Effect of glycogen synthase kinase 3 β-mediated presenilin 1 phosphorylation on amyloid β production is negatively regulated by insulin receptor cleavage.
Presenilin 1 (PS1), a causative molecule of familial Alzheimer's disease (AD), is known to be an unprimed substrate of glycogen synthase kinase 3 β (GSK3β) [Twomey and McCarthy (2006) FEBS Lett 580:4015-4020] and is phosphorylated at serine 353, 357 residues in its cytoplasmic loop region [Kirschenbaum et al. (2001) J Biol Chem 276:7366-7375]. In this report, we investigated the effect of PS1 phosphorylation on AD pathophysiology and obtained two important results--PS1 phosphorylation increased amyloid β (Aβ) 42/40 ratio, and PS1 phosphorylation was enhanced in the human AD brains. Interestingly, we demonstrated that PS1 phosphorylation promoted insulin receptor (IR) cleavage and the IR intracellular domain (IR ICD) generated by γ-secretase led to a marked transactivation of Akt (PKB), which down-regulated GSK3β activity. Thus, the cleavage of IR by γ-secretase can inhibit PS1 phosphorylation in the long run. Taken together, our findings indicate that PS1 phosphorylation at serine 353, 357 residues can play a pivotal role in the pathology of AD and that the dysregulation of this mechanism may be causally associated with its pathology.
School of Human Health Sciences, Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
M
M
Maesako
K
K
Uemura
M
M
Kubota
K
K
Hiyoshi
K
K
Ando
A
A
Kuzuya
T
T
Kihara
M
M
Asada
H
H
Akiyama
A
A
Kinoshita
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006868:Hydrolysis; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000235:genetics; D053764:Presenilin-1 / Q000737:chemistry / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism* / Q000502:physiology; D012694:Serine / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D053764:Presenilin-1; D012694:Serine; D011972:Receptor, Insulin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3