The neuronal adaptor protein X11alpha reduces Abeta levels in the brains of Alzheimer's APPswe Tg2576 transgenic mice.
Increased production and deposition of the 40-42-amino acid beta-amyloid peptide (Abeta) is believed to be central to the pathogenesis of Alzheimer's disease. Abeta is derived from the amyloid precursor protein (APP), but the mechanisms that regulate APP processing to produce Abeta are not fully understood. X11alpha (also known as munc-18-interacting protein-1 (Mint1)) is a neuronal adaptor protein that binds APP and modulates APP processing in transfected non-neuronal cells. To investigate the in vivo effect of X11alpha on Abeta production in the brain, we created transgenic mice that overexpress X11alpha and crossed these with transgenics harboring a familial Alzheimer's disease mutant APP that produces increased levels of Abeta (APPswe Tg2576 mice). Analyses of Abeta levels in the offspring generated from two separate X11alpha founder mice revealed a significant, approximate 20% decrease in Abeta(1-40) in double transgenic mice expressing APPswe/X11alpha compared with APPswe mice. At a key time point in Abeta plaque deposition (8 months old), the number of Abeta plaques was also deceased in APPswe/X11alpha mice. Thus, we report here the first demonstration that X11alpha inhibits Abeta production and deposition in vivo in the brain.
Lee
Ju-Hyun
JH
Department of Neuroscience and Section of Old Age Psychiatry, The Institute of Psychiatry, Kings College, De Crespigny Park, Denmark Hill, London SE5 8AF, U.K.
Lau
Kwok-Fai
KF
Perkinton
Michael S
MS
Standen
Claire L
CL
Shemilt
Stephen J A
SJ
Mercken
Luc
L
Cooper
Jonathan D
JD
McLoughlin
Declan M
DM
Miller
Christopher C J
CC
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology; D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000096:biosynthesis* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry; D002352:Carrier Proteins / Q000502:physiology*; D006801:Humans; D007118:Immunoassay; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000502:physiology*; D011499:Protein Processing, Post-Translational
C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C513072:Apba1 protein, mouse; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins