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

Alzheimer’s Disease: Animal Model Demonstrates Ability of Novel Enzyme to Decrease Amyloid Plaques

MedicalResearch.com 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

Dr. Wagner

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

MedicalResearch.com: 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.

MedicalResearch.com: What should readers take away from your report?

Response: 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.

“Alzheimer’s disease is an extraordinarily complex and multi-faceted condition that has, so far, defied effective treatment, let alone prevention,” said senior author Steven L. Wagner, PhD, professor in the Department of Neurosciences at UC San Diego School of Medicine. “Our findings suggest a potential therapy that might prevent one of the key elements of AD.”

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: In the new JEM study, researchers created a novel GSM and tested it on mice, rats and macaques. They found that repeated, low doses of the GSM eliminated Aβ42 production in mice and rats, without causing any toxic side effects. The drug was also safe and effective in macaques, reducing Aβ42 levels by up to 70 percent.

The novel GSM was then 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, write the authors, either in patients with genetic mutations that increase susceptibility to AD or in cases where amyloid plaques have been detected by brain scans.

“In this study, we have pharmacologically characterized a potent GSM that, based on its preclinical attributes, appears to equal or exceed the potency of any previously tested GSMs,” said co-author Rudolph Tanzi, PhD, professor neurology at Harvard Medical School and director of the Genetics and Aging Research Unit at Massachusetts General Hospital.

“Future clinical trials will determine whether this promising GSM is safe in humans and could be used to effectively treat or prevent Alzheimer’s disease.”

Citation:

Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention” by Steven L. Wagner et al. Journal of Experimental Medicine

Mar 3, 2021 @ 12:27 am

The information on MedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.