X11alpha haploinsufficiency enhances Abeta amyloid deposition in Alzheimer's disease transgenic mice.
The neuronal adaptor protein X11alpha/mint-1/APBA-1 binds to the cytoplasmic domain of the amyloid precursor protein (APP) to modulate its trafficking and metabolism. We investigated the consequences of reducing X11alpha in a mouse model of Alzheimer's disease (AD). We crossed hAPPswe/PS-1DeltaE9 transgenic (AD tg) mice with X11alpha heterozygous knockout mice in which X11alpha expression is reduced by approximately 50%. The APP C-terminal fragments C99 and C83, as well as soluble Abeta40 and Abeta42, were increased significantly in brain of X11alpha haploinsufficient mice. Abeta/amyloid plaque burden also increased significantly in the hippocampus and cortex of one year old AD tg/X11alpha (+/-) mice compared to AD tg mice. In contrast, the levels of sAPPalpha and sAPPbeta were not altered significantly in AD tg/X11alpha (+/-) mice. The increased neuropathological indices of AD in mice expressing reduced X11alpha suggest a normal suppressor role for X11alpha on CNS Abeta/amyloid deposition.
Saluja
Inderjeet
I
Department of Neurology, University of Michigan, USA. isaluja@med.umich.edu
Paulson
Henry
H
Gupta
Ashwin
A
Turner
R Scott
RS
D048868:Adaptor Proteins, Signal Transducing / Q000145:classification / Q000172:deficiency* / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000145:classification / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C513071:Apba1 protein, rat; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)