Roles of AMP-activated protein kinase in Alzheimer's disease

Zhiyou Cai, Liang Jun Yan, Keshen Li, Sohel H. Quazi, Bin Zhao

Research output: Contribution to journalReview article

91 Citations (Scopus)

Abstract

AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis and a central player in glucose and lipid metabolism, is potentially implicated in the pathogenesis of Alzheimer's disease (AD). AMPK activity decreases in AD brain, indicating decreased mitochondrial biogenesis and function. Emerging evidence demonstrates that AMPK activation is a potential target for improving perturbed brain energy metabolism that is involved in the pathogenesis of AD. The roles of AMPK in the pathogenesis of AD include β-amyloid protein (Aβ) generation and tau phosphorylation. In particular, AMPK may regulate Aβ generation through modulating neuronal cholesterol and sphingomyelin levels and through regulating APP distribution in the lipid rafts. AMPK is activated by phosphorylation of Thr-172 by LKB1 complex in response to increase in the AMP/ATP ratio and by calmodulin-dependent protein kinase kinase-beta in response to elevated Ca 2+ levels, which contributes to regulating Aβ generation. AMPK is a physiological tau kinase and can increase the phosphorylation of tau at Ser-262. AMPK can also directly phosphorylate tau at Thr-231 and Ser-396/404. Furthermore, AMPK activation decreases mTOR signaling activity to facilitate autophagy and promotes lysosomal degradation of Aβ. However, AMPK activation has non-neuroprotective property and may lead to detrimental outcomes, including Aβ generation and tau phosphorylation. Therefore, it is still unclear whether AMPK could serve a potential therapeutic target for AD, and hence, further studies will be needed to clarify the role of AMPK in AD.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalNeuroMolecular Medicine
Volume14
Issue number1
DOIs
StatePublished - 1 Mar 2012

Fingerprint

AMP-Activated Protein Kinases
Alzheimer Disease
Phosphorylation
Phosphotransferases
Serum Amyloid A Protein
Calcium-Calmodulin-Dependent Protein Kinases
Sphingomyelins
Autophagy
Brain
Organelle Biogenesis
Adenosine Monophosphate
Lipid Metabolism
Energy Metabolism
Homeostasis
Adenosine Triphosphate
Cholesterol

Keywords

  • AMP-activated protein kinase
  • Alzheimer's disease
  • Aβ generation
  • Tau phosphorylation

Cite this

Cai, Zhiyou ; Yan, Liang Jun ; Li, Keshen ; Quazi, Sohel H. ; Zhao, Bin. / Roles of AMP-activated protein kinase in Alzheimer's disease. In: NeuroMolecular Medicine. 2012 ; Vol. 14, No. 1. pp. 1-14.
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Roles of AMP-activated protein kinase in Alzheimer's disease. / Cai, Zhiyou; Yan, Liang Jun; Li, Keshen; Quazi, Sohel H.; Zhao, Bin.

In: NeuroMolecular Medicine, Vol. 14, No. 1, 01.03.2012, p. 1-14.

Research output: Contribution to journalReview article

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