title: Glycogen synthase kinase 3 inhibition promotes lysosomal biogenesis and autophagic degradation of the amyloid-β precursor protein.
abstract: Alzheimer's disease (AD) has been associated with altered activity of glycogen synthase kinase 3 (GSK3) isozymes, which are proposed to contribute to both neurofibrillary tangles and amyloid plaque formation. However, the molecular basis by which GSK3 affects the formation of Aβ remains unknown. Our aim was to identify the underlying mechanisms of GSK3-dependent effects on the processing of amyloid precursor protein (APP). For this purpose, N2a cells stably expressing APP carrying the Swedish mutation were treated with specific GSK3 inhibitors or transfected with GSK3α/β short interfering RNA. We show that inhibition of GSK3 leads to decreased expression of APP by enhancing its degradation via an increase in the number of lysosomes. This induction of the lysosomal/autophagy pathway was associated with nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis. Our data indicate that GSK3 inhibition reduces Aβ through an increase of the degradation of APP and its carboxy-terminal fragment (CTF) by activation of the lysosomal/autophagy pathway. These results suggest that an increased propensity toward autophagic/lysosomal alterations in AD patients could have consequences for neuronal function.
authors.affiliation: Division of Brain Sciences, Imperial College London, London, United Kingdom.
authors.forename: Callum
authors.initials: C
authors.lastname: Parr
authors.forename: Raffaela
authors.initials: R
authors.lastname: Carzaniga
authors.forename: Steve M
authors.initials: SM
authors.lastname: Gentleman
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
authors.forename: Magdalena
authors.initials: M
authors.lastname: Sastre
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D058225:Plaque, Amyloid; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D034741:RNA, Small Interfering; C064972:TFEB protein, human; D038362:Glycogen Synthase Kinase 3