title: γ-Secretase component presenilin is important for microglia β-amyloid clearance.
abstract: OBJECTIVE
  The cleavage of amyloid precursor protein by γ-secretase is an important aspect of the pathogenesis of Alzheimer's disease. γ-Secretase also cleaves other membrane proteins (eg, Notch), which control cell development and homeostasis. Presenilin 1 and 2 are considered important determinants of the γ-secretase catalytic site. Our aim was to investigate whether γ-secretase can be important for microglial phagocytosis of Alzheimer's disease β-amyloid.
  
  
  METHODS
  We investigated the role of γ-secretase in microglia activity toward β-amyloid phagocytosis in cell culture using γ-secretase inhibitors and small hairpin RNA and presenilin-deficient mice.
  
  
  RESULTS
  We found that γ-secretase inhibitors impair microglial activity as measured in gene expression, protein levels, and migration ability, which resulted in a reduction of soluble β-amyloid phagocytosis. Moreover, microglia deficient in presenilin 1 and 2 showed impairment in phagocytosis of soluble β-amyloid. Dysfunction in the γ-secretase catalytic site led to an impairment in clearing insoluble β-amyloid from brain sections taken from an Alzheimer's disease mouse model when compared to microglia from wild-type mice.
  
  
  CONCLUSIONS
  We suggest for the first time, a dual role for γ-secretase in Alzheimer's disease. One role is the cleavage of the amyloid precursor protein for pathologic β-amyloid production and the other is to regulate microglia activity that is important for clearing neurotoxic β-amyloid deposits. Further studies of γ-secretase-mediated cellular pathways in microglia may provide useful insights into the development of Alzheimer's disease and other neurodegenerative diseases, providing future avenues for therapeutic intervention.
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Dorit
authors.initials: D
authors.lastname: Farfara
authors.forename: Dorit
authors.initials: D
authors.lastname: Trudler
authors.forename: Niva
authors.initials: N
authors.lastname: Segev-Amzaleg
authors.forename: Ronit
authors.initials: R
authors.lastname: Galron
authors.forename: Reuven
authors.initials: R
authors.lastname: Stein
authors.forename: Dan
authors.initials: D
authors.lastname: Frenkel
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D017737:Macrophages, Peritoneal / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism / Q000502:physiology; D010587:Phagocytosis / Q000502:physiology; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology*; D053763:Presenilins / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014162:Transfection / Q000379:methods
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053763:Presenilins; D053829:Amyloid Precursor Protein Secretases