Neurotoxic astrocytes express the D-serine synthesizing enzyme, serine racemase, in Alzheimer's disease

• Type of Material: Article
• Authors: Darrick T. Balu, Harvard Medical School; Harry Pantazopoulos, Harvard Medical School; Cathy C. Y. Huang, Harvard Medical School; Kevin Muszynski, Harvard Medical School; Theresa Lynn Harvey, Harvard Medical School; Yota Uno, Harvard Medical School; Jacki M. Rorabaugh, Emory University; Claire R. Galloway, Emory University; Christian Botz-Zapp, Emory University; Sabina Berretta, Harvard Medical School; David Weinshenker, Emory University; Joseph T. Coyle, Harvard Medical School
• Language: English
• Date: 2019-10-01
• Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2019 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2019.104511
• Title of Journal or Parent Work: NEUROBIOLOGY OF DISEASE
• Volume: 130
• Start Page: 104511
• End Page: 104511
• Grant/Funding Information: The research described in this manuscript was supported by 5R00MH099252-04 and a subcontract of R01NS098740-02 to DTB, Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2702) of the Japan Society for the Promotion of Science to YU, RF1AG047667 to DW, R01MH104488 and R01MH105608 to SB, and R01MH51290-18 to JTC.
• Keywords: Neurosciences & Neurology; Tg-F344AD; Hippocampus; MICE; Entorhinal cortex; DENDRITIC ARCHITECTURE; Life Sciences & Biomedicine; Extrasynaptic; Glial fibrillary acidic protein; ACTIVATION; NMDA RECEPTOR; N-methyl-D-asparate receptor; BIPOLAR DISORDER; GLUTAMATE; MOUSE MODEL; BRAIN; STEREOLOGY; Neurosciences; Death associated protein kinase; RAT; Science & Technology; Complement C3

Abstract

Although β-amyloid plaques are a well-recognized hallmark of Alzheimer's disease (AD) neuropathology, no drugs reducing amyloid burden have shown efficacy in clinical trials, suggesting that once AD symptoms emerge, disease progression becomes independent of Aβ production. Reactive astrocytes are another neuropathological feature of AD, where there is an emergence of neurotoxic (A1) reactive astrocytes. We find that serine racemase (SR), the neuronal enzyme that produces the N-methyl-D-aspartate receptor (NMDAR) co-agonist D-serine, is robustly expressed in A1-reactive neurotoxic astrocytes in the hippocampus and entorhinal cortex of AD subjects and an AD rat model. Furthermore, we observe intracellular signaling changes consistent with increased extra-synaptic NMDAR activation, excitotoxicity and decreased neuronal survival. Thus, reducing neurotoxic D-serine release from A1 inflammatory astrocytes could have therapeutic benefit for mild to advanced AD, when anti-amyloid strategies are ineffective.