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Published on: January 30, 2014
γ-Secretase in microglia - implications for neurodegeneration and neuroinflammation
Jochen Walter1, Nadja Kemmerling1, Patrick Wunderlich1
1Department of Neurology, University of Bonn, Bonn, Germany.
Abstract:
γ-Secretase is an intramembrane cleaving protease involved in the generation of the Alzheimer's disease (AD)-associated amyloid β peptide (Aβ). γ-Secretase is ubiquitously expressed in different organs, and also in different cell types of the human brain. Besides the involvement in the proteolytic generation of Aβ from the amyloid precursor protein, γ-secretase cleaves many additional protein substrates, suggesting pleiotropic functions under physiological and pathophysiological conditions. Microglia exert important functions during brain development and homeostasis in adulthood, and accumulating evidence indicates that microglia and neuroinflammatory processes contribute to the pathogenesis of neurodegenerative diseases. Recent studies demonstrate functional implications of γ-secretase in microglia, suggesting that alterations in γ-secretase activity could contribute to AD pathogenesis by modulation of microglia and related neuroinflammatory processes during neurodegeneration. In this review, we discuss the involvement of γ-secretase in the regulation of microglial functions, and the potential relevance of these processes under physiological and pathophysiological conditions. This article is part of the series "Beyond Amyloid".
Insights
Gamma-secretase, a protease linked to Alzheimer's disease (AD), regulates microglial functions. Its activity impacts neuroinflammation and neurodegeneration, offering new therapeutic insights.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Gamma-secretase is an intramembrane protease crucial for amyloid beta peptide (Aβ) generation in Alzheimer's disease (AD).
- This protease has diverse substrates, indicating broad physiological and pathophysiological roles beyond Aβ production.
- Microglia, the brain's immune cells, are increasingly recognized for their involvement in neurodegenerative disease pathogenesis.
Purpose of the Study:
- To review the role of gamma-secretase in regulating microglial functions.
- To explore the implications of gamma-secretase activity in microglial-mediated neuroinflammation.
- To discuss the potential relevance of these interactions in AD and other neurodegenerative conditions.
Main Methods:
- Literature review of studies investigating gamma-secretase and microglial function.
- Analysis of research on neuroinflammation and neurodegeneration.
- Synthesis of findings on gamma-secretase substrates and their impact on microglia.
Main Results:
- Gamma-secretase activity influences microglial functions, including their role in brain homeostasis and development.
- Alterations in gamma-secretase activity may modulate neuroinflammatory processes driven by microglia.
- These modulations have potential implications for the pathogenesis of neurodegenerative diseases like AD.
Conclusions:
- Gamma-secretase plays a significant role in regulating microglial functions and neuroinflammation.
- Understanding gamma-secretase's impact on microglia could reveal novel therapeutic targets for neurodegenerative diseases.
- This review highlights the importance of exploring gamma-secretase beyond its role in amyloid beta production.
