# GHSR1a and Hippocampal Pathology in Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF KANSAS LAWRENCE · 2021 · $452,727

## Abstract

Characterized by progressive cognitive decline, Alzheimer's disease (AD) is the most common type of dementia
primarily attacking the aging population. Hippocampal synaptic injury and neurodegeneration are defining
pathological features of the cognitive deficits in Alzheimer's disease (AD). In order to better understand the
pathogenesis of the disease, and to improve AD treatment options, we need to elucidate the molecular
mechanisms that cause cellular stress in the hippocampus. The growth hormone secretagogue receptor
(GHSR), also known as ghrelin receptor, is highly expressed in neurons of the hypothalamus and hippocampus.
In addition to its roles in stimulating appetite and growth hormone release, recent studies have revealed an
important contribution of GHSR1a, the functional isoform of GHSR, in the regulation of hippocampal synaptic
plasticity and memory consolidation. GHSR1a heteromerizes with the dopamine receptor D1 (DRD1), thus
regulating DRD1-mediated modulation of synaptic plasticity. Moreover, recent studies have shown GHSR1a-
dependent apoptosis of hippocampal neurons, indicating a critical role for GHSR1a in hippocampal neuronal
survival. GHSR-null mice exhibit hippocampal pathology and cognitive impairments that resemble AD-like
symptoms. In preliminary studies we found substantially reduced GHSR1a/DRD1 heteromerization in
hippocampal tissue from human AD cases, as well as in an AD mouse model (5xFAD mice), even though the
expression levels of membrane-bound GHSR1a and DRD1 remained relatively preserved. In addition, our
preliminary studies revealed an unexpected physical interaction between GHSR1a and Amyloid beta (Aβ), a key
mediator of AD, in both the AD patients and 5xFAD mice. Changes in GHSR1a/DRD1 heteromerization and the
presence of GHSR1a/Aβ complexes were accompanied by increased apoptotic neuronal death. Finally, we
found that GHSR1a deficiency exacerbates hippocampal pathology in the 5xFAD mice without significantly
altering Aβ production. These observations lead us to hypothesize that GHSR1a dysfunction that results from
its interaction with Aβ constitute a key molecular mechanism for hippocampal synaptic injury and neuronal death,
leading to cognitive impairments in AD. Here, we will determine the influence of Aβ on GHSR1a function, and
we will establish the link between GHSR1a deregulation and hippocampal synaptic injury, neuronal death, and
cognitive deficits in 5xFAD mice. In addition, we will address the mechanisms underlying Aβ interaction-mediated
GHSR1a dysfunction. Taken together, the proposed studies will allow the causative examination of the role of
GHSR1a deregulation in hippocampal pathology in AD and the evaluation of GHSR1a as a therapeutic target
for AD treatment. In addition, the results can be extended to further our understanding of hippocampal pathology
in other neurodegenerative diseases that involve hippocampal amyloidopathy.

## Key facts

- **NIH application ID:** 10163763
- **Project number:** 5R01AG059753-05
- **Recipient organization:** UNIVERSITY OF KANSAS LAWRENCE
- **Principal Investigator:** Heng Du
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $452,727
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10163763

## Citation

> US National Institutes of Health, RePORTER application 10163763, GHSR1a and Hippocampal Pathology in Alzheimer's Disease (5R01AG059753-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10163763. Licensed CC0.

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