# Astrocytic Na/H exchanger in AD astrogliosis

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $48,974

## Abstract

PROJECT SUMMARY/ABSTRACT
Reactive astrocytes and astrogliosis are one of the earliest pathological markers associated with
Alzheimer’s Disease (AD) development, appearing months before amyloid-beta A plaques, Tau
neurofibrillary tangles, and cognitive deficits. However, underlying mechanisms and whether modulating
astrocyte function can attenuate prevent AD progression remain under studied. Recent findings from our
lab show that reactive astrocytes upregulated Na+/H+ exchanger 1 (NHE1) protein activity, a proton
extrusion ion transporter in pH homeostasis, in mouse models of stroke and vascular dementia. Both
pharmacological inhibition and transgenic knockout of astrocytic NHE1 protein significantly attenuated
astrogliosis and neurodegeneration in these studies. In this application, our preliminary study with AD
comorbidity post-mortem human brain tissues reveals significantly increased cell counts of NHE1+ and
GFAP+ reactive astrocytes in cortical regions, compared to control specimens. Using APP/PS1dE9 AD
mouse model, we also detected increased NHE1 protein expression in hippocampus at 8-10-month-old
AD mice than wild-type (WT) mice. These preliminary findings led me to hypothesize that abnormal
astrocytic NHE1 activation contributes to astrogliosis and AD pathogenesis, and that NHE1 inhibition may
be effective at mitigating AD-induced astrogliosis pathologies and cognitive decline. To test my
hypothesis, I will first characterize the correlation between changes of NHE1 protein expression and
activity and astrogliosis during AD development over a 4-8-month period using the APP/PS1dE9 AD
mouse model (Aim 1). Secondly, I will test efficacy of pharmacological NHE1 inhibitor HOE642 in the
APP/PS1E9 model or genetic deletion of astrocytic NHE1 in APP/PS1E9-NHE1 KO line to assess
whether targeting NHE1 protein is effective at attenuating AD astrogliosis, neurodegeneration, A
accumulation, and cognitive decline (Aim 2). Completion of this project will determine the potential of
NHE1 as a possible therapeutic target for AD treatment. Through these research activities, I will acquire
expertise in studying astrocyte morphological and transcriptional transformation and their roles in AD
pathogenesis. Concentrating on non-neurocentric approaches in AD research in the enriched
environment within the University of Pittsburgh’s ADRC, PIND, and Aging Institute will enhance my
training and prepare me to develop innovative research throughout my career development as an
independent neuroscientist.

## Key facts

- **NIH application ID:** 10899976
- **Project number:** 1F31AG084260-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jenelle Monet Collier
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899976

## Citation

> US National Institutes of Health, RePORTER application 10899976, Astrocytic Na/H exchanger in AD astrogliosis (1F31AG084260-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10899976. Licensed CC0.

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