Endotype reversal as a novel strategy for screening drugs targeting familial Alzheimer's disease

Year: 2022

Type: article

Abstract: While amyloid‐β (Aβ) plaques are considered a hallmark of Alzheimer's disease, clinical trials focused on targeting gamma secretase, an enzyme involved in aberrant Aβ peptide production, have not led to amelioration of AD symptoms or synaptic dysregulation. Screening strategies based on mechanistic, multi‐omics approaches that go beyond pathological readouts can aid in the evaluation of therapeutics. Using early‐onset Alzheimer's (EOFAD) disease patient lineage PSEN1A246E iPSC‐derived neurons, we performed RNA‐seq to characterize AD‐associated endotypes, which are in turn used as a screening evaluation metric for two gamma secretase drugs, the inhibitor Semagacestat and the modulator BPN‐15606. We demonstrate that drug treatment partially restores the neuronal state while concomitantly inhibiting cell cycle re‐entry and dedifferentiation endotypes to different degrees depending on the mechanism of gamma secretase engagement. Our endotype‐centric screening approach offers a new paradigm by which candidate AD therapeutics can be evaluated for their overall ability to reverse disease endotypes.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz.12553

Authors: Andrew B. Caldwell, Qing Liu, Can Zhang, Gary P. Schroth, Douglas R. Galasko, Kevin D. Rynearson, Rudolph E. Tanzi, Shauna H. Yuan, Steven L. Wagner, Shankar Subramaniam

Institutions: University of California San Diego, Massachusetts General Hospital, Illumina (United States), University of Minnesota, Minneapolis VA Health Care System, Minneapolis VA Medical Center, VA San Diego Healthcare System

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,000

Funders: National Science Foundation, U.S. Department of Veterans Affairs, Alzheimer's Association, Cure Alzheimer's Fund, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, U.S. National Library of Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development

OpenAlex ID: W4210689175