The Neuronal Adaptor Protein X11α Reduces Aβ Levels in the Brains of Alzheimer's APPswe Tg2576 Transgenic Mice

Abstract

Increased production and deposition of the 40 -42-amino acid ␤-amyloid peptide (A␤) is believed to be central to the pathogenesis of Alzheimer's disease. A␤ is derived from the amyloid precursor protein (APP), but the mechanisms that regulate APP processing to produce A␤ are not fully understood. X11␣ (also known as munc-18-interacting protein-1 (Mint1)) is a neuronal adaptor protein that binds APP and modulates APP processing in transfected non-neuronal cells. To investigate the in vivo effect of X11␣ on A␤ production in the brain, we created transgenic mice that overexpress X11␣ and crossed these with transgenics harboring a familial Alzheimer's disease mutant APP that produces increased levels of A␤ (APPswe Tg2576 mice). Analyses of A␤ levels in the offspring generated from two separate X11␣ founder mice revealed a significant, approximate 20% decrease in A␤(1-40) in double transgenic mice expressing APPswe/X11␣ compared with APPswe mice. At a key time point in A␤ plaque deposition (8 months old), the number of A␤ plaques was also deceased in APPswe/X11␣ mice. Thus, we report here the first demonstration that X11␣ inhibits A␤ production and deposition in vivo in the brain.One pathological hallmark of Alzheimer's disease is deposition of the 40 -42-amino acid ␤-amyloid peptide (A␤) 1 within the brains of affected individuals. A␤ is derived by proteolytic cleavage from the amyloid precursor protein (APP). APP is a type-1 membrane-spanning protein that contains a large ectodomain and a smaller, intracellular endodomain, and A␤ is derived from sequences that encompass parts of both ecto-and trans-membrane domains. Aberrant APP processing/metabolism leading to increased production and deposition of A␤ is believed to be central to the pathogenesis of Alzheimer's disease (for reviews see Refs. 1 and 2).A number of proteins have now been shown to interact with the APP endodomain, including a variety of phosphotyrosinebinding domain proteins (3, 4). These phosphotyrosine-binding domain proteins comprise the Fe65 and X11 families. Disabled and JNK-interacting proteins and their interactions are mediated via the phosphotyrosine-binding domains and sequences surrounding the YENPTY motif in APP (5-18).One such protein is the neuronal adaptor X11␣, which contains a single, centrally located phosphotyrosine-binding domain through which it binds APP. However, X11␣ also contains a number of other protein-protein interaction domains and via these domains mediates the assembly of multi-protein complexes. Aside from APP family members, X11␣-binding partners identified to date include CASK, munc-18, spinophilin/ neurabin, neurexins, the N-type Ca 2ϩ channel pore-forming ␣ 1B subunit, the kinesin superfamily motor protein KIF17, presenilin 1, and the copper chaperone for superoxide dismutase-1 (19 -30).The binding of X11␣ to APP has now been shown to inhibit A␤ production in transfected non-neuronal cells, although the mechanisms that underlie this effect are not known (16,(31)(32)(33). However, whether it fulfills similar functio...

A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model

“…After overexpression of the adapter protein X11α in APPswe Tg2576 transgenic mice, amyloid plaque formation was reduced, although Aβ42 levels were unchanged and Aβ40 levels were decreased by only about 24% (43). Overexpression of a mutant copper transporter in transgenic APP mice (TgCRND8) clearly decreased the amyloid plaque burden in the cortex and hippocampus, although the brain levels of Aβ40 and Aβ42 were only slightly and not significantly reduced (44).…”

Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

“…The amount of A40 and the number of amyloid plaques were deceased in double-transgenic mice expressing X11 and APPswe compared to control [70]. There were also low levels of A peptides and plaque formation in the cerebrum of double-transgenic mice expressing X11L and APPswe [71].…”

X11 Proteins Regulate the Translocation of Amyloid β-Protein Precursor (APP) into Detergent-resistant Membrane and Suppress the Amyloidogenic Cleavage of APP by β-Site-cleaving Enzyme in Brain

“…Transgenic mice that overexpress Swedish mutant APP and X11 or X11L show lower levels of A␤ in their brains as compared with transgenic mice overexpressing Swedish mutant APP alone (20,21). Moreover, X11L-deficient mice show enhanced amyloidogenic metabolism of endogenous brain APP (22).…”

“…Transgenic mice expressing the APP Swedish mutation and also overexpressing X11 or X11L show a decreased level of cerebral A␤ and a reduction of A␤ plaques in the cerebral cortex and hippocampus in comparison with the mice expressing Swedish mutant APP alone (20,21). Conversely, the amyloidogenic metabolism of endogenous APP and the generation of A␤ are facilitated in the brains of X11L-deficient mice (22).…”