![]() ![]() This suppressive inhibition of human APP amyloidogenic metabolism by X11 and X11L was also confirmed in the brains of X11- or X11L-Tg mice expressing human Swedish mutant APP (APPswe/Tg2576) (Table 1). In this way, they regulate amyloidogenic cleavage of APP through suppression. These observations suggest that X11 and X11L function to form a complex with APP that then remains outside of the DRMs. DRMs in the brains of mice lacking X11 and X11L are rich in mature APP ( N- and O-glycosylated form), the substrate to secretases, and the amyloidogenic metabolite CTFβ. Recent evidence indicates that the majority of both β- and γ-secretases are located in cholesterol- and sphingolipid-rich detergent-resistant membrane domains (DRM domains or lipid rafts) as active forms. Specifically, the production of amyloidogenic CTFβ, but not amyloidolytic CTFα, derived from endogenous mouse APP was found to be enhanced, and accumulation of mouse Aβ was found to be increased, in the brains of X11-knockout, X11L-knockout, and X11 plus X11L double-gene knockout mice. This association has been shown to greatly suppress the amyloidogenic metabolism of APP in the brain in vivo. The association of X11s with APP is mediated by interaction between the phosphotyrosine interaction domain (PTB) of X11s and the 681-GYENPTY-687 motif of APP. Both CTFα and CTFβ are further cleaved by γ-secretase in the lipid bilayer, resulting in the secretion of the amyloidolytic p3 fragment from CTFα and the neurotoxic Aβ from CTFβ. Primary cleavage of APP by α-secretase is amyloidolytic and generates a C-terminal fragment, CTFα, which includes the C-terminal half of the Aβ sequence, whereas cleavage by β-secretase is amyloidogenic and generates CTFβ, which includes an intact Aβ sequence. APP is subjected to alternative cleavages by a combination of α- and γ-secretases or β- and γ-secretases. X11s associate with the cytoplasmic domain of amyloid β-protein precursor (APP) and suppress APP metabolism, including amyloid β-protein (Aβ) generation, which is widely believed to be the major cause of Alzheimer's disease (AD) pathogenesis. In mammals, X11 and X11L are expressed predominantly in neurons, while X11L2 is expressed ubiquitously ]. These molecules are evolutionally conserved in D. X11L appears to regulate human APP in a manner similar to that seen in endogenous mouse APP metabolism. X11L appears to aid in the suppression of amyloidogenic processing of human APP in brain in vivo, as has been demonstrated by previous studies using several human APP transgenic lines with various genetic backgrounds. In agreement with previous reports from our lab and others, we found that the amyloidogenic metabolism of human APP increased in the absence of X11L. To confirm the interaction of X11L with human APP ectopically expressed in mouse brain, we examined the amyloidogenic metabolism of human APP in two lines of human APP transgenic mice generated to also lack X11L. Therefore, the data on X11-family protein function in transgenic human APP metabolism in vivo are inconsistent. In vivo gene-knockout studies targeting X11, X11L, or both, and studies of X11 or X11L transgenic mice have reported that X11-family proteins suppress the amyloidogenic processing of endogenous mouse APP and ectopic human APP with one exception: knockout of X11, X11L or X11L2 has been found to suppress amyloidogenic metabolism in transgenic mice overexpressing the human Swedish mutant APP (APPswe) and the mutant human PS1, which lacks exon 9 (PS1dE9). X11L is predominantly expressed in excitatory neurons, in contrast to X11, which is strongly expressed in inhibitory neurons. Both X11 and X11L are expressed specifically in brain, while X11L2 is expressed ubiquitously. X11-family proteins, including X11, X11-like (X11L) and X11-like 2 (X11L2), bind to the cytoplasmic domain of amyloid β-protein precursor (APP) and regulate APP metabolism.
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