# Calcium dysregulation and vulnerability of entorhinal cortex neurons in Alzheimer's disease

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $737,032

## Abstract

ABSTRACT
The broad, long-term objective of this multi-PI grant application is to understand the role of calcium (Ca2+)
dysregulation as the mechanistic driver for synaptic loss between the lateral entorhinal cortex (LEC) and
hippocampus (HPC) in evolving Alzheimer’s disease (AD). While dysfunction of the LEC-HPC circuit has been
implicated, the cause of the early, selective vulnerability of LEC neurons and projections remain unknown. We
will test the hypothesis that dysregulation of neuronal Ca2+ signaling plays a key role in LEC-HPC circuit
dysfunction in early AD. Specifically, in experiments with the APPKI mouse model of AD, we will investigate
if normalization of the activity of two key proteins, the Ca2+-dependent phosphatase calcineurin (CaN) or
the prolyl isomerase, Pin1 rescues defects in LEC–HPC communication, function and stability in early
AD. Pin1 is a key target of CaN-mediated inhibition in neurons, directly leading to synaptic and neuronal loss. In
experiments with APPKI mice, we will also determine if dominant negative Pin1 accelerates defects in
LEC–HPC communication irrespective of CaN normalization in APPKI mice. We will use a combination of
molecular, biochemical, imaging, electrophysiological, behavioral and neuropathological techniques to address
these specific aims. The proposed studies, if successful, will provide a mechanistic understanding of early AD
evolution as well as a rationale for the use of CaN inhibitors such as FK506 or voclosporin to treat early AD.

## Key facts

- **NIH application ID:** 10890888
- **Project number:** 5R01AG071310-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** James S Malter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $737,032
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890888

## Citation

> US National Institutes of Health, RePORTER application 10890888, Calcium dysregulation and vulnerability of entorhinal cortex neurons in Alzheimer's disease (5R01AG071310-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10890888. Licensed CC0.

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