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A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes
Published on: February 5, 2018
The endocytic pathway in microglia during health, aging and Alzheimer's disease
Santiago Solé-Domènech1, Dana L Cruz2, Estibaliz Capetillo-Zarate3
1Experimental Dementia Unit, Department of Medicine, Lund University, Sölvegatan 19, BMC B11, 221 84 Lund, Sweden; Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, United States.
Abstract:
Microglia, the main phagocytes of the central nervous system (CNS), are involved in the surveillance and maintenance of nervous tissue. During normal tissue homeostasis, microglia migrates within the CNS, phagocytose dead cells and tissue debris, and modulate synapse pruning and spine formation via controlled phagocytosis. In the event of an invasion by a foreign body, microglia are able to phagocytose the invading pathogen and process it proteolytically for antigen presentation. Internalized substrates are incorporated and sorted within the endocytic pathway and thereafter transported via complex vesicular routes. When targeted for degradation, substrates are delivered to acidic late endosomes and lysosomes. In these, the enzymatic degradation relies on pH and enzyme content. Endocytosis, sorting, transport, compartment acidification and degradation are regulated by complex signaling mechanisms, and these may be altered during aging and pathology. In this review, we discuss the endocytic pathway in microglia, with insight into the mechanisms controlling lysosomal biogenesis and pH regulation. We also discuss microglial lysosome function associated with Alzheimer's disease (AD) and the mechanisms of amyloid-beta (Aβ) internalization and degradation. Finally, we explore some therapies currently being investigated to treat AD and their effects on microglial response to Aβ, with insight in those involving enhancement of lysosomal function.
Insights
Microglia, the brain's immune cells, use their endocytic pathway to clear cellular debris and pathogens. This process is crucial for brain health and is impaired in Alzheimer's disease, offering therapeutic targets.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are the primary immune cells in the central nervous system (CNS), responsible for tissue surveillance and homeostasis.
- They perform essential functions like phagocytosis of debris, synaptic pruning, and pathogen clearance via the endocytic pathway.
- Dysregulation of microglial endocytic function is implicated in aging and neurodegenerative diseases, including Alzheimer's disease (AD).
Purpose of the Study:
- To review the microglial endocytic pathway, focusing on lysosomal biogenesis and pH regulation.
- To examine the role of microglial lysosomal function in Alzheimer's disease (AD).
- To explore therapeutic strategies targeting microglial lysosomal function for AD treatment.
Main Methods:
- Literature review of microglial endocytic pathways.
- Analysis of lysosomal mechanisms in microglia.
- Examination of amyloid-beta (Aβ) internalization and degradation by microglia.
- Review of current AD therapies affecting microglial response.
Main Results:
- The endocytic pathway in microglia involves complex sorting, transport, and degradation processes within vesicular compartments.
- Lysosomal function, including biogenesis and pH regulation, is critical for efficient degradation of internalized material.
- Impaired lysosomal function in microglia contributes to AD pathogenesis, particularly in handling amyloid-beta (Aβ).
Conclusions:
- Understanding microglial endocytosis and lysosomal mechanisms is key to addressing CNS homeostasis and neurodegeneration.
- Therapeutic strategies aimed at enhancing microglial lysosomal function show promise for treating Alzheimer's disease.
- Targeting microglial pathways offers a novel approach for managing neuroinflammatory and neurodegenerative conditions.
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