# Mechanisms of Synaptic Protection in Cognitive Resilence to Alzheimer's Disease Neuropathology

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2021 · $458,529

## Abstract

PROJECT SUMMARY/ABSTRACT
 There is ample scientific evidence that toxic oligomers of A and tau, considered the major neuropathological
factors in Alzheimer’s disease (AD) lead to synaptic failure and dementia, but is also well recognized that some
individuals can accumulate significant AD neuropathology without clinical manifestations. The established
existence of these non-demented with high pathology (NDAN) individuals, suggests that if binding of A
oligomers to specific AMPA and NMDA receptors trigger Ca2+ disruption and synaptic failure in AD, then
modifications in the pharmacology or abundance of these receptors may underlie synaptic protection in NDAN
individuals. However, little is known about the pharmacological sensitivity of human native glutamate receptors
to A and tau oligomers in AD, or their role in resilience, as information primarily has come from studies in animal
models of AD or protein expression systems. Here we will fill in this critical gap of our current knowledge by
identifying the synaptic proteins involved in glutamatergic signaling and Ca2+ dysregulation in AD, evaluating
whether modifications of these proteins correlate with metrics of synaptic preservation in NDAN individuals, and
determining whether A and tau oligomers differentially activate human native synaptic receptors in NDAN
individuals compared to those in AD and controls. The present proposal will test the hypothesis that differences
in the regional abundance of Ca2+-permeable glutamate receptors and/or their pharmacodynamics profile in
response to oligomeric species distinguishes NDAN from AD and control subjects. We will test our hypothesis
in a rigorously characterized cohort of postmortem NDAN, AD, and age-matched normal cognitive control brains,
using two unique and innovative approaches: Microtransplantation of Synaptic Membranes (MSM) to evaluate
receptor electrical activity of native receptors complexes isolated from autopsy human brain, and
Electrophysiologically-anchored Dataset Analysis (EDA) to identify proteins that correlate with receptors’ activity.
The rationale for this project is that determining the pharmacological sensitivity of the natural targets of toxic
oligomers is likely to offer a strong framework whereby novel strategies to AD therapy can be developed. Two
complementary aims are proposed. Aim 1 will identify the impact of gene expression modifications on the
abundance and function of Ca2+ permeable human native glutamate receptors in NDAN compared to AD and
control cases, and aim 2 will evaluate the efficacy of A and tau oligomers to activate human native synaptic
glutamate receptors from NDAN, AD and control cases. At the end of the proposed research we expect to have
defined the mechanisms whereby oligomers trigger synaptic Ca2+ dysregulation in AD but not in NDAN subjects.
These results will lay the foundations for the future development of innovative target-directed pharmacologic
interventions to promote synaptic resilien...

## Key facts

- **NIH application ID:** 10099066
- **Project number:** 1R01AG070255-01
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Agenor Limon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $458,529
- **Award type:** 1
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10099066

## Citation

> US National Institutes of Health, RePORTER application 10099066, Mechanisms of Synaptic Protection in Cognitive Resilence to Alzheimer's Disease Neuropathology (1R01AG070255-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10099066. Licensed CC0.

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