# Dysregulation of glutamate transporter-dependent neurovascular coupling in Alzheimer's disease

> **NIH NIH R01** · DREXEL UNIVERSITY · 2024 · $430,678

## Abstract

Dysregulation of glutamate transporter-dependent neurovascular coupling in Alzheimer’s disease
Decreases in cerebral blood flow, glucose metabolism, and impairment of neurovascular coupling are
associated with a number of neurodegenerative disease and cognitive decline, including Alzheimer’s
disease
and may precede or exacerbate disease. These deficits are also accompanied by loss of glutamate
transporters, Na+/Ca2+ exchanger (NCX) isoforms, and deficits in mitochondrial dynamics and
 Over the last few years, we have demonstrated that astrocytic Glu transporters couple to
increases in intracellular Ca2+ through reversed operation of Na+/Ca2+ exchange (NCX). We demonstrated
that mitochondria co-compartmentalize with Glu transporters in astrocyte processes and that
mitochondrial positioning relative to Glu transporters and synapses is dependent upon Ca2+ and that
mitochondria shape Ca2+ signal. Moreover, we found that glutamate transport is sufficient to evoke
increases in arteriole diameter (transporter-dependent NVC) downstream of reversed NCX. These and
other observations have prompted the central hypothesis that Glu transport and reversed Na+/Ca2+
exchange form a functional signaling pathway in astrocytes that is modulated by mitochondria and that
excessive activation of this pathway contributes to pathology observed during the development of AD. In
bioenergetics.
Aim 1Determine if transporter-mediated NVC is impaired in AD. In Aim 2, we will determine if altered
astrocytic mitochondria distribution function effects of AD. Using in vivo imaging or cortical blood flow,
local application of glutamate transporters, and selective manipulation (genetic and pharmacologic) of
downstream signaling and mitochondrial dynamics, we will dissect the relationship between glutamate
transport, NCX, and mitochondria in the control of cortical blood flow and determine if loss of this
signaling axis impacts blood flow regulation/neurovascular coupling in AD.

## Key facts

- **NIH application ID:** 10820458
- **Project number:** 5R01AG081929-02
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Joshua Goodyear Jackson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $430,678
- **Award type:** 5
- **Project period:** 2023-04-15 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820458

## Citation

> US National Institutes of Health, RePORTER application 10820458, Dysregulation of glutamate transporter-dependent neurovascular coupling in Alzheimer's disease (5R01AG081929-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10820458. Licensed CC0.

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