New studies in mice show another origin of plaques in Alzheimer’s disease

New studies in mice show that disruption of the way brain cells get rid of waste products precedes the accumulation of debris-filled plaques known to occur in Alzheimer’s disease.

For decades, scientists have claimed that such plaques, including the protein amyloid beta, accumulated outside the cells as an important first step towards the brain damage observed in Alzheimer’s disease. Led by researchers at the NYU Grossman School of Medicine and the Nathan S. Kline Institute for Psychiatric Research, this new study challenges this idea, known as the amyloid cascade hypothesis.

The latest research results instead claim that the nerve damage characteristic of Alzheimer’s disease takes root in the cells long before these filamentous amyloid plaques are fully formed and aggregate in the brain.

Published as a journal cover article Nature Neuroscience An online study on June 2 followed the root dysfunction observed in mice reared to develop Alzheimer’s disease to the lysosomes of brain cells. These are all intracellular small bags filled with acidic enzymes involved in the daily decomposition, removal and recycling of metabolic waste from routine cellular reactions and diseases. Researchers also point out that lysosomes are the key to breaking down and disposing of parts of the cell itself when the cell dies naturally.

As part of the study, researchers tracked a decrease in acid activity in intact mouse cell lysosomes due to cell damage as a result of the disease. Imaging tests developed at NYU Langone and the Nathan Klein Institute to track the removal of cellular waste products fuse specific brain cell lysosomes with so-called autophagic vacuoles filled with undegraded waste products. Shown to expand with. These autophagy vacuoles also contained previous forms of amyloid beta.

As a result, in neurons destined for premature death with the greatest damage, vacuoles are pooled together in a “flower-like” pattern, bulging from the outer membrane of the cell and gathering around the nucleus of each cell. rice field. Accumulation of amyloid beta formed filaments in the cells. This is another feature of Alzheimer’s disease. Indeed, researchers have observed plaques that are almost completely formed inside some damaged neurons.

Our results are the first to cause the nerve damage observed in Alzheimer’s disease to problems within the lysosomes of brain cells where amyloid beta first appears. “

Dr. Lee Joo-hyun, Principal Researcher

“Previously, the working hypothesis was primarily due to the damage observed in Alzheimer’s disease that occurred after amyloid accumulation outside the brain cells rather than inside the neurons,” the ministry said. Dr. Lee, an assistant professor, said. Psychiatry Research scientist at the Nathan Klein Institute at NYU Langone.

“This new evidence changes the basic understanding of how Alzheimer’s disease progresses, and brain cells are already dysfunctional before the amyloid plaque is completely formed extracellularly. It also explains why so many treatments designed to remove amyloid plaque could not stop the progression of the disease, “says Principal Investigator Ralph A. Nixon, MD, PhD. increase.

“Our research suggests that future treatments should focus on reversal of lithosome dysfunction and rebalancing of acid levels in neurons of the brain,” NYU Langone’s psychiatry and cell biology. Dr. Nixon, a professor of the department and director of the center, says for dementia research at the Nathan Klein Institute.

Researchers say they are already working on treatments to treat the lysosomal problems observed in their study.

Recent studies published in April Science Advances According to the NYU Langone team, one cause of cell waste disposal problems lies in a gene called PSEN1. This gene has long been known to cause Alzheimer’s disease, but its additional role in causing the disease through lysosomal dysfunction is now becoming apparent.

Their recent studies have also shown that neuronal damage in the PSEN1 mouse model of Alzheimer’s disease can be reversed by restoring appropriate acid levels in lysosomes.

This study is covered by US patent 9,265,735 on how to treat Alzheimer’s disease based on reversing the deoxidation of lysosomes, which is the root cause of waste accumulation. The terms of the patent are governed by the policies of the medical system.

According to the National Institute on Aging, which is part of the National Institutes of Health (NIH), more than 6 million Americans (mostly 65 and older) have dementia (thinking, memory, reasoning progression) due to Alzheimer’s disease. I am suffering from sexual loss). disease.