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The Amyloid Precursor Protein (APP) undergoes sequential proteolytic cleavages through the action of β- and γ-secretase, which result in the generation of toxic β-amyloid (Aβ) peptides and a C-terminal fragment consisting of the intracellular domain of APP (AICD). Mutations leading to increased APP levels or alterations in APP cleavage cause familial Alzheimer's disease (AD). Thus, identification of factors that regulate APP steady state levels and/or APP cleavage by γ-secretase is likely to provide insight into AD pathogenesis. Here, using transgenic flies that act as reporters for endogenous γ-secretase activity and/or APP levels (GAMAREP), and for the APP intracellular domain (AICDREP), we identified mutations in  X11L  and  ubiquilin (ubqn)  as genetic modifiers of APP. Human homologs of both  X11L  ( X11/Mint ) and  Ubqn  ( UBQLN1 ) have been implicated in AD pathogenesis. In contrast to previous reports, we show that overexpression of  X11L  or human  X11  does not alter γ-secretase cleavage of APP or Notch, another γ-secretase substrate. Instead, expression of either  X11L  or human  X11  regulates APP at the level of the AICD, and this activity requires the phosphotyrosine binding (PTB) domain of X11. In contrast, Ubqn regulates the levels of APP: loss of  ubqn  function leads to a decrease in the steady state levels of APP, while increased  ubqn  expression results in an increase in APP levels. Ubqn physically binds to APP, an interaction that depends on its ubiquitin-associated (UBA) domain, suggesting that direct physical interactions may underlie Ubqn-dependent regulation of APP. Together, our studies identify X11L and Ubqn as in vivo regulators of APP. Since increased expression of X11 attenuates Aβ production and/or secretion in APP transgenic mice, but does not act on γ-secretase directly, X11 may represent an attractive therapeutic target for AD.

Role of X11 and ubiquilin as In Vivo Regulators of the Amyloid Precursor Protein in Drosophila