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Alzheimer's, Dementia & Mental Health
Cell Activities that
Protect against Alzheimer's Protein Buildup Found
Findings may lead to new therapies for
Neurodegenerative Diseases such as Alzheimer's and Parkinson's
 August 11, 2006 Yesterday there was news of
research finding it is aging that actually causes the brain to stop
cleaning out the protein build-up that causes Alzheimer's. Today, it was
announced that those researchers have combined their work with another
group and have found new avenues to combat age-onset protein aggregation
diseases, such as AD, Parkinson's, Huntington's, and ALS.
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Related Story |
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Aging is the Critical Factor Allowing Alzheimer's to
Develop
Aging process plays an active role, too, in
Parkinsons and Huntingtons
August 10, 2006 For those who have wondered if
Alzheimer's disease is a consequence of aging or if it just takes a long
time for the toxic protein aggregates that cause it to form, researchers
have the answer. A collaboration between researchers at the Salk
Institute for Biological Studies and the Scripps Research Institute
shows that aging is the critical factor.
Read more...
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This research was led by Professor Jeffery Kelly of
Scripps Research and Professor Andrew Dillin of the Salk Institute's
Molecular and Cell Biology Laboratory and is published as an advanced article in
an the online edition of the journal Science. Salk's Dillin led
the earlier research that pin-pointed aging as the major culprit in why the
accumulation of protein. (See sidebar)
The new study-conducted in a C. elegans model, a
roundworm that expresses a protein whose aggregation appears to cause
Alzheimer's disease-showed that toxicity from protein aggregation is
"drastically reduced" when aging is slowed by modulating the insulin
growth factor (IGF) signaling pathway.
Moreover, the researchers found two novel
independent activities promoting this cellular survival. The first
protective mechanism disassembles and cuts up protein aggregates.
Surprisingly, the second protective mechanism enables the formation of
larger aggregates from smaller ones that appear to be more toxic.
Unexpected Findings
Kelly, who is the Lita Annenberg Hazen Professor of
Chemistry at The Scripps Research Institute, a member of its Skaggs
Institute of Chemical Biology, and dean of graduate and postgraduate
studies, stresses that this novel work was a synergetic collaboration
between the research groups at the two institutions.
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Genetics Used to Learn How People Reach 90 with Good
Mental Ability
August 10, 2006 - Scientists have identified genes
related to reaching age 90 with preserved cognition, according to a
study to be published in the September issue of the American Journal of
Geriatric Psychiatry. The study is among the first to identify genetic
links to mental longevity. The finding that genetics, lifestyle decision
making, and their interactions, may influence the ability to reach old
age with preserved cognition is described as "exciting."
Read more...
Drug Fully Reverses Age-Related Memory Loss by
Triggering Natural Mechanism
Study with rats shows ampakines boost brains
protein in government financed study
July 27, 2006 - A drug made to enhance memory
appears to trigger a natural mechanism in the brain that fully reverses
age-related memory loss, even after the drug itself has left the body,
according to researchers at UC Irvine. This is a significant
discovery, said Christine Gall, professor of anatomy and neurobiology.
Our results indicate the exciting possibility that ampakines could be
used to treat learning and memory loss associated with normal aging.
Read more...
Read more
on
Alzheimer's, Dementia & Mental Health |
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The Dillin lab at Salk was interested in
investigating the connection between cell aging and the onset of
proteotoxicity.
So, the group set out to determine if the aging
process in the worm could be slowed by using RNA interference (RNAi), a
naturally occurring process known to suppress certain gene activity in
living cells, to lower the activity of the IGF signaling pathway.
Indeed, this approach worked and the researchers discovered that if
aging was delayed, the onset of proteotoxicity was also postponed.
"In switching this pathway on and off, we also
found that we altered the high molecular weight aggregates-the plaque
buildup in the animals," explains Dillin.
But the researchers also noticed an unexpected
phenomenon. "Curiously," Dillin continues, "some animals were totally
protected from proteotoxicity despite having high molecular weight
aggregation buildup, while other animals were extremely sensitive to
proteotoxicity even though they had no detectable high molecular weight
aggregates."
Dillin was eager to further investigate these
unexpected findings, so he contacted Kelly at Scripps Research, whose
lab had the expertise to examine and analyze these aggregates.
Opposite Activities
Intrigued, Kelly's colleague Jan Bieschke, in
collaboration with Ehud Cohen of the Dillin laboratory, did additional
experiments perturbing individual components of the IGF signaling
pathway. They focused on two downstream transcription factors, heat
shock factor-1 (HSF-1) and DAF 16, to see what effect they had on
aggregation. The results were surprising.
