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

Authors :
Theresa L. Harvey
Joseph T. Coyle
Kevin Muszynski
Claire R. Galloway
Harry Pantazopoulos
Cathy C.Y. Huang
Yota Uno
Christian A. Botz-Zapp
Sabina Berretta
Jacki M. Rorabaugh
David Weinshenker
Darrick T. Balu
Source :
Neurobiol Dis, Neurobiology of Disease, Vol 130, Iss, Pp 104511-(2019)
Publication Year :
2019

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.

Details

Language :
English
Database :
OpenAIRE
Journal :
Neurobiol Dis, Neurobiology of Disease, Vol 130, Iss, Pp 104511-(2019)
Accession number :
edsair.doi.dedup.....858b5bff250d09a080bcb33c7a6148da