Neurotoxic astrocytes express the D-serine synthesizing enzyme, serine racemase, in Alzheimer’s disease
| Autor: | 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 |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Excitotoxicity Racemases and Epimerases Hippocampus Neuropathology medicine.disease_cause Glial fibrillary acidic protein Article lcsh:RC321-571 Serine 03 medical and health sciences 0302 clinical medicine Alzheimer Disease medicine Animals Entorhinal Cortex Humans lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry biology business.industry Complement C3 Entorhinal cortex Extrasynaptic Rats Disease Models Animal 030104 developmental biology Neurology N-methyl-d-asparate receptor Serine racemase Astrocytes biology.protein NMDA receptor Rats Transgenic business Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Neurobiol Dis Neurobiology of Disease, Vol 130, Iss, Pp 104511-(2019) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|