Researchers
have cracked part of the code for an important gene function in familial
Alzheimer's disease (FAD), an early-onset type of AD. Alzheimer's
disease is the most common cause of dementia. Working with cells in
culture that had been altered to overexpress the amyloid precursor
protein (APP), the researchers were able to document that expression
of a mutant form of the presenilin-1 (PS-1) protein caused a significant
reduction in the amount of amyloid formed. This continuing study of
the mechanisms of plaque formation, researchers believe, moves them
ever closer to the possible development of novel drugs to intervene
in the processes leading up to Alzheimer's dementia.
Naturally
occurring mutations in PS-1 are found in about 40 percent of people
with FAD. Previous studies have suggested that these inherited
PS-1 gene mutations increase the amount of amyloid clipped out
from the larger amyloid precursor protein, but no one could determine
how that clipping occurred. Researchers named the elusive and not-well-understood
enzyme that is involved in the clipping, gamma secretase. The current
research suggests that either PS-1 may be the long sought gamma-secretase,
or that PS-1 is essential for gamma secretase's ability to clip
amyloid.
The
study of mutated PS-1 protein was published in the April 8, 1999,
issue of Nature by Dr. Dennis J. Selkoe and his colleagues
at Harvard Medical School and Brigham and Women's Hospital, Boston,
and the University of Tennessee, Memphis. Their work focuses on the
chemical events that may lead to the development of brain damage and
the symptoms of dementia. The National Institute on Aging (NIA), and
the National Institute of Neurological Disorders and Stroke (NINDS),
two components of the National Institutes of Health (NIH), funded
the study.
In their
search to explain why the amyloid fragments clump into plaques,
which surround the brain cells of Alzheimer's disease patients,
Dr. Selkoe's group gained an insight into the interaction of
two key molecules involved in amyloid formation. When they altered
the sequence of amino acids of the presenilin protein from the normal
sequence in two critical locations, buried within the cell membrane,
amyloid formation was reduced.
According
to Dr. D. Stephen Snyder, who directs studies of the Etiology of Alzheimer's
Disease at NIA's Neuroscience and Neuropsychology of Aging Program,
"These studies have implications for the treatment of AD and
related disorders of amyloid accumulation. If this gamma-secretase
finding proves true, it could lead to significant advances in therapeutics
research by showing us how to intervene before plaques form."
The
NIA is the lead federal agency supporting and conducting Alzheimer's
disease research, including studies of the basic, clinical, and epidemiological
aspects of this and other related dementias of aging. The NIA's
Alzheimer's Disease Education and Referral (ADEAR) Center can
provide more information on Alzheimer's disease by calling 1-800-438-4380.
The
NINDS is the nation's premier supporter of research on the brain
and nervous system and a lead agency for the Congressionally designated
Decade of the Brain. NINDS celebrates 50 years of brain and nervous
system research in the year 2000.
Reference:
Michael
S. Wolfe, Weiming Xia, Beth L. Ostaszewski, Thekla S. Diehl, W. Taylor
Kimberly, and Dennis J. Selkoe. Two transmembrane aspartates in presenilin-1
required for presenilin endoproteolysis and gamma-secretase activity.
Nature, 398, (513-517).
