Hampered AMPK-ULK1 cascade in Alzheimer’s disease (AD) instigates mitochondria dysfunctions and AD-related alterations which are alleviated by metformin
Arnaud Mary, Samantha Barale, Fanny Eysert, Audrey Valverde, Sandra Lacas‐Gervais, Charlotte Bauer, Sabiha Eddarkaoui, Luc Buée, Valérie Buée‐Scherrer, Frédéric Checler, Mounia Chami
Abstract
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.