|
Study outlines how stroke, head injury
can increase risk of Alzheimer's disease
Cellular chain of events could be
new target for protective therapies
BOSTON - June 6, 2007 - Researchers from the MassGeneral
Institute for Neurodegenerative Disorders (MGH-MIND) have discovered
how the death of brain cells caused by a stroke or head injury may
cause generation of amyloid-beta protein - the key component of
senile plaques seen in the brains of patients with Alzheimer's disease.
Their report appears in the June 7 issue of the journal Neuron.
"We have discovered how a stroke can trigger a series of biochemical
events that increase amyloid-beta production in the brain,"
says Giuseppina Tesco, MD, PhD, of the MGH-MIND Genetics and Aging
Research Unit, the paper's lead author. "These findings raise
the prospect of novel therapies that could interfere with this process
and reduce the risk of Alzheimer's disease in stroke or head trauma
patients."
It has been known for several years that strokes and head injuries
can increase the risk of Alzheimer's disease, but the mechanism
underlying that increased risk has not been understood. Alzheimer's
disease is characterized by plaques within the brain of amyloid-beta
protein, which is toxic to brain cells. Amyloid-beta is formed when
the larger amyloid precursor protein (APP) is clipped by two enzymes
- beta-secretase, also known as BACE, and gamma-secretase - which
releases the amyloid-beta fragment. The usual processing of APP
by an enzyme called alpha-secretase produces an alternative, non-toxic
protein.
The MGH-MIND team previously reported that cellular BACE levels
are normally controlled by the enzyme's breakdown in compartments
called lysosomes, a process that is disrupted if a molecular signal
on the enzyme is altered. That signal binds to GGA proteins, which
are required for the transport of several types of enzymes into
lysosomes. One of these proteins, GGA3, can be degraded by caspase,
an enzyme takes part in the cell-death process called apoptosis.
In a series of experiments the MGH-MIND researchers revealed how
cell death caused by a brain injury, including a stroke, can lead
to the production of amyloid-beta. Damaged brain cells undergo apoptosis,
releasing caspase which also breaks down GGA3. Without enough GGA3
to help transport BACE to lysosomes, levels of BACE rise and lead
to increased amyloid-beta production. Amyloid-beta itself is toxic
to brain cells, so it may cause further apoptosis, leading to a
vicious cycle of continued cell death and amyloid-beta production.
The importance of GGA3's control of BACE levels was supported by
the observation that, in brain tissue from Alzheimer's patients,
reductions in GGA3 corresponded with elevations in BACE, particularly
in those areas most affected by the disease.
"Our findings also shed new light on how the aged brain becomes
more vulnerable to AD, since any insult to the brain - head injury,
stroke, or the mini-strokes called TIAs - can set off this process
and turn up BACE activity," says Rudolph Tanzi, PhD, director
of the Genetics and Aging Research Unit and senior author of the
Neuron paper. "Therapies that protect GGA3 from caspase
cleaving might be able to reduce the risk of AD or the more transient
type of dementia that can occur after such injuries." Tanzi
is a professor of Neurology at Harvard Medical School, where Tesco
is an assistant professor.
The research was supported by grants from the National Institute
of Health, the National Institute of Mental Health, the American
Health Assistance Foundation, the Cure Alzheimer's Fund, and the
John French Douglas Foundation. Additional co-authors of the Neuron
paper are Young Ho Koh, PhD, Eugene Kang, MPH, Andrew Cameron, Shinjita
Das, and Mikko Hiltunen, PhD, of MGH-MIND; Miguel Sena-Esteves,
PhD, MGH Neuroscience Center; Shao-Hua Yang, MD, PhD, and James
Simpkins, PhD, University of North Texas; and Zhenyu Zhong, PhD,
and Yong Shen, MD, PhD, Sun Health Research Institute.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine.
MGH and Brigham and Women's Hospital are founding members of Partners
HealthCare HealthCare System, a Boston-based integrated health care
delivery system.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
Information about Clinical Trials
|
|
|
