Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-32130-5
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Funding
- NIH [NS089456, NS091526]
- Thompson Foundation (TAME-AD)
- Henry and Marilyn Taub Foundation
- Ludwig Foundation
- Fondation Roger De Sproelberch
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This study reveals that soluble Amyloid-beta 1-42 oligomers (A beta 42o) trigger the loss of excitatory synapses in early Alzheimer's disease, prior to the formation of insoluble amyloid plaques. The researchers also found that A beta 42o leads to structural remodeling of mitochondria in specific regions and mediates synaptic loss through certain signaling pathways.
During the early stages of Alzheimer's disease (AD) in both mouse models and human patients, soluble forms of Amyloid-beta 1-42 oligomers (A beta 42o) 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 A beta 42o-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 A beta 42o-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.
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