# SLC9A1 and Neurodegenerative Disease

> **NIH NIH R21** · UNIVERSITY OF KENTUCKY · 2020 · $191,250

## Abstract

Age-related neurologic disease is a significant and growing burden on our society. Although the largest share
of research effort has typically been devoted to the common neurodegenerative illnesses (such as Alzheimer's
disease, or AD), the reality is that nearly all cases of neurodegenerative disease possess elements of mixed
pathology. Individuals diagnosed with AD frequently harbor neuropathologic hallmarks common in other
diseases. For example, tau pathology is also found in some forms of frontotemporal dementia, ALS, and other
forms of neurodegenerative disease, and is also believed to be a key form of neuropathology that develops
following traumatic brain injury. Cerebrovascular disease (CVD) is abundant in individuals with a history of
obesity (and type 2 diabetes, or T2D), which have a well known elevated risk of dementia. In general, it is
actually quite rare to identify AD cases lacking elements of co-morbid cerebrovascular pathology. It is unclear
as to whether these elements of pathology contribute to dementia in an additive or synergistic manner. In
recent studies in our lab, we have observed an intriguing relationship between various aspects of
neuropathology that could potentially connect to AD and CVD. We have identified a membrane ion exchanger,
NHE1 (SLC9A1), as potentially involved in both pathologic processes. NHE1 has been shown to be involved
with neuronal injury, and tau pathology as our preliminary data indicates. This project seeks to determine
whether the function of this exchanger is important for either, or both, of these pathologies. This project
combines both genetic and pharmacologic approaches to explore this exciting new target that has not
previously been examined as a major player in age-related neurodegenerative disease. In specific aim 1
(SA1), we will investigate the mechanism of the membrane ion exchanger NHE1 in a unique mouse model
combining AD- and CVD-related pathology, using a highly specific pharmacologic agent. In SA2, we will
investigate how this membrane ion exchanger drives the formation of tau pathology, by over expressing tau on
a background of NHE1 genetic reduction. Efficacy will be determined using a range of immunohistochemical,
molecular, and biochemical markers of pathology, as well as gauging changes in cognitive function. We
hypothesize that NHE1 will be responsible for multiple aspects of neurodegenerative disease pathology, and
that interfering with its activity will ameliorate these problems, and will alleviate cognitive dysfunction. This is a
highly innovative hypothesis that, to our knowledge, has not been previously explored. Another strength of this
proposal is the use of a novel mouse model with unique features. This project has the capacity to significantly
improve our understanding of co-morbid neuropathologies, and could have significant implications for the
treatment and prevention of age-related neurodegenerative disease.

## Key facts

- **NIH application ID:** 9898214
- **Project number:** 5R21AG059123-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** ADAM D BACHSTETTER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $191,250
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898214

## Citation

> US National Institutes of Health, RePORTER application 9898214, SLC9A1 and Neurodegenerative Disease (5R21AG059123-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9898214. Licensed CC0.

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