechanisms can be targeted by a well-tolerated
drug (nicorandil) that has been shown to be clinically safe and effective, with high potential public health
impact. The research will be conducted with the following Specific Aims: Aim 1: Characterize ABCC9/SUR2
transcripts and proteins in human astrocytes. We will test the hypothesis that the ABCC9 genetic variant
associated with LATE+HS risk is also associated with decreased ABCC9 expression in astrocytes. Astrocyte
ABCC9 transcripts are mostly unknown. In human samples, we will evaluate the repertoire of mRNA
transcripts and splicing in astrocytes. We will characterize ABCC9 gene expression with RNA-Seq data
across cell types. In genotyped human brains from Core C (LATE+HS and controls), we will evaluate ABCC9
proteins immunohistochemically, and we will explore Sur2 expression in mouse models. Aim 2: Test the
hypothesis that modulation of astrocytic ABCC9//KATP leads to improved neurovascular and metabolic
function in LATE+HS model mice. The novel (TetR-TDP) mouse, an excellent animal model that has proven
hippocampal cell loss, astrocytosis, TDP-43 proteinopathy, and memory impairment, will be used to test the
impact of astrocyte specific ABCC9 upregulation on neurovascular function (multiphoton to look at
neurovascular coupling and vessel leakiness; MRI to look at cerebral blood flow and other endpoints). The
impact of astrocyte specific upregulation of SUR2B on brain metabolism will also be tested (glutamate uptake
in astrocytes; Ca2+ dynamics [GCaMP]; and, MRS to characterize brain metabolites). Aim 3: Test the
hypothesis that pharmacological modulation with nicorandil (a KATP channel agonist well-tolerated in oral
preparations) leads to improved neuronal and astrocyte function and neurobehavioral assessment outcomes
in TetR-TDP mice. These outcomes will include readouts of neurobehavioral parameters (RAWM and Y-
maze) and other endpoints including electrophysiological assessments in astrocytes. Follow-up assessments
will include detailed neuropathology (astrocytosis, HS, TDP-43 proteinopathy, and small vessel morphology).
In summary, while studying the mechanisms of astrocyte metabolic and neuro...

## Key facts

- **NIH application ID:** 10495938
- **Project number:** 1P01AG078116-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** PETER T. NELSON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $622,653
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10495938

## Citation

> US National Institutes of Health, RePORTER application 10495938, Project 4 - Astrocytic KATP channels in LATE+HS (1P01AG078116-01). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10495938. Licensed CC0.

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