Continuing Studies of the Effects of GSM 776890 Administration on Amyloid Species and Microgliosis in Older Alzheimer’s Model Mice

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 memory loss that is characteristic of the widespread neurological disorder. Researchers at the University of California, San Diego School of Medicine, Massachusetts General Hospital and elsewhere have identified a new drug that could prevent AD by modulating, rather than inhibiting, a key enzyme involved in forming amyloid plaques. In studies using rodents and monkeys, the researchers report the drug was found to be safe and effective, paving the way for possible clinical trials in humans. Amyloid plaques are composed of small protein fragments called amyloid beta (Aβ) peptides. These peptides are generated by enzymes called beta-secretase and gamma-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 beta-secretase or gamma-secretase, but many of these drugs have proved to be highly toxic or unsafe in humans, likely because beta-secretase and gamma-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 gamma-secretase modulators or GSMs, which, instead of inhibiting the gamma-secretase enzyme, slightly alter its activity so that it produces fewer Aβ peptides that are prone to form plaques, while continuing to cleave other protein targets. The novel GSM then was tested in a mouse model of early-onset AD, treating the animals either before or shortly after they began to form amyloid plaques. In both cases, the novel GSM decreased plaque formation and reduced plaque-associated inflammation, which is thought to contribute to the development of disease. The findings suggest that the novel GSM could be used prophylactically to prevent AD, either in patients with genetic mutations that increase susceptibility to AD, or in cases where amyloid plaques have been detected by brain scans.