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Updated: Jul 13, 2026
Saccharomyces cerevisiae Models of Alzheimer's Disease to Screen Genes, Mutations, and Chemicals Affecting Amyloid Beta Production by γ-Secretase
Published on: June 24, 2025
Induction of serine racemase expression and D-serine release from microglia by secreted amyloid precursor protein
Shengzhou Wu1, Anthony S Basile, Steven W Barger
1Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Abstract:
Alzheimer's disease (AD) involves neuronal loss and reduction of synaptic density in specific brain region. Some of the neuronal deaths are associated with excitotoxicity. We previously reported that amyloid beta-peptide (Abeta) induced release of N-methyl-D-aspartate receptor (NMDA-R) co-agonists, including glutamate and D-serine. The induction of D-serine production by Abeta involves transcriptional and/or translational regulation of serine racemase gene. Similarly, we report here that conditioned medium from microglia treated with secreted amyloid precursor protein (sAPP) contained elevated levels of D-serine. In microglia, sAPP increased the steady-state dimeric protein level of serine racemase. Promoter-reporter and mRNA analyses suggested that serine racemase is transcriptionally induced by sAPP. These data extend the link between excitotoxicity and neuroinflammation. D-serine may cooperate with glutamate to link neuroinflammation with excitotoxicity, suggesting a pathogenic mechanism applicable to neuronal death in AD and other neurodegenerative diseases.
Insights
Amyloid beta and microglia activation in Alzheimer's disease (AD) increase D-serine levels, contributing to excitotoxicity and neuronal death. This links neuroinflammation to neurodegeneration in AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Alzheimer's disease (AD) is characterized by neuronal loss and synaptic density reduction.
- Neuronal death in AD can be linked to excitotoxicity, a process involving overstimulation of neurons.
- Amyloid beta-peptide (Abeta) has been implicated in releasing glutamate and D-serine, NMDA-R co-agonists.
Purpose of the Study:
- To investigate the role of secreted amyloid precursor protein (sAPP) in D-serine production by microglia.
- To elucidate the molecular mechanisms underlying sAPP-induced D-serine production.
- To extend the understanding of the link between neuroinflammation and excitotoxicity in AD pathogenesis.
Main Methods:
- Culturing microglia and treating them with sAPP.
- Measuring D-serine levels in conditioned medium.
- Analyzing serine racemase gene expression and protein levels using promoter-reporter assays and mRNA analysis.
Main Results:
- Conditioned medium from sAPP-treated microglia showed elevated D-serine levels.
- sAPP treatment increased serine racemase protein levels in microglia.
- Serine racemase was transcriptionally induced by sAPP, as indicated by promoter-reporter and mRNA analyses.
Conclusions:
- sAPP, a protein fragment involved in AD, induces D-serine production in microglia.
- This induction occurs via transcriptional regulation of the serine racemase gene.
- D-serine, in conjunction with glutamate, may mediate the link between neuroinflammation and excitotoxicity in Alzheimer's disease and other neurodegenerative conditions.
