# Enhancing Glutamate Transport in Age-related Cognitive Decline and Alzheimer's Disease

> **NIH NIH K76** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $157,587

## Abstract

PROJECT SUMMARY:
The long-term objective of the Paul B. Beeson Emerging Leaders Career Development Award in Aging (K76) is
to support the development of the candidate into a leading physician-scientist in translational neuroscience of
Aging and Alzheimer's disease (AD). The proposed K76 award will enable the candidate to develop the skills
necessary to design and conduct multi-modal scientifically rigorous studies to advance our understanding of
the pathophysiology of Aging and AD that will have a significant impact in the field. This overall objective will be
accomplished through a structured, supervised research experience along with formal didactic instruction
focused on (1) neurobiology of aging, AD, and glutamatergic neural systems, (2) structural brain analysis with
electron microscopy, (3) genomics and (4) leadership development. AD is a serious public health concern
associated with significant morbidity and mortality. There is a compelling need for studies that offer the
possibility to advance the neurobiological understanding of AD and aging, which is AD's major risk factor, and
the development of novel targets and more effective treatments.
The neural circuits affected in aging and in AD are similar, involving the glutamatergic connections among
cortical areas and with the hippocampal formation. In aging, synaptic changes occur with minimal neuronal
death while in AD, there is frank loss of neurons. With the goal of further understanding the susceptibility of
glutamatergic neural circuits to aging and AD that culminates in cognitive decline, the proposed project utilizes
a multi-dimensional investigative approach focusing on the major glutamate transporter in the brain, EAAT2.
EAAT2 plays a critical role in determining glutamate levels synaptically and extrasynaptically, and regulating
physiological glutamatergic neurotransmission, that all are critical for learning, memory, and synaptic health.
Importantly, EAAT2 activity is significantly decreased in both aging and AD, and associated with
neurodegeneration in the latter. This proposal investigates EAAT2's pathophysiological role in aging and AD
by, first, quantifying changes at the synaptic level, with correlative behavioral assays, and gene expression
profiles in aging and AD mouse models, and second, with an intervention with an EAAT2-enhancer, the
glutamate modulator riluzole. Moreover, this proposal uses a newly developed conditional EAAT2 knock-out
(KO) mouse for further mechanistic studies on EAAT2's impact on gene expression patterns and behavior in
the aging brain. These integrated aims will delineate the biology of EAAT2 in aging and AD brains at the
structural, molecular and functional levels and will test EAAT2 enhancement as a therapeutic target for age-
related cognitive decline and AD. This proposal builds on PI's recent work on glutamatergic dysregulation in
the vulnerable excitatory synapses in aging and AD, her outstanding leadership skills and on the very
extensive e...

## Key facts

- **NIH application ID:** 9933763
- **Project number:** 5K76AG054772-06
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ana C. Pereira
- **Activity code:** K76 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $157,587
- **Award type:** 5
- **Project period:** 2016-09-15 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933763

## Citation

> US National Institutes of Health, RePORTER application 9933763, Enhancing Glutamate Transport in Age-related Cognitive Decline and Alzheimer's Disease (5K76AG054772-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9933763. Licensed CC0.

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