The neuronal adaptor protein X11beta reduces amyloid beta-protein levels and amyloid plaque formation in the brains of transgenic mice.
Accumulation of cerebral amyloid beta-protein (Abeta) is believed to be part of the pathogenic process in Alzheimer's disease. Abeta is derived by proteolytic cleavage from a precursor protein, the amyloid precursor protein (APP). APP is a type-1 membrane-spanning protein, and its carboxyl-terminal intracellular domain binds to X11beta, a neuronal adaptor protein. X11beta has been shown to inhibit the production of Abeta in transfected non-neuronal cells in culture. However, whether this is also the case in vivo in the brain and whether X11beta can also inhibit the deposition of Abeta as amyloid plaques is not known. Here we show that transgenic overexpression of X11beta in neurons leads to a decrease in cerebral Abeta levels in transgenic APPswe Tg2576 mice that are a model of the amyloid pathology of Alzheimer's disease. Moreover, overexpression of X11beta retards amyloid plaque formation in these APPswe mice. Our findings suggest that modulation of X11beta function may represent a novel therapeutic approach for preventing the amyloid pathology of Alzheimer's disease.
Lee
Ju-Hyun
JH
Department of Neuroscience and Section of Old Age Psychiatry, The Institute of Psychiatry, King's College London SE5 8AF, United Kingdom.
Lau
Kwok-Fai
KF
Perkinton
Michael S
MS
Standen
Claire L
CL
Rogelj
Boris
B
Falinska
Agnieszka
A
McLoughlin
Declan M
DM
Miller
Christopher C J
CC
D000544:Alzheimer Disease / Q000628:therapy; D000682:Amyloid / Q000096:biosynthesis*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D001921:Brain / Q000196:embryology / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics* / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D003001:Cloning, Molecular; D003433:Crosses, Genetic; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism
D000682:Amyloid; D016229:Amyloid beta-Peptides; C491635:Apba2 protein, mouse; D015820:Cadherins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger