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

Darrick T. Balu, Harry Pantazopoulos, Cathy C.Y. Huang, Kevin Muszynski, Theresa Lynn Harvey, Yota Uno, Jacki M. Rorabaugh, Claire R. Galloway, Christian Botz-Zapp, Sabina Berretta, David Weinshenker, Joseph T. Coyle

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish
Article number104511
JournalNeurobiology of Disease
Volume130
DOIs
StatePublished - Oct 2019

Keywords

  • Complement C3
  • Death associated protein kinase
  • Entorhinal cortex
  • Extrasynaptic
  • Glial fibrillary acidic protein
  • Hippocampus
  • N-methyl-D-asparate receptor
  • Tg-F344AD

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