Route of mapped cell death in the Alzheimer's brain

Scientists have identified a new mechanism that accelerates brain aging and gives birth to the most devastating biological features of Alzheimer's disease.

The results also bring together three long-standing theories about the origin of the disease in a coherent narrative that explains how healthy cells get sick and gives scientists new ways to screen compounds designed to slow or stop progression of the disease, what existing drugs can not do.

"We now better understand the molecular factors at the origin of Alzheimer's disease, which we can rely on to develop improved and desperately needed treatment and prevention strategies," said Viviane Labrie, Ph. D., Assistant Professor at the Van Andel Research Institute. (VARI) and lead author of the study, which appears in the May 21 edition of the Nature Communications. "Alzheimer's disease is a growing public health problem around the world, we need better options for patients and we need it quickly."

Alzheimer's disease is the sixth leading cause of death in the United States and the most common cause of dementia in the world. It is estimated that 5.8 million people in the United States and 44 million people worldwide are afflicted with Alzheimer's disease. By 2050, these numbers are expected to reach 14 million and 135 million respectively, partly because of the growth and aging of the world's population.

The discoveries focus on genetic "volume wheels" called activators, which activate or inhibit the activity of genes based on influences such as aging and environmental factors. Labrie and colleagues extensively examined amplifiers in the brain cells of people at different stages of Alzheimer's disease and compared them to the cells of healthy people. They found that in normal aging, there was a gradual loss of important epigenetic marks on activators. This loss is accelerated in the brains of people with Alzheimer's disease, which has the effect of making their brain cells older than they are and making them vulnerable to the disease.

At the same time, these activators over-activate a series of genes involved in Alzheimer's pathology in brain cells, thereby stimulating plaque and node formation and reactivating the cell cycle in fully formed cells, a combination of highly toxic.

"In the adult, brain cells are usually divided.When activators reactivate cell division, it is extremely damaging," Labrie said. "The enhancer modifications we found also encourage the development of plaques that act as gasoline for the spread of toxic entanglements, spreading them in the brain like wildfire. Activator-promoting plaques, entanglements, and reactivation of the cell cycle seem to pave the way for brain cell death in Alzheimer's disease. "

It is important to note that Labrie and colleagues have linked activation changes to the rate of cognitive decline in Alzheimer's patients.

This is the first comprehensive study of enhancers in human brain cells and Alzheimer's disease. It includes a thorough analysis of epigenetic, genetic, gene expression and protein data.

The team then plans to develop new experimental systems for the screening of compounds that can cure the dysregulation of activators and may constitute new treatments or preventive measures.