title: The endocytic pathway in microglia during health, aging and Alzheimer's disease.
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.
authors.affiliation: Experimental 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.
authors.forename: Santiago
authors.initials: S
authors.lastname: Solé-Domènech
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, United States.
authors.forename: Dana L
authors.initials: DL
authors.lastname: Cruz
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, United States; IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain; Achucarro Basque Center for Neurosciences, 48170 Zamudio, Spain; Department of Neuroscience, Faculty of Medicine and Odontology, University of the Basque Country EHU/UPV, Leioa, Spain.
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Capetillo-Zarate
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, United States. Electronic address: frmaxfie@med.cornell.edu.
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Maxfield
mesh_terms: D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D017628:Microglia / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides
keywords: Alzheimer’s disease; Amyloid-beta; Endocytosis; Lysosome; MITF; Microglia; TFEB