Alzheimer's - Dementia, Author Interviews, UCSD / 03.03.2021 Interview with: Dr. Steven L. Wagner PhD University of California, San Diego Department of Neurosciences Professor in Residence School of Medicine, Medical Teaching Facility Room 150 La Jolla, California 92093-0624 What is the background for this study? What are the main findings?  Response: Amyloid plaques are pathological hallmarks of Alzheimer’s disease (AD)—clumps of misfolded proteins that accumulate in the brain, disrupting and killing neurons and resulting in the progressive cognitive impairment that is characteristic of the widespread neurological disorder.  Amyloid plaques are composed of small protein fragments called amyloid beta (Aβ) peptides. These peptides are generated by enzymes called β-secretase and γ-secretase, which sequentially cleave a protein called amyloid precursor protein on the surfaces of neurons to release Aβ fragments of varying lengths. Some of these fragments, such as Aβ42, are particularly prone to forming plaques, and their production is elevated in patients with mutations predisposing them to early-onset AD. Several attempts have been made to treat or prevent AD using drugs that inhibit either β-secretase or γ-secretase, but many of these drugs have proved to be highly toxic or unsafe in humans, likely because β-secretase and γ-secretase are required to cleave additional proteins in the brain and other organs. Instead, Wagner and colleagues investigated the therapeutic potential of drugs known as γ-secretase modulators or GSMs, which instead of inhibiting the γ-secretase enzyme, slightly alter its activity so that it produces fewer Aβ peptides that are prone to form plaques while continuing to duties cleaving other protein targets. “GSMs offer the ability to mitigate mechanism-based toxicities associated with γ-secretase inhibitors,” said Wagner.  (more…)