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

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...

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Vydáno v:	Nature communications Ročník 13; číslo 1; s. 4444 - 20
Hlavní autoři:	Lee, Annie, Kondapalli, Chandana, Virga, Daniel M., Lewis, Tommy L., Koo, So Yeon, Ashok, Archana, Mairet-Coello, Georges, Herzig, Sebastien, Foretz, Marc, Viollet, Benoit, Shaw, Reuben, Sproul, Andrew, Polleux, Franck
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 01.08.2022 Nature Publishing Group Nature Portfolio
Témata:	13 14 14/19 42 42/41 631/378 631/378/1689 631/378/1689/1283 631/378/340 631/378/87 Alzheimer Disease - genetics Alzheimer Disease - metabolism Alzheimer's disease AMP-Activated Protein Kinases - metabolism Amyloid beta-Peptides - metabolism Animal models Animals Calcium-Calmodulin-Dependent Protein Kinase Kinase - genetics Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism Dendrites Dendritic structure Disease Models, Animal Fission Hippocampus Humanities and Social Sciences Kinases Life Sciences Mice Mice, Transgenic Mitochondria Mitochondrial Dynamics Mitophagy multidisciplinary Neurobiology Neurodegenerative diseases Neurons Neurons and Cognition Oligomers Peptide Fragments Phosphorylation Pyramidal cells Science Science (multidisciplinary) Senile plaques Synapses Synapses - metabolism β-Amyloid
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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 APP Swe/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. Loss of excitatory synapses occur prior to the formation of amyloid plaques in Alzheimer’s disease. Here the authors show in an animal model that the loss of synapses induced by amyloid-beta oligomers requires over-activation of a stress-response pathway inducing structural remodelling of mitochondria in dendrites of cortical and hippocampal neurons.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC9343354
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-022-32130-5