Summary: A new study in mice found that the process of clearing brain cells of debris before the formation of amyloid plaques in Alzheimer’s disease is disrupted.
A source: NYU Langone Health
New research in mice has shown that how brain cells get rid of debris, they form plaques filled with debris from Alzheimer’s disease.
This field has been argued for decades that such plaques containing amyloid beta protein were built outside the cells as the first important step towards the brain damage observed in Alzheimer’s disease. A new study led by researchers at New York University’s Grossman School of Medicine and the Nathan Klein Institute argues this idea, called the amyloid cascade hypothesis.
Recent research suggests that the neuronal damage characteristic of Alzheimer’s disease can be absorbed into the vascular cells and before these filamentous amyloid plaques have fully formed and accumulated in the brain.
Publication as a cover article Nature Neuroscience online On June 2, the study looked at the lysosomes of brain cells from vascular dysfunction observed in mice bred to develop Alzheimer’s disease.
These are tiny sacs inside each cell, which are filled with acidic enzymes that are involved in the regular breakdown, removal, and processing of metabolic wastes from daily cell reactions as well as disease. Lysosomes are also important for breaking down and destroying parts of the cell when the cell dies naturally, the researchers note.
As part of the study, the researchers observed a decrease in acid activity inside the lysosomes of diseased mice. Visual tests developed by NYU Langone Health and Nathan Kline (to monitor cellular waste removal) have shown that the lysosomes of some brain cells grow together with autophagic vacuoles filled with undigested waste. These autophagy vacuoles also contained earlier forms of amyloid beta.
In the most severely damaged neurons, resulting in premature death, the vacuoles accumulate in a “flower-like” shape, emerge from the outer membranes of the cells, and massage the center or nucleus of each cell. The accumulation of amyloid beta forms fibers inside the cell, another sign of Alzheimer’s disease. In fact, the researchers found plaques that formed almost completely inside some damaged neurons.
“Our results suggest that the neuronal damage observed in Alzheimer’s disease for the first time leads to problems within the lysosomes of brain cells, where amyloid beta first appears,” said Joo-Hyun Lee, PhD, chief researcher.
“Previously, the working hypothesis was that the damage observed in Alzheimer’s disease was often due to the accumulation of amyloid outside the brain cells, not in front of or inside the neurons,” said Lee, a research assistant at the Langone Department of Psychiatry and New York University. Nathan Klein is a research scientist.
“This new evidence changes our basic understanding of how Alzheimer’s disease develops; It also explains why many experimental therapies designed to remove amyloid plaques have not been able to stop the disease from developing because the brain cells became disabled before the plaques formed completely outside the cell, ”said Ralph Nixon, MD, PhD, senior researcher.
“Our research suggests that future treatment should focus on restoring lysosomal dysfunction and restoring acid levels in brain neurons,” said Nixon, a professor at the Department of Psychiatry and Cell Biology at New York University and director of Langone University. Dementia Research Center at Nathan Klein.
Researchers say they are working on experimental therapies to treat lysosomal problems.
The latest study (published in April) Science Advances) A gene called PSEN1 has been identified by the NYU Langone team as one of the causes of cell waste disposal problems. The gene has long been known to cause Alzheimer’s disease, but its additional role in causing the disease (through lysosomal dysfunction) is only now becoming clear.
Their latest study also showed that neuronal damage in the PSEN1 mouse model of Alzheimer’s disease can be reversed by restoring the correct level of acid in the lysosomes.
This work is contained in 9,265,735 patents in the United States, which focus on the treatment of Alzheimer’s disease based on the return of lysosomal de-acid, the main cause of waste accumulation. The terms and conditions of the patent are governed by the policy of the health care system.
According to the National Institute on Aging, more than 6 million Americans, most of them over the age of 65, suffer from Alzheimer’s disease and progressive loss of thinking, memory, and reasoning.
Funding: Funding for these studies was provided by the National Institutes of Health P01AG017617, P50AG025688 and R01AG062376.
Lee and Nixon, other New York University researchers Langone and Nathan Kline In addition to this study, Dong-Sheng Young, Chris Gulburne, Yongju Im, Philip Stavrids, Anne Pensalfini, Cynthia Blaivas, Martin Berg, Chunfen Huo, James Paddy, Monica. , and Mala Rao. Additional researchers include Khan Chan and Cedric Boucher-Marquis, Thermo-Fisher Scientific in Hillsborough, Ore .; and Matthias Staufenbiel, of the University of Tübingen, Germany.
Research on Alzheimer’s disease
Author: David March
A source: NYU Langone Health
The connection: David March – NYU Langone Health
Photo: Photo courtesy of Springer-Nature Publishing
Original study: Open access.
“Error autolysosomal oxidation in mouse models of Alzheimer’s disease induces the autophagy structure of Aβ in neurons and forms aging plaques,” Ju-Hyun Lee et al. Nature Neuroscience
Improper autolysosomal oxidation in mouse models of Alzheimer’s disease induces the autophagic structure of Aβ in neurons and forms aging plaques.
In Alzheimer’s disease (BP), autophagy is markedly impaired. Here, we reveal the unique autophagy dysregulation and neuron-specific transgenic mRFP-eGFP-LC3 autophagy and pH based on the detection of neurons in five AD mouse models in vivo.
Oxidation of autolysosomes decreases to the deposition of extracellular amyloid in neurons, which is due to a sharp decrease in vATPase activity and selective accumulation of Aβ / APP-βCTF in enlarged deoxidized autolysosomes.
In more damaged but still intact neurons, Aβ-positive autophagy vacuoles (AVs) accumulate in large membrane membranes that form flower-like pericardial sockets. This unique pattern, called PANTHOS (poisonous anthos (flower)), is also present in the AD brain.
If additional AVs connect to the peri-nuclear networks of membrane tubes, fibrillar β-amyloid is collected intraluminally. Lysosomal membrane permeability, catepsin secretion, and lysosomal cell death are associated with microglial invasion.
Quantitative analysis confirms that the individual neurons shown by PANTHOS are the main source of aging plaques in amyloid precursor protein AD models.