Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy

Annie Lee, Chandana Kondapalli, Daniel M. Virga, Tommy L. Lewis, So Yeon Koo, Archana Ashok, Georges Mairet-Coello, Sebastien Herzig, Marc Foretz, Benoit Viollet, Reuben Shaw, Andrew Sproul and Franck Polleux ()
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Annie Lee: Columbia University Medical Center New York
Chandana Kondapalli: Columbia University Medical Center New York
Daniel M. Virga: Columbia University Medical Center New York
Tommy L. Lewis: Columbia University Medical Center New York
So Yeon Koo: Columbia University Medical Center
Archana Ashok: Columbia University Medical Center
Georges Mairet-Coello: UCB Biopharma
Sebastien Herzig: Salk Institute for Biological Studies
Marc Foretz: Université de Paris, CNRS, INSERM
Benoit Viollet: Université de Paris, CNRS, INSERM
Reuben Shaw: Salk Institute for Biological Studies
Andrew Sproul: Columbia University Medical Center
Franck Polleux: Columbia University Medical Center New York

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract During the early stages of Alzheimer’s disease (AD) in both mouse models and human patients, soluble forms of Amyloid-β 1–42 oligomers (Aβ42o) trigger loss of excitatory synapses (synaptotoxicity) in cortical and hippocampal pyramidal neurons (PNs) prior to the formation of insoluble amyloid plaques. In a transgenic AD mouse model, we observed a spatially restricted structural remodeling of mitochondria in the apical tufts of CA1 PNs dendrites corresponding to the dendritic domain where the earliest synaptic loss is detected in vivo. We also observed AMPK over-activation as well as increased fragmentation and loss of mitochondrial biomass in Ngn2-induced neurons derived from a new APPSwe/Swe knockin human ES cell line. We demonstrate that Aβ42o-dependent over-activation of the CAMKK2-AMPK kinase dyad mediates synaptic loss through coordinated phosphorylation of MFF-dependent mitochondrial fission and ULK2-dependent mitophagy. Our results uncover a unifying stress-response pathway causally linking Aβ42o-dependent structural remodeling of dendritic mitochondria to synaptic loss.

Date: 2022
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DOI: 10.1038/s41467-022-32130-5

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