XML Feed for RxPG News   Add RxPG News Headlines to My Yahoo!   Javascript Syndication for RxPG News

Research Health World General
 
  Home
 
 Latest Research
 Cancer
 Psychiatry
 Genetics
 Surgery
 Aging
  Parkinson's
  Dementia
   Alzheimer's
 Ophthalmology
 Gynaecology
 Neurosciences
 Pharmacology
 Cardiology
 Obstetrics
 Infectious Diseases
 Respiratory Medicine
 Pathology
 Endocrinology
 Immunology
 Nephrology
 Gastroenterology
 Biotechnology
 Radiology
 Dermatology
 Microbiology
 Haematology
 Dental
 ENT
 Environment
 Embryology
 Orthopedics
 Metabolism
 Anaethesia
 Paediatrics
 Public Health
 Urology
 Musculoskeletal
 Clinical Trials
 Physiology
 Biochemistry
 Cytology
 Traumatology
 Rheumatology
 
 Medical News
 Health
 Opinion
 Healthcare
 Professionals
 Launch
 Awards & Prizes
 
 Careers
 Medical
 Nursing
 Dental
 
 Special Topics
 Euthanasia
 Ethics
 Evolution
 Odd Medical News
 Feature
 
 World News
 Tsunami
 Epidemics
 Climate
 Business
 
 India
Search

Last Updated: Nov 18, 2006 - 12:32:53 PM

Alzheimer's Channel
subscribe to Alzheimer's newsletter

Latest Research : Aging : Dementia : Alzheimer's

   DISCUSS   |   EMAIL   |   PRINT
New research points toward mechanism of age-onset toxicity of Alzheimer's protein
Aug 11, 2006 - 1:40:00 PM, Reviewed by: Dr. Venkat Yelamanchili

"Our study revealed that the age onset of these diseases is not simply a matter of time but that the aging process plays an active role in controlling the onset of toxicity"

 
Like most neurodegenerative diseases, Alzheimer's disease usually appears late in life, raising the question of whether it is a disastrous consequence of aging or if the toxic protein aggregates that cause the disease simply take a long time to form.

Now, a collaboration between researchers at the Salk Institute for Biological Studies and the Scripps Research Institute shows that aging is what's critical. Harmful beta amyloid aggregates accumulate when aging impedes two molecular clean-up crews from getting rid of these toxic species.

This finding opens the door for development of drugs preventing build-up of toxic protein aggregates in the brain. The study appears in the Aug. 10 issue of Science Express, the advanced online edition of the journal Science.

"Aging is the most important risk factor for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease," says senior author Andrew Dillin, Ph.D., an assistant professor in the Salk Molecular and Cell Biology Laboratory. "Our study revealed that the age onset of these diseases is not simply a matter of time but that the aging process plays an active role in controlling the onset of toxicity," he explains.

Beta amyloid production occurs in all brains, but healthy cells clear away excess amounts. Brains of people with Alzheimer's disease, on the other hand, are unable to control beta amyloid accumulation. For years, scientists have scrambled to find out why.

To answer this vexing question, Dillin analyzed protein aggregation in the roundworm, a streamlined organism that, like mammals, uses the insulin/IGF-1 pathway to control lifespan but can be rapidly manipulated genetically. Dillin used roundworms that produce human beta amyloid peptide in body wall muscles. As the worms aged, the protein formed toxic aggregates causing paralysis.

Then researchers experimentally decelerated aging in engineered worms by lowering activity of the insulin/IGF-1 pathway and asked whether it was simply the passage of time--not aging per se--that favored protein aggregation. It wasn't: chronologically "old" worms crawled around happily, while counterparts whose insulin/IGF-1 pathway was normal could only helplessly wriggle their heads.

However, close inspection of the data revealed a surprise: "Worms with reduced insulin signaling seemed perfectly fine although they had high molecular weight aggregates, while worms with an accelerated aging program were extremely sensitive to the toxic effects of beta amyloid but we couldn't detect any large fibrils," explains postdoctoral researcher and co-lead author Ehud Cohen, Ph.D.

Intrigued, Dillin turned to an expert on beta amyloid biochemistry, Jeffery Kelly, Ph.D., a professor of chemistry at Scripps and a member of its Skaggs Institute of Chemical Biology.

Together they found that cells use an unexpected two-pronged strategy to rid themselves of harmful aggregates. Kelly explains, "One pathway disaggregated beta amyloid fibrils, while the other actively packed them into high molecular weight aggregates. But the latter only kicks in when the cell is left with no other options."

The surprise was that very high molecular weight species were actually less toxic than smaller aggregates. "For a long time large protein aggregates were considered the toxic species," explains Cohen. "The fact that cells protect themselves by temporarily storing small fibrils as high molecular weight aggregates marks a clear paradigm shift."

Two proteins controlled by insulin/IGF-1 signaling orchestrate detoxification--HSF-1, which takes care of aggregate break-down, and DAF-16, which mediates formation of safer, super-sized aggregates as debris accumulates. "We assumed that DAF-16 and HSF-1 would do the same job, but they don't. This is extremely exciting because it gives us two unique opportunities to attenuate beta amyloid-mediated toxicity by manipulating the activity of these factors," says Dillin.

Half of all people who reach age 85 will likely be affected by Alzheimer's disease, and the onset age � usually around 75 � is almost the same for all sporadic neurodegenerative aggregation diseases. Thus, Salk researchers have developed a model that explains why these disorders diseases occur late in life.

Throughout life, brain cells produce aggregation-prone beta-amyloid fragments that must be cleared. "This process is very efficient when we are young but as we get older it gets progressively less efficient," says Cohen. As the affected individual reaches the seventh decade of life the clearance machineries fail to degrade the continually forming toxic aggregates and the disease emerges. In individuals who carry early onset Alzheimer's-linked mutation, an increased "aggregation challenge" leads to clearance failure and the emergence of Alzheimer's much earlier � usually during their fifth decade.

"It was very satisfying when the biochemical data from Jeffery's lab and genetic results from our lab came together," recalls Dillin. Both scientists are continuing the collaboration by searching for small molecules that delay the aging program and boost protective mechanisms.
 

- The study appears in the Aug. 10 issue of Science Express, the advanced online edition of the journal Science
 

www.salk.edu

 
Subscribe to Alzheimer's Newsletter
E-mail Address:

 

Other contributing authors were co-lead author Jan Bieschke, Ph.D., formerly at Scripps and now at Max Delbrueck Center in Berlin, and research assistant Rhonda M. Perciavalle.

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.


Related Alzheimer's News

Hope remains for Alzheimer's sufferers
CATIE Study: Antipsychotics in Alzheimer's No Better Than Placebo
Mediterranean diet associated with a lower risk for Alzheimer�s disease
Omega-3 fatty acid supplements may slow cognitive decline
Microscopic brain damage detected in early Alzheimer's disease
Novel technique can identify early cellular damage in Alzheimer's disease
Cathepsin B - Part of protective mechanism against Alzheimer's
Boosting ubiquitin C-terminal hydrolase L1 (Uch-L1) restores lost memory
New research points toward mechanism of age-onset toxicity of Alzheimer's protein
Structure of calbindin-D28K Protein Involved in Preventing Alzheimer�s, Huntington�s Diseases Characterised


For any corrections of factual information, to contact the editors or to send any medical news or health news press releases, use feedback form

Top of Page

 

© Copyright 2004 onwards by RxPG Medical Solutions Private Limited
Contact Us