# Direct activation of CRF neurons by Abeta disrupts the stress response in Alzheimer's Disease

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $429,000

## Abstract

Project Summary
Depression, anxiety, and other neuropsychiatric co-morbidities have been found to predict or coincide with the
earliest stages of Alzheimer's Disease (AD). These changes in the mental health of AD patients are believed to
correlate with previously documented changes in the function of the Hypothalamic-Pituitary-Adrenal (HPA) axis
which controls the release of cortisol into the bloodstream. We have demonstrated that these changes in
behavior and endocrine output are due, in part, to mis-regulation of Corticotropin Releasing Factor (CRF)
signaling, which controls HPA axis activity, in model mice. The proposed project is designed to answer how
AD pathogenesis leads to mis-regulation of CRF signaling and HPA axis activity. Early evidence suggests
that local production of toxic species may directly impact CRF neuron excitability. We have generated a novel
mouse model in which we can mis-express disease-causing mutant forms of Amyloid Precursor Protein (APP)
selectively in CRF neurons. These mice will allow us to test the hypothesis that cell autonomous APP dysfunction
directly impacts CRF neuron activity to cause mood disturbances in Alzheimer's Disease. First, we will evaluate
the anxiety-related changes in behavior and endocrine output that result from selective mis-expression of FAD
mutant forms of APP in CRF neurons. Animals genetically designed to express humanized, FAD mutant APP,
only in CRF neurons (CRF-APP mice) will be tested for changes in anxiety-related behavior and cognitive
performance. The integrity of HPA axis regulation will be evaluated by measuring ACTH and corticosteroid levels
at rest and at peak levels of stress as well as repeatedly during a prolonged stress exposure. Next, we will
determine the impact of chronic selective mis-expression of FAD mutant APP on CRF neuron health. We will
characterize CRF neurons to determine whether expression of APP mutants leads to changes in neuronal
morphology, synaptic connectivity, neuronal excitability, and neurodegeneration. Finally, we will assess features
of AD pathogenesis, specifically testing whether there is local deposition of A in regions containing high
densities of CRF neurons. Our goal is to identify a direct mechanism connecting AD pathogenesis with CRF/HPA
axis mis-regulation. The knowledge of such a mechanism would allow for new strategies for early diagnosis and
treatment of AD, by examining stress responses and circulating cortisol levels in early stage patients. In addition,
targeting of the CRF system with pharmacologic therapies (CRFR1 antagonists) to limit mis-regulation of the
HPA axis might prevent the toxicity associated with higher levels of glucocorticoids in the circulation, and thereby
limit progression of the disease. By selectively targeting this pathway, we might improve mood alterations such
as depression, anxiety, and increased aggression to improve the quality of life for both patient and caregiver.

## Key facts

- **NIH application ID:** 11057216
- **Project number:** 1R21AG086907-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** NICHOLAS J JUSTICE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $429,000
- **Award type:** 1
- **Project period:** 2024-09-30 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11057216

## Citation

> US National Institutes of Health, RePORTER application 11057216, Direct activation of CRF neurons by Abeta disrupts the stress response in Alzheimer's Disease (1R21AG086907-01A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/11057216. Licensed CC0.

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