Development of therapeutic strategy for Alzheimer's disease by targeting amyloid precursor protein C99

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Accumulation of amyloid-b (Ab) in the brain underlies the pathogenesis of Alzheimer's disease (AD). Ab is produced by b- and g-secretase-mediated sequential proteolysis of Ab precursor protein (APP). Although g-secretase is a major target of therapeutic intervention, non-selective inhibition of its activity causes serious adverse effects due to blockade of Notch signaling. We have identified a secretory protein named ILEI as a negative regulator of Ab production. ILEI destabilized the b-secretase-cleaved APP C-terminal fragment, APP-C99, by binding to the g-secretase complex and interfering with its chaperone properties. Notch signaling and g-secretase activity were not affected by ILEI. We also show neuronal expression of ILEI and its reduction in the brains of AD patients. transgenic over expression of ILEI significantly reduced the brain Ab burden and ameliorates the memory deficit in AD model mice. ILEI may be a plausible target for the development of disease-modifying therapies.