GSK3 inhibition promotes lysosomal biogenesis and the autophagic degradation of the Amyloid-β Precursor Protein
Parr, Callum × Carzaniga, Raffaela Gentleman, Steve Van Leuven, Fred Walter, Jochen Sastre, Magdalena #
American Society for Microbiology (ASM)
Molecular and Cellular Biology vol:32 issue:21 pages:4410-4418
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 effect 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 siRNA. 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 indicates 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 an increased propensity toward autophagic/lysosomal alterations in AD patients could have consequences for neuronal function.