Understanding How Inflammation Kills Brain Cells During Alzheimer’s Disease Progression

Darrick T. Balu, PhD
McLean Hospital, Harvard Medical School (Belmont, MA)
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2022
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2019034S
Award Type:
Standard
Award Region:
US Northeastern
Darrick T. Balu, PhD

Glial D-serine in the Amygdala and Alzheimer's Disease

Summary

As Alzheimer’s disease progresses, inflammation changes the characteristics of particular cells in the brain called, astrocytes. These transformed astrocytes, which are classified as inflammatory astrocytes, release chemical compounds that are toxic to another population of brain cells, called neurons. This grant aims to understand how one of the molecules released by reactive astrocytes kills neurons, in hopes of finding new drugs to treat patients with Alzheimer’s disease.

Details

The overall goal of my grant is to understand how D-serine released by inflammatory astrocytes kills neurons, in hopes of finding new drugs to treat patients with Alzheimer’s disease (AD).

The predominant strategy for developing treatments for AD has focused on reducing amyloid burden in the brain. Unfortunately, no drug using this approach has improved cognitive and functional outcomes, suggesting that once clinical AD symptoms emerge, disease progression becomes independent of Aβ production. In addition to plaques and tangles, inflammatory (reactive) astrocytes are a neuropathological hallmark of AD. We have shown that production of the N-methyl-D-aspartate receptor (NMDAR) co-agonist, D-serine, by reactive astrocytes following traumatic brain injury is detrimental to synaptic plasticity and memory. My grant proposes to test the novel hypothesis that D-serine released from reactive astrocytes causes cell death in AD. Aim 1 will use brain tissue from subjects with an AD diagnosis, as well as from 5x familial AD (5xFAD) transgenic mice, to quantify the expression of serine racemase (SR), the enzyme that produces D-serine, in neurotoxic, inflammatory astrocytes of the amygdala. In Aim 2, we will inject Aβ1-42 a oligomers (oAβ) into the amygdala of WT mice and mice that lack SR specifically in astrocytes (SRKOGFAP) to determine whether oAβ causes glial D-serine production, cell death, and amygdala-dependent memory impairments due to over-activation of extrasynaptic NMDARs.  Aim 3 will determine whether a glucagon-like peptide-1-receptor agonist (Exenatide), which has neuroprotective properties, can prevent the expression of SR in inflammatory astrocytes and amygdala-dependent cognitive impairments in
5xFAD mice. 

My award proposes a novel theoretical concept linking the production of D-serine in reactive astrocytes to the overstimulation of extrasynaptic NMDARs and neuronal loss. By eliminating SR from astrocytes in an inducible and cell-type specific manner in mice, we will determine whether preventing astrocytic D-serine production reduces extrasynaptic NMDAR-dependent signaling, neurotoxicity, and memory impairments induced by oAβ. Finally, we will test whether Exenatide, an FDA approved drug that has shown disease-modifying effects in Parkinson’s disease, blocks the conversion of A1 astrocytes in 5xFAD mice, thereby reducing both astrocytic D-serine production and extrasynaptic NMDAR activation, as well as normalizing memory. 

Results from this proposal 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 degeneration.

About the Researcher

Dr. Balu’s education and training were in neuropsychopharmacology, where he earned his PhD in Pharmacology from the University of Pennsylvania (2008), studying the mechanisms of action of antidepressant drugs in various genetic mouse models. He then began his postdoctoral training in the fall of 2008 at McLean Hospital. Dr. Balu’s work focused on elucidating the mechanisms by which hypofunction of the NMDA receptor, via reduced co-agonist availability (D-serine), can lead to the synaptic and behavioral abnormalities associated with schizophrenia. In 2014, he was promoted to Assistant Professor in the Department of Psychiatry (Harvard Medical School) and in 2015 became director of his own laboratory, the Translational Psychiatry Laboratory. While Dr. Balu’s laboratory continues to pursue investigations into the neurobiology and treatment of schizophrenia, new lines of investigation include how D-serine produced by reactive astrocytes are involved in the pathophysiology of traumatic brain injury and Alzheimer’s disease.

Personal Story

Since my undergraduate years, I have been fascinated in how the brain functions and what goes awry in disease. After writing a research paper for one of my classes on Alzheimer’s disease (AD), I have had an interest in understanding the causes of AD and what new treatments could be developed to help patients. Even though my graduate and postdoctoral work focused on the neurobiology of psychiatric disorders, I continued to follow the AD literature. My recent findings on traumatic brain injury led me to investigate whether similar changes occur in the brains of AD patients. The results I obtained using human post-mortem brain tissue and rodent models of AD in turn, helped me secure this award. The financial support from the BrightFocus Foundation will enable my laboratory to conduct research that is in the early stages of development, at a time when it is difficult to obtain federal funding. Therefore, I am extremely grateful to the donors of the BrightFocus Foundation for recognizing the potential importance of my research project, as well as to the patients and their families for their gift of brain donation that will enable us to do our research. Positive results from this award will hopefully identify novel drug targets related to neuroinflammation that could lead to improved therapies for patients with mild to advanced AD when anti-amyloid strategies appear to be ineffective.

Publications

Wolosker, H. and Balu, D.T., 2020. d-Serine as the gatekeeper of NMDA receptor activity: implications for the pharmacologic management of anxiety disorders. Translational Psychiatry, 10(1), pp.1-10. PMID: 32518273 PubMed Icon Google Scholar Icon

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