REVIEW: γ-Secretase inhibitors for the treatment of Alzheimer's disease: The current state

Abstract

Aims: Drugs currently used for the treatment of Alzheimer's disease (AD) partially stabilize patients' symptoms without modifying disease progression. Brain accumulation of oligomeric species of β-amyloid (Aβ) peptides, the principal components of senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being spent to identify drugs able to interfere with proteases regulating Aβ formation from amyloid precursor protein (APP). This article briefly reviews the profile of γ-secretase inhibitors, compounds that inhibit γ-secretase, the pivotal enzyme that generates Aβ, and that have reached the clinic.

Discussion: Several classes of potent γ-secretase inhibitors have been designed and synthesized. Preclinical studies have indicated that these compounds are able to lower brain Aβ concentrations and, in some cases, reduce Aβ plaque deposition in transgenic mouse models of AD. The most developmentally advanced of these compounds is semagacestat, presently in Phase III clinical trials. In animals, semagacestat reduced Aβ levels in the plasma, cerebrospinal fluid (CSF), and the brain. However, studies have not reported on its cognitive effects. Studies in both healthy volunteers and patients with AD have demonstrated a dose-dependent inhibition of plasma Aβ levels, and a recent study in healthy subjects demonstrated a robust, dose-dependent inhibition of newly generated Aβ in the CSF after single oral doses.

Conclusions: Unfortunately, γ-secretase inhibitors may cause intestinal goblet cell hyperplasia, thymus atrophy, decrease in lymphocytes, and alterations in hair color, effects associated with the inhibition of the cleavage of Notch, a protein involved in cell development and differentiation. Nevertheless, at least other two promising γ-secretase inhibitors are being tested clinically. This class of drugs represents a major hope to slow the rate of decline of AD.

Figure 1

Schematic representation of the γ‐secretase complex. γ‐Secretase is composed of four different integral membrane proteins: presenilin (PS), nicastrin, anterior pharynx‐defective‐1 (Aph‐1), and presenilin enhancer‐2 (Pen‐2). Presenilin undergoes endoproteolysis into an N‐terminal fragment (NTF) and a C‐terminal fragment (CTF) that remain associated. Two conserved aspartates (D) within adjacent transmembrane domains are essential for both presenilin endoproteolysis and γ‐secretase activity.