Alzheimer's Research at Red Cross Lab Could Lead to Treatments

Written by Becky Orfinger, Staff Writer, RedCross.org

February 21, 2001 — Approximately 4 million Americans suffer from Alzheimer's Disease, a progressive, degenerative disease of the brain that is the most common form of dementia among the elderly. According to the Alzheimer's Association, the largest private supporter of research on the disease, an even greater number of people in the United States care for family members with Alzheimer's. In the past few decades, scientists throughout the world have devoted countless hours of research to finding treatments — if not a cure — for this devastating disease. Scientists at the American Red Cross Jerome H. Holland Laboratory for the Biomedical Sciences in Rockville, Md., in collaboration with a research group at Massachusetts General Hospital, have patented a potential approach to treatment for Alzheimer's disease. This research could lead to a treatment that might delay the onset of the disease — and the progressive memory loss that accompanies it — once it is diagnosed.

The brain of an Alzheimer's patient is marked by two major abnormalities: neurofibrillary tangles and amyloid (or senile) plaques. Neurofibrillary tangles are bundles of protein filaments found inside nerve cells, and senile plaques are clusters of amyloid (hard protein deposits resulting from tissue degeneration) surrounded by dead or dying cells. Senile plaques are mainly composed of a small peptide, called beta amyloid, which is derived from a much larger precursor protein called beta amyloid precursor protein (APP). Other than manufacturing the protein that becomes a plaque that can lead to Alzheimer's, APP's function in the body is unknown.

Establishing a Link Between LRP and AP

Dr. Dudley Strickland, head of the Vascular Biology Department at the Holland Laboratory, has been collaborating with Bradley Hyman, MD, at Massachusetts General Hospital since 1995 to determine the role that the low-density lipoprotein receptor-related protein (LRP) plays in the brain. LRP is a large receptor that is located on the surface of cells, and functions to transport a variety of proteins into compartments within the cell where they are broken down by digestive enzymes. Although they didn't know it when they began their work, it turned out that there was an important relationship between LRP and APP. "We found that LRP can bind to certain forms of APP, and speculated that this association may alter the production of beta amyloid, which in turn causes the symptoms characteristic of Alzheimer's disease," said Strickland.

In 1995, Strickland and his colleagues published their findings about the relationship between APP and LRP in the scientific journal Cell. The paper reported that a soluble form of APP is taken in and broken down by cells in a process mediated by LRP. Moreover, the researchers found that cells lacking LRP were unable to break down APP. Strickland's research also demonstrated that the use of LRP "antagonists" — agents that block the function of LRP — prevents the breakdown of soluble APP as well. Based on the 1995 study, they speculated that if LRP is associated with the transmembrane form of APP, this could lead to increased breakdown of APP, resulting in increased formation of amyloid plaques.

In a study published in the Journal of Biological Chemistry last year, Strickland and his colleagues tested the hypothesis that had been generated from the first study — that LRP-mediated internalization of APP can modulate APP processing, and, in turn, affect beta amyloid production. They found that when cells were grown in the presence of the LRP antagonists, or blockers, cell-surface levels of APP increased and levels of beta amyloid decreased. These results suggested that the precursor protein was not being internalized by the cells and, in turn, not synthesizing beta amyloid in large amounts. Conversely, when the researchers restored LRP function in cells that had been LRP-deficient, they saw a significant increase in beta amyloid synthesis, strongly supporting the hypothesis that LRP contributes to beta amyloid production.

In December 2000, Strickland and his colleagues were granted a patent based on the possible pharmacological applications of their research. "Based on what we discovered about LRP-that it modifies the processing of APP and enhances the synthesis of beta amyloid — there is potential to develop a drug to block the interaction between the APP and LRP," said Strickland. The patent, which was awarded to both the American Red Cross and Massachusetts General Hospital, covers the use of any pharmacological agent that would block the ability of LRP to bind to APP.

Although a cure for Alzheimer's disease still eludes researchers, each development brings scientists closer to developing new treatments for the disease. No one can be sure what the clinical applications of this research on LRP will be. However, Strickland hopes that the group's findings may lead to the development of drugs that could influence the course of this disease or at least increase the age at which the body begins to produce amyloid plaques. Strickland expects that the research team's technology will be licensed by the end of this year, which will likely result in the development of a chemical compound with the potential to treat Alzheimer's disease. He said that it will be at least five years before clinical trials of this type of treatment begin, and even longer before a drug is available on the market.

But Strickland is confident the research team's results will eventually contribute to some sort of drug treatment to slow down the progression of Alzheimer's. "Evidence suggests that amyloid production and removal in the body are in a delicate balance," he said. "Somehow, this balance is tipped as we age, and for this reason age is the most significant risk factor for Alzheimer's. By pursuing more research on the relationship between LRP and APP, we hope to be able to understand how LRP influences amyloid production and prevent this increase until a much later age in life."