Effect of glycogen synthase kinase 3 β-mediated presenilin 1 phosphorylation on amyloid β production is negatively regulated by insulin receptor cleavage.

• Maesako, M

• Uemura, K

• Kubota, M

• Hiyoshi, K

• Ando, K

• Kuzuya, A

• Kihara, T

• Asada, M

• Akiyama, H

• Kinoshita, A

Bibliographic Information

Other Title

• Effect of glycogen synthase kinase 3 beta-mediated presenilin 1 phosphorylation on amyloid beta production is negatively regulated by insulin receptor cleavage

Abstract

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.

Journal

• Neuroscience

  Neuroscience 177 298-307, 2011-03-17

  Elsevier Ltd.

Keywords

• Alzheimer's disease
• presenilin 1
• phosphorylation
• regulated intramembrane proteolysis
• insulin receptor
• Akt

Details

• CRID: 1050845760642727296
• NII Article ID: 120002970866
• NII Book ID: AA0075489X
• ISSN: 03064522
• DOI: 10.1016/j.neuroscience.2010.12.017
• HANDLE: 2433/139539
• Web Site: https://api.elsevier.com/content/article/PII:S0306452210015952?httpAccept=text/xml
• Web Site: https://api.elsevier.com/content/article/PII:S0306452210015952?httpAccept=text/plain
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN