Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease.
BACKGROUND
The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr protein kinase that plays a pivotal role in multiple fundamental biological processes, including synaptic plasticity. We explored the relationship between the mTOR pathway and β-amyloid (Aβ)-induced synaptic dysfunction, which is considered to be critical in the pathogenesis of Alzheimer's disease (AD).


RESULTS
We provide evidence that inhibition of mTOR signaling correlates with impairment in synaptic plasticity in hippocampal slices from an AD mouse model and in wild-type slices exposed to exogenous Aβ1-42. Importantly, by up-regulating mTOR signaling, glycogen synthase kinase 3 (GSK3) inhibitors rescued LTP in the AD mouse model, and genetic deletion of FK506-binding protein 12 (FKBP12) prevented Aβ-induced impairment in long-term potentiation (LTP). In addition, confocal microscopy demonstrated co-localization of intraneuronal Aβ42 with mTOR.


CONCLUSIONS
These data support the notion that the mTOR pathway modulates Aβ-related synaptic dysfunction in AD.
Ma
Tao
T
Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York, USA.
Hoeffer
Charles A
CA
Capetillo-Zarate
Estibaliz
E
Yu
Fangmin
F
Wong
Helen
H
Lin
Michael T
MT
Tampellini
Davide
D
Klann
Eric
E
Blitzer
Robert D
RD
Gouras
Gunnar K
GK
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D017774:Long-Term Potentiation; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity; D010446:Peptide Fragments / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D058570:TOR Serine-Threonine Kinases