New York, New York, May 22, 2017 – Scientists at the Fisher Center for Alzheimer’s Research in New York, led by Nobel Laureate Dr. Paul Greengard, have identified new ways in which a protein called presenilin 1 may act to cause the sticky brain plaques that are a hallmark of Alzheimer’s disease. The findings could open up new avenues of research for the development of novel, more effective drugs for Alzheimer’s, a disease that currently has no cure.
Presenilin 1, or PS1, plays a critical role in the buildup of beta-amyloid, the toxic protein that clumps together to form the telltale brain plaques of Alzheimer’s. In two new studies, both published in the Proceedings of the National Academy of Sciences, the researchers reveal unique ways in which the PS1 molecule may raise or lower levels of beta-amyloid.
“Presenilin 1 has come under increasing scrutiny in recent years, as researchers aim to unravel the underlying processes that lead to beta-amyloid buildup and the devastating brain losses of Alzheimer’s disease,” said Victor Bustos, the lead author of both studies and a scientist at the Fisher Center for Alzheimer’s Research at The Rockefeller University in New York. “Better understanding of how presenilin 1 works in the brain may lead to novel treatments for Alzheimer’s disease.”
Researchers already knew that PS1 plays a key role in Alzheimer’s disease. Some people, for example, carry certain mutations of presenilin genes and go on to develop early-onset Alzheimer’s disease, exhibiting severe memory and thinking problems as early as their 30s or 40s. Their young brains are riddled with the sticky deposits of toxic beta-amyloid.
Scientists also knew that the formation of beta-amyloid is a multistep process. The process begins with a long protein called amyloid precursor protein, which is first cleaved by an enzyme called beta-secretase to form a protein called beta-C-terminal fragment, or beta-CTF. PS1, a core component of another enzyme called gamma-secretase, then comes into play. It cuts the beta-CTF protein into still smaller fragments, creating the sticky protein known as beta amyloid.
But even thought scientists have long known that PS1 plays a critical role in beta-amyloid creation, less was known about the factors that control PS1 itself. “Although it has a central role in the pathogenesis of Alzheimer’s disease, knowledge of the mechanisms that regulate PS1 function is limited,” the authors wrote.
The new research helps to elucidate some of those mechanisms. In the first paper, the Fisher Center scientists showed how targeting a specific site on the PS1 protein called Ser367 could dramatically alter levels of beta amyloid. Indeed, adding a phosphate molecule — a regulatory process known as phosphorylation that commonly occurs in nature — to that site only led to a significant decrease in the level of beta-amyloid produced.
“The phosphorylation process acts as a kind of “on” and “off” switch, setting off a cascade of events that leads to more or less beta-amyloid production,” said Marc Flajolet, an author in these studies and a scientist at the Fisher Center for Alzheimer’s Research at The Rockefeller University “We show that phosphorylation of PS1 at Ser367 does not affect gamma-secretase activity, but has a dramatic effect on beta-amyloid levels.”
The researchers identified the specific enzyme responsible for the phosphorylation process. Inhibiting that enzyme, and thereby dampening the phosphorylation process, led to higher levels of beta amyloid, the researchers reported.
Furthermore, a gene mutation that altered the phosphorylation process in mice that had been bred to develop a disease resembling Alzheimer’s disease led to dramatic increases in levels of beta-amyloid as well as beta-CTF, the beta-amyloid precursor protein, in the lab animals.
The gene mutations also diminished the cell’s ability to break down beta-CTF, leading to higher levels of plaque in the animal’s brains. Conversely, the researchers found, selective phosphorylation of the site on PS1 led to increased degradation of the beta-amyloid precursor protein, resulting in lower levels of beta-amyloid. “We are very excited by these new developments and are more committed than ever to prevent the onslaught of this disease. The Foundation is extremely proud to be funding Drs. Greengard, Busto, and Flajolet and their colleagues,” said Kent Karosen, President/CEO, Fisher Center for Alzheimer’s Research Foundation.
In a second report, scientists at the Fisher Center and Yale University took a closer look at how presenilin 1 regulates the breakdown of the beta-amyloid precursor protein. They found that when presenilin 1 was phosphorylated at the Ser367 site, it promotes a cascade of reactions that cause beta-CTF to become walled off in isolated specific compartments (vesicles), which then fuse with another type of vesicle containing enzymes that dissolve the protein. Excess beta-CTF is essentially “eaten” by the cell, a cell cleaning process called autophagy.
“Our results demonstrate that PS1 regulates beta-amyloid levels by a unique bifunctional mechanism,” the authors wrote. “We show that PS1, in addition to generating beta-amyloid, can also decrease beta-amyloid levels by directing beta-CTF degradation through autophagy. This previously unrecognized mechanism of regulation of beta-amyloid by presenilin 1 could provide an attractive target for potential Alzheimer’s disease therapies.”
Better understanding of how presenilin functions, scientists hope, could provide new targets for Alzheimer’s treatments. Creating a drug that targets the phosphorylation site of PS1 might, for example, dramatically lower levels of beta amyloid. That could result in less accumulation of the toxic protein, and less buildup of plaques. Drugs might also be created that target other steps in the process.
“Drugs designed to increase the level of PS1 phosphorylated at Ser367 should be useful in the treatment of Alzheimer’s disease,” the authors concluded. The studies were funded by the Fisher Center for Alzheimer’s Research Foundation and by the National Institutes of Health.
About the Fisher Center for Alzheimer’s Research Foundation
Led by President and CEO, Kent L. Karosen, the Foundation was established in 1995 by Zachary Fisher to primarily fund the work of the scientists at the Fisher Center for Alzheimer’s Research at The Rockefeller University. The Foundation has received the exceptional 4-Star rating from Charity Navigator for the sixth consecutive year.
The Fisher Center at The Rockefeller University is one of the largest and most modern facilities in the world dedicated to solving the puzzle of Alzheimer’s, and is considered by many to be a prototype for Alzheimer’s research. The Center is led by Nobel Laureate Dr. Paul Greengard, recipient of multiple awards and honors throughout his career, and includes a research team of over 50 world-renowned scientists. To learn more about the Fisher Center’s innovative research, go to www.ALZinfo.org.
About The Rockefeller University
The Rockefeller University is the world’s leading biomedical research university and is dedicated to conducting innovative, high-quality research to improve the understanding of life for the benefit of humanity. Our 79 laboratories conduct research in neuroscience, immunology, biochemistry, genomics, and many other areas, and a community of 1,800 faculty, students, postdocs, technicians, clinicians, and administrative personnel work on our 14-acre Manhattan campus. Our unique approach to science has led to some of the world’s most revolutionary and transformative contributions to biology and medicine. During Rockefeller’s 115-year history, 24 of our scientists have won Nobel Prizes, 21 have won Albert Lasker Medical Research Awards, and 20 have garnered the National Medal of Science, the highest science award given by the United States.
Contact: The Fisher Center for Alzheimer’s Research Foundation