Therapeutic Potential of γ -Secretase Inhibitors and Modulators

Bruno   P.   Imbimbo

doi:10.2174/156802608783334015

Abstract

According to the β-amyloid (Aβ) hypothesis, compounds that inhibit γ-secretase, the pivotal enzyme that generates Aβ, are potential therapeutics for Alzheimers disease (AD). Studies in both transgenic and non-transgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aβ concentrations. However, scanty data are available on the effects of these compounds on brain Aβ deposition after prolonged administration. Behavioral studies are also scarce with only one study indicating positive cognitive effects of a peptidomimetic compound (DAPT). γ-Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus and spleen in rodents. These toxic effects are likely due to inhibition of Notch cleavage, a transmembrane receptor involved in regulating cell-fate decisions. Interestingly, some non-steroidal anti-inflammatory drugs (NSAIDs) and other small organic molecules have been found to modulate γ-secretase and to selectively reduce β-amyloid1-42 (Aβ42) levels without affecting Notch cleavage. Long-term histopathological and behavioral animal studies are available with these NSAIDs (mainly ibuprofen) but it is unclear if the observed in vivo effects on Aβ brain pathology and learning depend on their activity on γ-secretase or on other biological targets. The first published clinical studies in healthy subjects and in AD patients with a γ-secretase inhibitor, LY- 450139, confirmed the dose-dependent inhibition of plasma Aβ but evidenced a later rebound in Aβ plasma levels and absence of a significant effect on cerebrospinal fluid Aβ concentrations. Some observed gastrointestinal adverse events have raised concerns. Clinical studies with other potent γ-secretase inhibitors will tell us if these pharmacodynamic and tolerability profiles observed in humans are typical of the pharmacological class or are compound-specific. Given the uncertain Aβ reduction target and the potential for mechanismbased toxicity, it has been suggested that biomarkers for efficacy (cerebrospinal fluid Aβ42 levels) and toxicity (plasma adipsin levels) would be helpful in initial clinical trials with γ-secretase inhibitors. A large ongoing Phase 3 study with (R)-flurbiprofen, a claimed selective Aβ42 lowering agent, will tell us if allosteric modulation of γ-secretase is clinically effective.

Keywords: γ-secretase inhibitors, γ-secretase modulators, β-amyloid, Alzheimer's disease

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