# Defining the Role of Glial D-serine in Alzheimer's Disease

> **NIH NIH R03** · MCLEAN HOSPITAL · 2020 · $164,000

## Abstract

Alzheimer’s disease (AD) is the most common cause of late-onset dementia, affecting more than 5 million
Americans. AD is characterized by the deposition of amyloid beta (Ab) aggregates that form plaques and
accumulation of neurofibrillary tangles. The prevailing hypothesis is that Ab fibrils damage neurons causing the
accumulation of tau-related neurofibrillary tangles and ultimately neurodegeneration. As such, the predominant
strategy for developing treatments for AD has focused on targets that could reduce amyloid burden in the
brain. Unfortunately, no drug using this approach has improved cognitive and functional outcomes in large-
scale clinical trials, even in patients with mild-to-moderate AD, suggesting that once clinical AD symptoms
emerge disease progression becomes independent of Ab production. In addition to plaques and tangles,
activated glial cells, including astrocytes and microglia, are neuropathological hallmarks of AD. Although the
precise mechanism(s) by which reactive glia contribute to AD pathophysiology is unclear, recent findings show
that activated microglia induce type A1 reactive astrocytes that are neurotoxic through unidentified
mechanisms. We have shown that the N-methyl-D-aspartate receptor (NMDAR) co-agonist, D-serine, which is
produced by reactive astrocytes following traumatic brain injury (TBI) in mice, is responsible for the damaging
effects of TBI on synaptic plasticity and memory. Furthermore, glutamate excitotoxicity has been implicated in
AD pathophysiology, as supported by the use of memantine, an uncompetitive NMDAR partial antagonist, to
treat late-stage AD patients. Thus, we propose to test the novel hypothesis that glial released D-serine causes
glutamate-induced excitotoxicity in AD by binding to extrasynaptic NMDARs. Aim 1 will use dual-antigen
immunofluorescence on human brain tissue from age-matched, non-demented controls (Braak stages I/II) and
subjects with an AD diagnosis (Braak stages III-VI) to quantify the expression of serine racemase (SR), the
enzyme that produces D-serine, in reactive astrocytes and microglia. This aim will also determine if SR is
expressed by A1 type reactive astrocytes. Aim 2 will use RNA-seq to profile SR mRNA transcripts in controls
and subjects with AD, as well as in tissue from wild-type (WT) and TgF344 transgenic AD rats. Aim 3 will use
transgenic mice lacking SR either in astrocytes or microglia to determine whether the D-serine produced by
reactive glia following the intrahippocampal injection of soluble b-amyloid oligomers is neurotoxic. This grant
will help to identify novel pathways related to SR and D-serine that could lead to improved therapies for
patients with mild to advanced AD when anti-amyloid strategies appear to be ineffective. Our findings will have
important implications not only for AD, but for other diseases associated with SR-expressing reactive
astrocytes, and highlight this pathway as a potential therapeutic target to prevent neuronal degeneratio...

## Key facts

- **NIH application ID:** 10017812
- **Project number:** 5R03AG063201-02
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** DARRICK T BALU
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $164,000
- **Award type:** 5
- **Project period:** 2019-09-15 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017812

## Citation

> US National Institutes of Health, RePORTER application 10017812, Defining the Role of Glial D-serine in Alzheimer's Disease (5R03AG063201-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10017812. Licensed CC0.

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