New Strategy to Fight Alzheimer’s May Come From
Control of a Gene Associated with Aging
SIRT1 gene found to control production of peptides
that form amyloid plaque in AD brains
SIRT1
Protein Protects Cells but Levels Decrease as Humans Age - See
report below news story.
July 22, 2010 – Drugs to activate the SIRT1 gene
may lead to a way to fight Alzheimer’s disease, according to MIT
biologists that have discovered the first link between the amyloid
plaques that form in the brains of Alzheimer's patients and this gene
previously implicated in the aging process.
The researchers found that SIRT1 appears to control
production of the devastating protein fragments, termed A-beta peptides,
that make up amyloid plaques.
Much-studied protein
involved in aging, and tied to red wine ingredient resveratrol, is
required for recall in mice; but over-expression fails to improve
performance - July 22, 2010
Taking one anticholinergic (Tylenol PM, Benadryl,
etc.) significantly increases
risk of developing mild cognitive impairment and taking two doubles this
risk - July 14, 2010
They also showed that in mice engineered
to develop Alzheimer's plaques and symptoms, learning and memory
deficits were improved when SIRT1 was overproduced in the brain, and
exacerbated when SIRT1 was deleted.
The results, to be reported in the July 23 issue of
the journal Cell, indicate that drugs that activate SIRT1 could
be a promising strategy to combat Alzheimer's, says Leonard Guarente,
the MIT biology professor who led the study.
Alzheimer's disease is a neurodegenerative disorder
that affects up to one-third of people who reach the age of 80. Patients
suffer from memory loss and other cognitive impairments believed to be
the result of damage from amyloid plaques.
July 20, 2005 - Researchers
Researchers have determined that a gene present in mouse
cells limits the number of times that a cell can divide. The
gene is involved in a process, called senescence, which is
thought to ensure that aging cells do not pass on harmful
mutations.
The researchers said the gene, known
as SIRT1, suppresses longevity, and may play a role in
regulating the aging process, but they caution against
interpreting the results too broadly. Dividing mouse cells
in culture are an imperfect model of how aging affects human
cells.
Amyloid plaques form when proteins called amyloid
precursor proteins (APPs) are broken into smaller amyloid peptides.
However, APPs can also be cleaved into harmless protein fragments.
In this study, the MIT researchers showed that
SIRT1 activates the production of an enzyme that cleaves APPs into
harmless fragments instead of the Alzheimer's-associated amyloid
peptides. Mice engineered to produce excess SIRT1 had reduced peptide
levels, while mice with SIRT1 knocked out showed increased peptide
levels.
The SIRT1 gene, which produces proteins called
sirtuins, has previously been shown to regulate many cell activities,
especially those involved in stress response and calorie deprivation.
Guarente first drew attention to sirtuins about 15 years ago when he
discovered that the yeast version of the gene, SIR2, regulates longevity
in yeast. Later work revealed similar effects in worms, mice and rats.
Other authors of the Cell paper are MIT
postdoctoral associates Gizem Donmez and Dena Cohen and junior Diana
Wang. The research was funded by an American Parkinson Disease
Association fellowship, a grant from the National Institutes of Health
and a gift from the Paul F. Glenn Foundation.
SIRT1 Protein Protects Cells but Levels
Decrease as Humans Age
May help explain why protein misfolding
diseases, such as Alzheimer's, Parkinson's, Huntington's and
adult-onset diabetes, are diseases of aging
"When SIRT1 levels are high, you are in
a high-protection mode," says Richard I. Morimoto, Bill and
Gayle Cook Professor of Biochemistry, Molecular Biology and
Cell Biology in Northwestern's Weinberg College of Arts and
Sciences. He made the statement in discussing a finding from
research he led to better understand how cells are protected
from stress and damage. His team of Northwestern University
researchers studied the effect of resveratrol, a beneficial
chemical found in red wine, on human cells in tissue
culture.
The SIRT1 protein is activated by
resveratrol, which is most often associated with red wine
and the skin of red grapes according to information in the
report released April 19, 2009.
His team discovered the SIRT1 protein –
previously associated with caloric restriction and longer
lifespan – also causes, regulates heat shock factor 1
(HSF1), keeping it active. HSF1 in turn senses the presence
of damaged proteins in the cell and elevates the expression
of molecular chaperones to keep a cell's proteins in a
folded, functional state. Regulation of this pathway has a
direct beneficial effect to cells, the research shows.
"Ironically, triggering the stress
response and perhaps maintaining the cell in a protective
state over a long period of time can keep cells healthy,"
said Morimoto. "The cell is protected against an
accumulation of damage when HSF1 is more active."
SIRT1 levels decrease as humans age,
Morimoto explained. Cells can't respond to stress as well.
This decrease in SIRT1 may help explain why protein
misfolding diseases, such as Alzheimer's, Parkinson's,
Huntington's and adult-onset diabetes, are diseases of
aging.
The findings may help explain what
happens in neurodegenerative diseases, which are
age-related, when cell protection fails, proteins misfold,
lots of damage accumulates and the system falls apart.
"We now have a powerful way to think
about addressing neurodegenerative diseases," said Morimoto.
"We have identified a pathway that can be manipulated to
alter lifespan. Discovering this new basis for therapeutics
is very exciting."
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