P1‐022: Inhibitory mechanism of amyloidgenic APP metabolism by X11 and X11L in brain

Background: X11 (X11 ) and X11-like (X11L/X11 ) are an adaptor protein composed of an independent amino terminal half, a conserved central phosphotyrosine interaction (PI) domain, and two carboxyl PDZ domains. X11 and X11L are largely brain-specific, while another family member X11-like 2 (X11L2/X11 ) is expressed ubiquitously. X11L, also X11 and X11L2, binds to the GYENPTY motif within APP cytoplasmic region through its PI domain and suppress APP metabolism in cultured cells (J. Biol. Chem. [1999] 274, 2243). We previously reported that generation of CTF and A from endogenous mouse APP is facilitated in the brains of X11L-deficient mice (J. Biol. Chem. [2006] 281, 37853), suggesting that X11L suppresses the amyloidogenic metabolism of APP. Although the distinct expression between X11 and X11L in brain neurons is observed, APP metabolism in the brains of X11-deficient mice has not been analyzed. Methods: To reveal the role of X11 in suppressing amyloidogenic cleavage of APP in vivo, we generated and analyzed X11 and X11L genes homozygous doublydeficient (X11-/-, X11L-/-) mice. Results: The double-deficient mutant mice showed normal brain morphology and no compensatory changes in the expression of other X11L2, although 50% of the doubly-deficient mice died just after birth and the weight of surviving double-KO mice is decreased. Using survivors, we analyzed APP metabolism in brain of doubly-deficient mice along with that of X11-deficient mice. The doubly-deficient mice strongly and X11-deficient mice weakly showed enhanced -site cleavage of APP along with increased accumulation of A in brain. Conclusions: Based on the biochemical analysis with X11 and X11L doubly-deficient mice, we present molecular mechanism how X11s suppresses -site cleavage of APP in brain. Our results provide the possibility that dysfunction of X11 proteins might play a role in the pathogenesis of AD.