Hampered AMPK-ULK1 cascade in Alzheimer's disease (AD) instigates mitochondria dysfunctions and AD-related alterations which are alleviated by metformin.
[en] The adenosine monophosphate-activated protein kinase (AMPK) and its downstream effector Unc-51 like autophagy activating kinase 1 (ULK1) represent a key cellular signaling node, the alteration of which likely contribute to AD development. This study investigated the AMPK-ULK1 pathway activation state in AD and the impact of its modulation on mitochondria structure and function as well as on AD-related alterations. We show in human sporadic AD and 3xTgAD mice brains a defective activating phosphorylation of ULK1 despite the active phosphorylation of AMPK. In addition, we reported defective p-AMPK and p-ULK1 in cells expressing the amyloid precursor protein with the familial Swedish mutation. We then show that the antidiabetic metformin (Met) drug-mediated AMPK-ULK1 cascade activation alleviates structural and functional mitochondrial abnormalities in AD cells and mice brains. Furthermore, in the 3xTgAD brains, it reduces the early accumulation of APP C-terminal fragments (APP-CTFs) as well as amyloid beta (Aβ) burden, microgliosis and astrogliosis occurring at a later disease stage. AMPK-ULK1 activation increases the localization of APP-CTFs within cathepsin D-positive lysosomal compartments and the recruitment of Iba1+ cells to Aβ plaques in vivo and enhances cathepsin D activity and phagocytic activity of microglia in vitro. Additionally, AMPK-ULK1 activation normalizes dendritic spine morphology in organotypic hippocampal slice cultures modeling AD and alleviates learning deficit in symptomatic 3xTgAD mice. Our study demonstrates potential therapeutic benefits of targeting AMPK-ULK1 cascade to reverse both early and late AD-related alterations, deserving further investigation in fundamental research and in human clinical studies.
Disciplines :
Neurology
Author, co-author :
MARY, Arnaud ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Neuroinflammation Group ; Institute of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, Valbonne, 06560, France
Barale, Samantha; Institute of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, Valbonne, 06560, France
Eysert, Fanny; Institute of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, Valbonne, 06560, France
Valverde, Audrey; Institute of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, Valbonne, 06560, France ; Fonds Clinatec, Centre de recherche biomédicale Edmond J. Safra, Grenoble, France
Lacas-Gervais, Sandra; Université Côte d'Azur, Centre Commun de Microscopie Appliquée (CCMA), Parc Valrose, Nice, 06108, France
Bauer, Charlotte; Institute of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, Valbonne, 06560, France
Eddarkaoui, Sabiha; Université Lille, Inserm, CHU-Lille , Lille Neuroscience and Cognition, Place de Verdun, Lille, 59045, France ; Inserm UMR-S 1172 , Laboratory of Excellence DistALZ, 'Alzheimer and Tauopathies', Bâtiment Biserte, rue Polonovski, Lille Cedex, 59045, France
Buée, Luc; Université Lille, Inserm, CHU-Lille , Lille Neuroscience and Cognition, Place de Verdun, Lille, 59045, France ; Inserm UMR-S 1172 , Laboratory of Excellence DistALZ, 'Alzheimer and Tauopathies', Bâtiment Biserte, rue Polonovski, Lille Cedex, 59045, France
Buée-Scherrer, Valérie; Université Lille, Inserm, CHU-Lille , Lille Neuroscience and Cognition, Place de Verdun, Lille, 59045, France ; Inserm UMR-S 1172 , Laboratory of Excellence DistALZ, 'Alzheimer and Tauopathies', Bâtiment Biserte, rue Polonovski, Lille Cedex, 59045, France
Checler, Frédéric; Institute of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, Valbonne, 06560, France
Chami, Mounia; Institute of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, Valbonne, 06560, France. mchami@ipmc.cnrs.fr
External co-authors :
yes
Language :
English
Title :
Hampered AMPK-ULK1 cascade in Alzheimer's disease (AD) instigates mitochondria dysfunctions and AD-related alterations which are alleviated by metformin.
Initiative d'Excellence d'Université Côte d'Azur bearing the reference ANR-15-IDEX-01 Région Sud and the Conseil Départemental 06 Université Côte d’Azur LABEX (excellence laboratory, program investment for the future) DISTALZ Fondation Vaincre Alzheimer Association France Alzheimer
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