"When we inhibited only HSF-1, the result was a
tremendous amount of aggregate buildup; when we selectively inhibited
DAF 16, there were almost no aggregates observed," Kelly says. "That
clued us in to the fact that these two transcription factors must be
controlling effectively opposite activities."
His group had been using aggregation assays for a
long time, and it occurred to him and his colleagues to add samples of
the worm's ground-up tissue to these assays as a way of even more
sensitively detecting how these transcription factors were controlling
aggregation in the animal. The Scripps Research team subjected the worm
contents to aggregation assays, using fluorescent dyes that emit light
when amyloid is present to read out the extent of aggregation. "It
turned out that this worked really well," Kelly says.
When Cohen and Bieschke examined the results, they
expected to see less aggregation in the worms when insulin signaling was
inhibited. In fact, what they saw was more.
Teasing apart the results, the researchers
concluded that two mechanisms were protecting the worms against
protein-aggregation-associated proteotoxicity. One mechanism was taking
the aggregates apart and degrading them into small pieces; the second
mechanism was taking smaller, lower-molecular-weight aggregates and
transforming them into high molecular weight aggregates of lower
toxicity.
Kelly says that this second finding is "quite
surprising" in that heavier aggregates seem to be protective for the
cell, albeit in a transient fashion-until the cell can "re-group" to
dispose of the aggregates. "What we expected was that the amount of
aggregates would correlate with toxicity in these worms, but there was
no correlation."
"This second finding is clearly a shift in
paradigm," says Dillin. "For nearly a year in this work, we assumed that
large aggregates were the toxic species; however, our data proved
otherwise. These results further support a shift in thinking for this
field regarding the toxicity of small aggregates and lays the framework
for new avenues to combat age-onset protein aggregation diseases, such
as AD, Parkinson's, Huntington's, and ALS, owing to the protective
biological activities discovered."
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The
tiny worms used in the Alzheimer's research in this story are
also playing a leading role in the fight against cancer. See
story below. |
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Tiny Worm is Newest Weapon to Discover
Cancer-Causing Compounds in Household Products
Helps detect virtually any potential cancer-causing
chemical
June 21, 2006 A little worm has enabled scientist
to detect action that blocks "cell suicide," and causes chemical
compounds in household products, like mothballs and air fresheners, to
become possible cancer-causing agents.
Read
more...
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What Next?
"Now, we want to use this mechanistic information
to discover the macromolecular basis for these activities and to
discover small molecules that will delay the aging program and thus
delay the onset of proteotoxicity associated with these diseases by
modulating aggregation and disaggregation activities," Kelly states.
"The hope is that, by manipulating the protective mechanism inherent in
cells, we can find a single entity - a single drug - that would be useful
for a variety of neurodegenerative diseases where protein aggregation
leads to neurodegeneration."
In addition to Kelly and Bieschke at Scripps
Research and Dillin and Cohen at Salk, Technician Rhonda Perciavalle of
the Salk Institute also made significant contributions to the Science
study, titled "Opposing Activities Protect from Age Onset Proteotoxicity."
"This has been a wonderful, synergetic
collaboration," says Kelly. "This work could not have been done solely
in their lab or in ours. Fortunately, scientists at Salk are just down
the road and have always been great neighbors."
Alzheimer's disease now strikes more than one in 30
Americans, and about half the population that lives past 85 acquires
Alzheimer's. Approximately one million Americans have Parkinson's
disease, including three out of every 100 people over age 60. Aging is
the most important risk factor for both of these diseases.
Notes:
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest
independent, non-profit biomedical research organizations, at the
forefront of basic biomedical science that seeks to comprehend the most
fundamental processes of life. Scripps Research is internationally
recognized for its discoveries in immunology, molecular and cellular
biology, chemistry, neurosciences, autoimmune, cardiovascular, and
infectious diseases, and synthetic vaccine development. Established in
its current configuration in 1961, it employs approximately 3,000
scientists, postdoctoral fellows, scientific and other technicians,
doctoral degree graduate students, and administrative and technical
support personnel. Scripps Research is headquartered in La Jolla,
California. It also includes Scripps Florida, whose researchers focus on
basic biomedical science, drug discovery, and technology development.
Currently operating from temporary facilities in Jupiter, Scripps
Florida will move to its permanent campus in 2009.
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