Enhanced amyloidogenic metabolism of the amyloid beta-protein precursor in the X11L-deficient mouse brain.
X11L, a neuronal adaptor protein, associates with the cytoplasmic domain of APP and suppresses APP cellular metabolism. APP is the precursor of Abeta, whose metabolism is strongly implicated in Alzheimer disease pathogenesis. To examine the roles of X11L function in APP metabolism, including the generation of Abeta in the brain, we produced X11L-deficient mutant mice on the C57BL/6 background. The mutant mice did not exhibit histopathological alterations or compensatory changes in the expression of other X11 family proteins, X11 and X11L2. The expression level and distribution of APP in the brain of mutant mice were also identical to those in wild-type mice. However, in the hippocampus, where substantial levels of X11L and APP are expressed, the mutant mice exhibited a significant increase in the level of the C-terminal fragments of APP produced by cleavage with beta-secretase but not alpha-secretase. The levels of Abeta were increased in the hippocampus of aged mutant mice as compared with age-matched controls. These observations clearly indicate that X11L suppresses the amyloidogenic but not amyloidolytic processing of APP in regions of the brain such as the hippocampus, which express significant levels of X11L.
Sano
Yoshitake
Y
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Syuzo-Takabatake
Aiko
A
Nakaya
Tadashi
T
Saito
Yuhki
Y
Tomita
Susumu
S
Itohara
Shigeyoshi
S
Suzuki
Toshiharu
T
D000375:Aging / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D015820:Cadherins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; C491635:Apba2 protein, mouse; D015820:Cadherins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases