Isoform-specific dysregulation of AMP-activated protein kinase signaling in a non-human primate model of Alzheimer's disease.

Abstract

AMP-activated protein kinase (AMPK) is a molecular sensor that is critical for the maintenance of cellular energy homeostasis, disruption of which has been indicated in multiple neurodegenerative diseases including Alzheimer's disease (AD). Mammalian AMPK is a heterotrimeric complex and its enzymatic α subunit exists in two isoforms: AMPKα1 and AMPKα2. Here we took advantage of a recently characterized non-human primate (NHP) model with sporadic AD-like neuropathology to explore potential relationships between AMPK signaling and AD-like neuropathology. Subjects were nine female vervet monkeys aged 19.5 to 23.4 years old. Subjects were classified into three groups, control lacking AD pathology (n = 3), moderate AD pathology (n = 3), and more severe AD Pathology (n = 3). We found increased activity (assessed by phosphorylation) of AMPKα2 in hippocampi of NHP with AD-like neuropathology, compared to the subjects without AD pathology, with no alterations of AMPKα1 activity. Across all subjects, CSF Abeta42 was inversely associated with cerebral amyloid plaque density. Further, Aβ plaque burden is correlated with levels of either soluble or insoluble brain Aβ measurement. Unbiased mass spectrometry based proteomics studies combined with bioinformatics analysis revealed that many of the dysregulated proteins characteristic of AD neuropathology are associated with AMPK signaling. Our findings on the AMPK molecular signaling cascades provide further support for use of the NHP model to investigate new therapeutic strategies and development of novel biomarkers for Alzheimer's disease.

• Authors: Xin Wang, Xueyan Zhou, Beth Uberseder, Jingyun Lee, Caitlin S Latimer, Cristina M Furdui, C Dirk Keene, Thomas J Montine, Thomas C Register, Suzanne Craft, Carol A Shively, Tao Ma
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 158 Pg. 105463 (10 2021) ISSN: 1095-953X [Electronic] United States
• PMID: 34363967 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Biomarkers
• Peptide Fragments
• amyloid beta-protein (1-42)
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (genetics)
• Alzheimer Disease (genetics, pathology, psychology)
• Amyloid beta-Peptides (cerebrospinal fluid)
• Animals
• Behavior, Animal
• Biomarkers
• Brain Chemistry
• Cerebral Amyloid Angiopathy (pathology)
• Chlorocebus aethiops
• Computational Biology
• Disease Models, Animal
• Female
• Hippocampus (pathology)
• MAP Kinase Signaling System (genetics)
• Peptide Fragments (cerebrospinal fluid)