Sano Y, Syuzo-Takabatake A, Nakaya T, Saito Y, Tomita S, Itohara S, Suzuki T.
Enhanced amyloidogenic metabolism of the amyloid beta-protein precursor in the X11L-deficient mouse brain.
J Biol Chem. 2006 Dec 8;281(49):37853-60.
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This study contributes to further understanding of both biological and pathological properties of APP.
This paper reports increased levels of endogenous APP CTFβ as well as of Aβ in the hippocampus of X11L knockout mice. The researchers, headed by Toshi Suzuki of Hokkaido University, Sapporo, who has led APP research in relation to its cytoplasmic binding proteins, had cloned X11L (which is also termed X11β), an adaptor protein harboring a phosphotyrosine interaction domain as well as two PDZ domains. In cellular experiments they previously showed that overexpression of X11L results in overall suppression of APP metabolism, including Aβ production (Tomita et al., 1999). The present data convincingly demonstrate the in vivo role of X11L in suppressing Aβ production from endogenous APP. This also dovetails with the observation that crossing transgenic mice that overexpress X11L in neurons (Lee et al., 2004) with Tg2576 mice leads to reduced levels of Aβ deposition. Although the mechanism whereby ablation of X11L led to increased levels of CTFβ and Aβ remains elusive, it is noteworthy that these changes, exclusively observed in the hippocampus, were not accompanied by a decrease in CTFα or an increase in sAPPβ. Lack of X11L might have altered the interaction or intracellular localization of APP (including fragments thereof) and BACE, thereby leading to an increase in β-cleavage. Of future interest are changes in neuropathology when crossed with APP transgenic mice, as well as the results in X11L/X11 double knockout mice, that may presumably be underway. It would be fascinating if selective blockage of the X11L/APP interaction by small molecule compounds were feasible, highlighting X11L as a therapeutic target for reducing Aβ in AD.
Several groups have found that X11 and X11L1 interact with APP, affect APP metabolism, and decrease the production of Aβ. However, a recent study found that X11 siRNA and X11L siRNA treatment did not alter the levels of α-CTF and β-CTF, but decreased Aβ. Therefore, Dr. Suzuki’s group generated X11L1–deficient mice and analyzed APP processing in vivo compared to control mice. They found that X11L1 mutant mice did not exhibit histopathological alterations or changes in expression of other X11-family proteins. Importantly, the levels of Aβ were increased in the hippocampus of aged mutant mice as compared to age-matched controls. These results were consistent with previous in vitro findings and raise the possibility that X11L may serve as a suitable target for drug therapy.
Both X11 and APP are synaptic proteins, and both play roles in new synapse formation (Ashley et al., 2005). These interactions of APP with its various adaptor proteins (also including FE65 and Dab) will help define many of the functions of APP in the brain. We need a better understanding of the spatial separation of these interactions, their regulation, and their competition with each other. Further, we would benefit from understanding how extracellular interactors of APP affect intracellular interactors such as X11. These mice will be an important resource for answering these questions.