# NHE6: A Novel Rational Target For Alzheimer's Disease

> **NIH NIH F31** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $35,957

## Abstract

Alzheimer’s disease (AD) is characterized by both, an accumulation of extracellular Amyloid-β (Aβ) plaques and
intracellular tau tangles. The highest genetic risk factor for developing late-onset AD is Apolipoprotein E (ApoE)
isoform ϵ4. In humans there are three ApoE isoforms: ApoE2, ApoE3, and ApoE4 that vary by one or two amino
acids. ApoE4 impairs vesicular trafficking, resulting in synaptic dysfunction which occurs years before AD
symptoms and pathology develop, suggesting a molecular mechanism for the accelerated disease onset in
ApoE4 carriers. We have shown that the ApoE4-mediated synaptic defect is alleviated by acidifying the early
endosomal pH with either a pharmacological block or genetic ablation of the Sodium/Hydrogen Exchanger (NHE)
6. This significant finding implicates NHE6 inhibition as a potential therapy for preventing AD in ApoE4 carriers.
In order to move forward towards developing NHE6 inhibitor drugs, it is critical to evaluate how NHE6 inhibition
alters AD pathology. Thus, we created an NHE6 knockout (NHE6-KO) mouse and bred it with an Aβ producing
mouse model. Remarkably, Aβ plaque deposition is reduced by NHE6 depletion in vivo, further implicating NHE6
inhibition as a promising target for delaying AD. In this proposal, I will delineate the molecular mechanism behind
the reduced plaque deposition that occurs with NHE6 ablation. Depletion of NHE6 in vivo results in an increase
in glial activation, thus I hypothesize that the increased glial activation in NHE6-KO mice promotes the
degradation of Aβ. Currently, the effects of early endosomal acidification on glial activation and Aβ clearance
from the CNS has not been explored. The goal of this study is to determine if acidification of early endosomes
in glial cells is detrimental or whether increased Aβ clearance is predominantly protective. In addition, it is crucial
to investigate whether NHE6 inhibition in microglia causes an over-activated immune response. Thus, I will
determine if NHE6-KO microglia induces a heightened immune response to bacterial or viral insult. Lastly, in this
proposal I will investigate if NHE6-KO in microglia alone can reduce Aβ pathology and whether treatments with
NHE inhibitors in the brain can enhance Aβ clearance in vivo using reverse microdialysis. Overall, the long-term
goal for this grant is to evaluate the feasibility and efficacy of targeting NHE6 as a treatment for AD by using in
vitro and in vivo methods.

## Key facts

- **NIH application ID:** 9991585
- **Project number:** 1F31AG067708-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Connie Hua Wong
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $35,957
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991585

## Citation

> US National Institutes of Health, RePORTER application 9991585, NHE6: A Novel Rational Target For Alzheimer's Disease (1F31AG067708-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9991585. Licensed CC0.

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