Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production.

Increased Abeta42 production has been linked to the development of Alzheimer disease. We now identify a number of compounds that raise Abeta42. Among the more potent Abeta42-raising agents identified are fenofibrate, an antilipidemic agent, and celecoxib, a COX-2-selective NSAID. Many COX-2-selective NSAIDs tested raised Abeta42, including multiple COX-2-selective derivatives of two Abeta42-lowering NSAIDs. Compounds devoid of COX activity and the endogenous isoprenoids FPP and GGPP also raised Abeta42. These compounds seem to target the gamma-secretase complex, increasing gamma-secretase-catalyzed production of Abeta42 in vitro. Short-term in vivo studies show that two Abeta42-raising compounds increase Abeta42 levels in the brains of mice. The elevations in Abeta42 by these compounds are comparable to the increases in Abeta42 induced by Alzheimer disease-causing mutations in the genes encoding amyloid beta protein precursor and presenilins, raising the possibility that exogenous compounds or naturally occurring isoprenoids might increase Abeta42 production in humans.

Overexpression of nicastrin increases Abeta production.

Gamma-secretase cleavage is the final proteolytic step that releases the amyloid beta-peptide (Abeta) from the amyloid beta-protein precursor (APP). Significant evidence indicates that the presenilins (PS) are catalytic components of a high molecular weight gamma-secretase complex. The glycoprotein nicastrin was recently identified as a functional unit of this complex based on 1) binding to PS and 2) the ability to modulate Abeta production following mutation of a conserved DYIGS region. In contrast to the initial report, we find that overexpression of wild-type (WT) nicastrin increases Abeta production, whereas DYIGS mutations (MT) have little or no effect. The increase in Abeta production is associated with an increase in gamma-secretase activity but not with a detectable increase in PS1 levels. Subcellular fractionation studies show that WT but not MT nicastrin matures into buoyant membrane fractions enriched in gamma-secretase activity. These data support the hypothesis that nicastrin is an essential component of the gamma-secretase complex. The finding that WT nicastrin overexpression can increase gamma-secretase activity without altering levels of the presumed catalytic component (PS) of the enzyme may point to a role for nicastrin in facilitating cleavage by regulating substrate interactions with the gamma-secretase complex.