Microglial cathepsin B as a key driver of inflammatory brain diseases and brain aging
1Department of Pharmacology, Faculty of Pharmacy, Yasuda Women's University, Hiroshima, Japan.
Abstract:
Interleukin-1β is a potent proinflammatory cytokine that plays a key role in the pathogenesis of the brain aging and diverse range of neurological diseases including Alzheimer's disease, Parkinson's disease, stroke and persistent pain. Activated microglia are the main cellular source of interleukin-1β in the brain. Cathepsin B is associated with the production and secretion of interleukin-1β through pyrin domain-containing protein 3 inflammasome-independent processing of procaspase-3 in the phagolysosomes. The leakage of cathepsin B from the endosomal-lysosomal system during aging is associated with the proteolytic degradation of mitochondrial transcription factor A, which can stabilize mitochondrial DNA. Therefore, microglial cathepsin B could function as a major driver for inflammatory brain diseases and brain aging. Orally active and blood-brain barrier-permeable specific inhibitors for cathepsin B can be potentially effective new pharmaceutical interventions against inflammatory brain diseases and brain aging.
Insights
Microglial cathepsin B drives brain aging and inflammatory diseases by promoting interleukin-1β. Inhibiting cathepsin B may offer new treatments for neurological conditions and brain aging.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Interleukin-1β (IL-1β) is a key inflammatory cytokine in brain aging and neurological diseases like Alzheimer's.
- Activated microglia are the primary source of IL-1β in the brain.
- Cathepsin B contributes to IL-1β production via inflammasome-independent pathways.
Purpose of the Study:
- To investigate the role of microglial cathepsin B in brain aging and inflammatory neurological diseases.
- To explore cathepsin B as a therapeutic target for these conditions.
Main Methods:
- Analysis of cathepsin B's involvement in IL-1β production and secretion.
- Examination of cathepsin B's impact on mitochondrial DNA stability during aging.
- Assessment of cathepsin B's role in inflammatory pathways within the brain.
Main Results:
- Cathepsin B facilitates IL-1β production and secretion through procaspase-3 processing in phagolysosomes.
- Aging-associated cathepsin B leakage degrades mitochondrial transcription factor A, destabilizing mitochondrial DNA.
- Microglial cathepsin B is identified as a significant contributor to inflammatory brain diseases and aging.
Conclusions:
- Microglial cathepsin B is a critical mediator of brain aging and inflammatory neurological disorders.
- Targeting cathepsin B with specific inhibitors that cross the blood-brain barrier presents a promising therapeutic strategy.
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