Scientists at the Fisher Center for Alzheimer's Research in New York have identified how a protein called presenilin 1 (PS1) 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 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," 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 said. "Better understanding of how presenilin 1 works in the brain may lead to novel treatments for Alzheimer's disease."
Even though 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 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.
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.