A Career Long Effort to Discover a Drug to Treat Neurodegenerative Diseases. My Adventures with γ-Secretase for the Treatment of Alzheimer’s

Abstract

Neurodegenerative diseases encompass a range of chronic diseases marked by the progressive loss of structure or function of the nervous system, particularly within areas of the brain such as the neurons (or nerve cells). This degeneration leads to a decline in cognitive abilities, motor skills, and other neurological functions. The progression can be gradual, occurring over years or even decades, and often leads to significant disability and, ultimately, death. Alzheimer’s disease (AD) is the most prevalent degenerative disease that affects cognition and that rises dramatically with age. It is a progressive, chronic disease that occurs when nerve cells in the brain die. Current treatments largely address symptoms without altering or reversing disease progression. However, recent advancements with amyloid-β (Aβ) antibodies validate Aβ as a therapeutic target for AD. This article details my long-term experience as a medicinal chemist and project leader working on γ-secretase, a key target in AD drug discovery. I will share initial insights from a multi-disciplinary effort to discover a disease modifying treatment for Alzheimer’s disease.