X11beta rescues memory and long-term potentiation deficits in Alzheimer's disease APPswe Tg2576 mice.
Increased production and deposition of amyloid beta-protein (Abeta) are believed to be key pathogenic events in Alzheimer's disease. As such, routes for lowering cerebral Abeta levels represent potential therapeutic targets for Alzheimer's disease. X11beta is a neuronal adaptor protein that binds to the intracellular domain of the amyloid precursor protein (APP). Overexpression of X11beta inhibits Abeta production in a number of experimental systems. However, whether these changes to APP processing and Abeta production induced by X11beta overexpression also induce beneficial effects to memory and synaptic plasticity are not known. We report here that X11beta-mediated reduction in cerebral Abeta is associated with normalization of both cognition and in vivo long-term potentiation in aged APPswe Tg2576 transgenic mice that model the amyloid pathology of Alzheimer's disease. Overexpression of X11beta itself has no detectable adverse effects upon mouse behaviour. These findings support the notion that modulation of X11beta function represents a therapeutic target for Abeta-mediated neuronal dysfunction in Alzheimer's disease.
Mitchell
Jacqueline C
JC
MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, London SE5 8AF, UK.
Ariff
Belall B
BB
Yates
Darran M
DM
Lau
Kwok-Fai
KF
Perkinton
Michael S
MS
Rogelj
Boris
B
Stephenson
John D
JD
Miller
Christopher C J
CC
McLoughlin
Declan M
DM
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D015820:Cadherins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D017774:Long-Term Potentiation; D008297:Male; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*
C491636:APBA2 protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015820:Cadherins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins