Road to cell death mapped in the Alzheimer’s brain

GRAND RAPIDS, Mich. (May 21, 2019) — Scientists have identified a new mechanism that accelerates aging in the brain and gives rise to the most devastating biological features of Alzheimer’s disease.

The findings also unify three long-standing theories behind the disease’s origins into one cohesive narrative that explains how healthy cells become sick and gives scientists new avenues for screening compounds designed to slow or stop disease progression, something existing medications cannot do.

“We now have a better understanding of the molecular factors that lead to Alzheimer’s disease, which we can leverage to develop improved and desperately needed treatment and prevention strategies,” said Viviane Labrie, Ph.D., an assistant professor at Van Andel Research Institute (VARI) and senior author of the study, which appears in the May 21 edition of Nature Communications. “Alzheimer’s is a major growing public health problem around the world. We need better options for patients and we need them soon.”

Alzheimer’s disease is the sixth leading cause of death in the U.S. and the most common cause of dementia worldwide. An estimated 5.8 million people in the U.S. and 44 million people worldwide have Alzheimer’s. By 2050, those numbers are expected to rise to 14 million and 135 million respectively, due in part to a growing and aging global population.

The findings center on genetic “volume dials” called enhancers, which turn the activity of genes up or down based on influences like aging and environmental factors. Labrie and her colleagues took a comprehensive look at enhancers in brain cells of people at varying stages of Alzheimer’s and compared them to the cells of healthy people. They found that in normal aging, there is a progressive loss of important epigenetic marks on enhancers. This loss is accelerated in the brains of people with Alzheimer’s, essentially making their brain cells act older than they are and leaving them vulnerable to the disease.

At the same time, these enhancers over-activate a suite of genes involved in Alzheimer’s pathology in brain cells, spurring the formation of plaques and tangles, and reactivating the cell cycle in fully formed cells — a highly toxic combination.

“In adults, brain cells typically are done dividing. When enhancers reactivate cell division, it’s incredibly damaging,” Labrie said. “The enhancer changes we found also encourage the development of plaques, which act as gasoline for the spread of toxic tangles, propagating them through the brain like wildfire. Taken together, enhancer abnormalities that promote plaques, tangles and cell cycle reactivation appear to be paving the way for brain cell death in Alzheimer’s disease.”

Importantly, Labrie and her colleagues linked enhancer changes to the rate of cognitive decline in Alzheimer’s patients.

The study is the first comprehensive investigation of enhancers in human brain cells and in Alzheimer’s disease, and included in-depth analysis of epigenetic, genetic, gene expression and protein data.

Next, the team plans to develop new experimental systems to screen compounds that may fix dysregulation in enhancers and that have potential as new treatments or preventative measures.

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Other authors include Peipei Li, Ph.D., Lee Marshall, Ph.D., and Jennifer L. Jakubowski of VARI; Gabriel Oh, Ph.D., Daniel Groot and Arturas Petronis, M.D., Ph.D., of the Centre for Addiction and Mental Health; and Yu He and Ting Wang, Ph.D., of Washington University. Petronis also is affiliated with the Institute of Biotechnology at Vilnius University.

This work was supported by the U.S. Army Medical Research Materiel Command through the Parkinson’s Research Program under award no. W81XWH1810512 (Labrie). Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the U.S. Army.

Research reported in this publication also was supported by the Brain Behavior and Research Foundation award no. 23482 (Labrie); Alzheimer’s Society of Canada (Labrie); the Scottish Rite Charitable Foundation of Canada (Labrie); Canadian Institutes of Health Research award nos. MOP-199170, MOP-119451 and MOP-776689 (Petronis); National Institute of Mental Health award no. MH088413 (Petronis); the Krembil Foundation (Petronis); and Brain Canada (Petronis). The content is solely the responsibility of the authors and does not necessarily represent the official views of the granting organizations.

Van Andel Institute (VAI) is an independent nonprofit biomedical research and science education organization committed to improving the health and enhancing the lives of current and future generations. Established by Jay and Betty Van Andel in 1996 in Grand Rapids, Michigan, VAI has grown into a premier research and educational institution that supports the work of more than 400 scientists, educators and staff. Van Andel Research Institute (VARI), VAI’s research division, is dedicated to determining the epigenetic, genetic, molecular and cellular origins of cancer, Parkinson’s and other diseases and translating those findings into effective therapies. The Institute’s scientists work in onsite laboratories and participate in collaborative partnerships that span the globe. Learn more about Van Andel Institute at vai.org.