γ-secretase inhibitors for treating Alzheimer’s disease: rationale and clinical data

Abstract

There are no drugs available for slowing down the rate of deterioration of patients with Alzheimer’s disease (AD). With the aim of altering the natural history of the disease, the pharmaceutical industry has designed and developed several compounds inhibiting γ-secretase, the enzymatic complex generating β-amyloid (Aβ) peptides (Aβ1–40 and Aβ1–42), believed to be involved in the pathophysiological cascade of AD, from amyloid precursor protein (APP). This article briefly reviews the profile of γ-secretase inhibitors that have reached the clinic. Studies in both transgenic and nontransgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aβ concentrations. However, few data are available on the effects of these compounds on brain Aβ deposition after prolonged administration. γ-secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen, skin, and decrease in lymphocytes and alterations in hair color in ex...