A perspective of the role of the y-secretase inhibition and the p75-CTF in cholinergic neurons is in press in Neuronal Regeneration Research.
The amyloid hypothesis of Alzhemer’s disease (AD) postulates that the generation of amyloid-beta (Aβ) peptide from the amyloid precursor protein (APP) by the action of the γ-secretase complex is one of the principal causes of AD. This idea is supported by the identification of several hereditary mutations in the APP gene or in the PSEN1 and PSEN2 genes that encode Presenilin-1 and Presenilin-2, the catalytic component of the γ-secretase complex. The assumption at that time was that familial AD (FAD), mutations lead to a gain of function phenotype, increasing the ratio between the levels of the toxic Aβ1–42, and the less toxic Aβ1–40 peptide (Kuperstein et al., 2010). Actually, the ratio Aβ1–42/Aβ1–40 is the principal cause of the toxic effect as some FAD mutations in APP decrease the levels of Aβ1–40 without changing the total levels of Aβ1–42 (Ancolio et al., 1997). Pharmaceutical companies started the race to design new highly specific γ-secretase inhibitors (GSIs)with good pharmacological properties to jump into the clinic. The reduction of the circulating levels of Aβ1–42 in AD mouse models rapidly supported this approximation, and one of the lead compounds, Semagacestat (Lilly), entered the phase III clinical trials. However, results were not as good as initially expected, and the appearance of several skin cancer problems and a reduction, rather than an improvement, in the cognitive performance of the patients lead the FDA to stop the clinical trials. Meanwhile, it was reported that inhibition of the γ-secretase could lead to skin problems in the mice (Li et al., 2007), and that FAD mutations are actually the loss of function mutations (Chávez-Gutiérrez et al., 2012). The molecular mechanism of γ-secretase activity showed that FAD mutations alter its proteolytic processing leading to an increase in the long toxic peptides Aβ1–42 and a reduction of the shorter Aβ1–37 species (Chávez-Gutiérrez et al., 2012). Nowadays, it is clear that the goal is to increase the processing with the identification of new γ-secretase modulators.
Read more in:
Vilar M. Neurotrophin receptors, gamma-secretase inhibitors, and neurodegeneration of basal forebrain cholinergic neurons. Neural Regen Res [serial online] 2022 [cited 2022 Jan 5];17:1493-4. Available from: http://www.nrronline.org/text.asp?2022/17/7/1493/330607
