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Calcium
may be the key to understanding Alzheimer's
Disease
Newswise — Researchers at the University of
Pennsylvania School of Medicine have shown
that mutations in two proteins associated
with familial Alzheimer's disease disrupt
the flow of calcium ions within neurons.
The two proteins, called PS1 and PS2 (presenilin
1 and 2), interact with a calcium release
channel in an intracellular cell
compartment.
“The ‘calcium dysregulation’ hypothesis for
inherited, early onset familial Alzheimer's
disease has been suggested by previous
research findings, but our current study
identifies a molecular mechanism that makes
this hypothesis very compelling,” says lead
author J. Kevin Foskett, PhD, Professor of
Physiology.
“Mutated PS1 and PS2 caused exaggerated
cellular calcium signaling in cells through
a calcium channel in the endoplasmic
reticulum called the inositol trisphosphate
receptor [InsP3R], suggesting that it or
other proteins in this calcium signaling
pathway could be targets for new Alzheimer’s
disease therapies.” The study appeared in
the June 26 issue of Neuron.
Alzheimer’s disease affects as many as 5
million Americans, 5 percent of whom have
the familial form.
The hallmark of the disease is the
accumulation of tangles and plaques of
amyloid beta protein in the brain.
“The amyloid hypothesis has long been
invoked to explain the cause of Alzheimer’s”
says Foskett. In the Neuron study, cells
that carried the disease-causing mutated
form of PS1 showed increased processing of
amyloid beta that depended on the
interaction of the PS proteins with the
InsP3R.
This observation links mis-regulation of
calcium inside cells with the production of
amyloid, a characteristic feature in the
brains of people with Alzheimer’s disease.
Current therapies for Alzheimer’s include
drugs that treat the symptoms of cognitive
loss and dementia.
Drugs that address the pathology of
Alzheimer’s are only experimental. For
example, a vaccine that stimulates
antibodies to amyloid beta is currently
being investigated.
But these new observations suggest that new
approaches could be explored. The next steps
are to find out if other mutations in PS1
and PS2 that cause Alzheimer’s disease have
a similar effect on calcium signaling in the
brain, and to identify drugs that might
inhibit the interaction between InsP3R and
PS1 or PS2 specifically in the brain.
“The significance of identifying the
molecular mechanism and pathway of disrupted
calcium signaling is that a number of novel
treatment targets can now be developed and
tested,” says Foskett.
The central role of calcium signaling
disruptions in Alzheimer’s is strengthened
by another study in which the Foskett
laboratory was involved.
This
research was published in the June 27 issue
of Cell. Investigators discovered a new gene
that influences calcium regulation and
amyloid beta levels in the brain.
In this genetic study, a polymorphism in the
gene CALHM1 significantly increased the risk
of sporadic, late-onset Alzheimer’s, the
more common form of disease.
The Foskett lab was responsible for showing
that the Alzheimer’s disease-associated
polymorphism disrupts the gene’s function in
cellular calcium regulation.
These investigations were led by a group
from The Feinstein Institute for Medical
Research, North Shore in Manhasset, NY and
the Albert Einstein College of Medicine,
Bronx, NY.
“Calcium is the common denominator in our
two studies, strongly suggesting that it
plays an important role in the development
of Alzheimer’s disease,” notes Foskett.
“However, our experiments have identified
calcium inside cells as the important
feature. No one should consider modifying
their dietary intake of calcium as a
strategy to limit the risk of developing
Alzheimer’s disease, because the body very
effectively regulates the amount of calcium
absorbed from food and the levels in the
blood and brain.
"And
it is also very important for people who
take calcium channel blockers, for
cardiovascular problems for example, not to
alter their medication regime as a response
to our studies”
This research was supported by grants from
the National Institutes of Health and the
Alzheimer's Disease Core Center at Penn.
PENN Medicine is a $3.5 billion enterprise
dedicated to the related missions of medical
education, biomedical research, and
excellence in patient care.
PENN Medicine consists of the University of
Pennsylvania School of Medicine (founded in
1765 as the nation's first medical school)
and the University of Pennsylvania Health
System.
Penn's School of Medicine is currently
ranked #4 in the nation in U.S.News & World
Report's survey of top research-oriented
medical schools; and, according to most
recent data from the National Institutes of
Health, received over $379 million in NIH
research funds in the 2006 fiscal year.
Supporting 1,400 fulltime faculty and 700
students, the School of Medicine is
recognized worldwide for its superior
education and training of the next
generation of physician-scientists and
leaders of academic medicine.
The University of Pennsylvania Health System
includes three hospitals — its flagship
hospital, the Hospital of the University of
Pennsylvania, rated one of the nation’s
“Honor Roll” hospitals by U.S.News & World
Report; Pennsylvania Hospital, the nation's
first hospital; and Penn Presbyterian
Medical Center — a faculty practice plan; a
primary-care provider network; two
multispecialty satellite facilities; and
home care and hospice.
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