RT Journal Article
SR Electronic
T1 Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 637199
DO 10.1101/637199
A1 Annie Lee
A1 Chandana Kondapalli
A1 Daniel M. Virga
A1 Tommy L. Lewis, Jr.
A1 So Yeon Koo
A1 Archana Ashok
A1 Georges Mairet-Coello
A1 Sebastien Herzig
A1 Reuben Shaw
A1 Andrew Sproul
A1 Franck Polleux
YR 2019
UL http://biorxiv.org/content/early/2019/05/14/637199.abstract
AB During the early stages of Alzheimer’s disease (AD) in both mouse models and human patients, soluble forms of Amyloid-β1-42 oligomers (Aβ42o) trigger loss of excitatory synapses (synaptotoxicity) in cortical and hippocampal pyramidal neurons (PNs) prior to the formation of insoluble Aβ plaques. We observed a spatially restricted structural remodeling of mitochondria in the apical tufts of CA1 PNs dendrites in the hAPPSWE,IND transgenic AD mouse model (J20), corresponding to the dendritic domain receiving presynaptic inputs from the entorhinal cortex and where the earliest synaptic loss is detected in vivo. We also observed significant loss of mitochondrial biomass in human neurons derived from a new model of human ES cells where CRISPR-Cas9-mediated genome engineering was used to introduce the ‘Swedish’ mutation bi-allelically (APPSWE/SWE). Recent work uncovered that Aβ42o mediates synaptic loss by over-activating the CAMKK2-AMPK kinase dyad, and that AMPK is a central regulator of mitochondria homeostasis in non-neuronal cells. Here, we demonstrate that Aβ42o-dependent over-activation of CAMKK2-AMPK mediates synaptic loss through coordinated MFF-dependent mitochondrial fission and ULK2-dependent mitophagy in dendrites of PNs. We also found that the ability of Aβ42o-dependent mitochondrial remodeling to trigger synaptic loss requires the ability of AMPK to phosphorylate Tau on Serine 262. Our results uncover a unifying stress-response pathway triggered by Aβo and causally linking structural remodeling of dendritic mitochondria to synaptic loss.