Home Cellular science The findings could explain why drugs designed to remove amyloid deposits failed to stop the disease

The findings could explain why drugs designed to remove amyloid deposits failed to stop the disease


A disruption in the way brain cells get rid of waste precedes the buildup of debris-filled plaques known to occur in Alzheimer’s disease, according to a new study in mice.

The field has argued for decades that such plaques, containing the beta-amyloid protein, accumulated outside cells as a crucial first step toward the brain damage seen in Alzheimer’s disease. Led by researchers from NYU Grossman School of Medicine and the Nathan Kline Institute, the new study challenges this idea, known as the amyloid cascade hypothesis.

Instead, the study’s latest findings support that the neuronal damage characteristic of Alzheimer’s disease takes root inside cells and long before those thread-like amyloid plaques fully form and clump together in the brain.

Publication as a cover article in the journal Natural neuroscience online June 2, the study traced the root dysfunction seen in mice bred to develop Alzheimer’s disease to the lysosomes of brain cells. They are little sacs inside every cell, filled with acidic enzymes involved in the routine breakdown, elimination, and recycling of metabolic waste products from daily cellular reactions, as well as disease. Lysosomes are also essential, the researchers note, for breaking down and eliminating a cell’s own parts when the cell dies naturally.

As part of the study, the researchers tracked the decrease in acid activity inside the intact lysosomes of mouse cells as the cells were injured by the disease. Imaging tests developed at NYU Langone Health and Nathan Kline (to follow the removal of cellular waste) showed that some brain cell lysosomes enlarged by merging with so-called autophagic vacuoles filled with waste that had not been broken down. These autophagic vacuoles also contained earlier forms of beta-amyloid.

In the most severely damaged neurons destined for premature death, the vacuoles clustered in “flower-like” patterns, bulging from the outer membranes of the cells and massing around the center or nucleus of each cell. Accumulations of beta-amyloid have formed filaments inside the cell, another hallmark of Alzheimer’s disease. Indeed, the researchers observed almost completely formed plaques inside some damaged neurons.

“Our first-time results link the neuronal damage seen in Alzheimer’s disease to problems inside the lysosomes of brain cells where beta-amyloid first appears,” says the study’s lead researcher. , Ju-Hyun Lee, PhD.

“Previously, the working hypothesis attributed the damage seen in Alzheimer’s disease primarily to what happened after amyloid builds up outside of brain cells, not before and inside neurons.” , says Lee, research assistant professor in the Department of Psychiatry and NYU Langone Health and research scientist at Nathan Kline.

“This new evidence changes our fundamental understanding of the progression of Alzheimer’s disease; it also explains why so many experimental therapies designed to remove amyloid plaques have failed to arrest disease progression, as brain cells are already paralyzed before the plaques form completely outside the cell,” says study lead researcher Ralph Nixon, MD, PhD.

“Our research suggests that future treatments should focus on reversing lysosomal dysfunction and rebalancing acid levels inside brain neurons,” says Nixon, a professor in the Department of Psychiatry and Department of Cell Biology. of NYU Langone, as well as director of the Dementia Research Center at Nathan Kline.

The researchers say they are already working on experimental therapies to address the lysosomal problems observed in their studies.

A recent study (published in April in Scientists progress) by the NYU Langone team attributed one of the causes of the cell’s waste disposal problems to a gene called PSEN1. The gene has long been known to cause Alzheimer’s disease, but its additional role in causing the disease (through lysosomal dysfunction) is only beginning to become clear.

Their recent work also showed that neuronal damage in a PSEN1 mouse model of Alzheimer’s disease could be reversed by restoring proper acid levels in lysosomes.

This work is covered by US Patent 9,265,735 which relates to methods of treating Alzheimer’s disease based on reversing lysosomal deacidification, the underlying cause of waste accumulation. Patent terms and conditions are managed in accordance with health system policies.

According to the National Institute on Aging, more than 6 million Americans, most aged 65 or older, suffer from dementia, a progressive loss of thinking, memory and reasoning due to Alzheimer’s disease.

Funding for these studies was provided by National Institute of Health grants P01AG017617, P50AG025688, and R01AG062376.

Besides Lee and Nixon, other NYU Langone and Nathan Kline study researchers involved in this research include Dun-Sheng Yang, Chris Goulbourne, Eunju Im, Philip Stavrides, Ann Pensalfini, Cynthia Bleiwas, Martin Berg, Chunfeng Huo, James Peddy, Monika Pawlik, Efrat Lévy and Mala Rao. Other co-investigators are Han Chan and Cédric Bouchet-Marquis of Thermo-Fisher Scientific in Hillsboro, Oregon; and Mathias Staufenbiel, from the University of Tubingen in Germany.