Satellite Banner
Technology
Networks
Scientific Communities
 
Become a Member | Sign in
Home>News>This Article
  News
Return

NIH-Funded Research Provides New Clues on How ApoE4 Affects Alzheimer's Risk

Published: Tuesday, October 30, 2012
Last Updated: Tuesday, October 30, 2012
Bookmark and Share
Researchers found that ApoE4 triggers an inflammatory reaction that weakens the blood-brain barrier.

Common variants of the ApoE gene are strongly associated with the risk of developing late-onset Alzheimer's disease, but the gene's role in the disease has been unclear.

Now, researchers funded by the National Institutes of Health have found that in mice, having the most risky variant of ApoE damages the blood vessels that feed the brain.

The researchers found that the high-risk variant, ApoE4, triggers an inflammatory reaction that weakens the blood-brain barrier, a network of cells and other components that lines brain's brain vessels.

Normally, this barrier allows nutrients into the brain and keeps harmful substances out.

The study appears in Nature, and was led by Berislav Zlokovic, M.D., Ph.D., director of the Center for Neurodegeneration and Regeneration at the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles.

"Understanding the role of ApoE4 in Alzheimer's disease may be one of the most important avenues to a new therapy," Dr. Zlokovic said. "Our study shows that ApoE4 triggers a cascade of events that damages the brain's vascular system," he said, referring to the system of blood vessels that supply the brain.

The ApoE gene encodes a protein that helps regulate the levels and distribution of cholesterol and other lipids in the body. The gene exists in three varieties.

ApoE2 is thought to play a protective role against both Alzheimer's and heart disease, ApoE3 is believed to be neutral, and ApoE4 confers a higher risk for both conditions.

Outside the brain, the ApoE4 protein appears to be less effective than other versions at clearing away cholesterol; however, inside the brain, exactly how ApoE4 contributes to Alzheimer's disease has been a mystery.

Dr. Zlokovic and his team studied several lines of genetically engineered mice, including one that lacks the ApoE gene and three other lines that produce only human ApoE2, ApoE3 or ApoE4. Mice normally have only a single version of ApoE.

The researchers found that mice whose bodies made only ApoE4, or made no ApoE at all, had a leaky blood-brain barrier. With the barrier compromised, harmful proteins in the blood made their way into the mice's brains, and after several weeks, the researchers were able to detect loss of small blood vessels, changes in brain function, and a loss of connections between brain cells.

"The study demonstrates that damage to the brain's vascular system may play a key role in Alzheimer's disease, and highlights growing recognition of potential links between stroke and Alzheimer's-type dementia," said Roderick Corriveau, Ph.D., a program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the research. "It also suggests that we might be able to decrease the risk of Alzheimer's disease among ApoE4 carriers by improving their vascular health."

The researchers also found that ApoE2 and ApoE3 help control the levels of an inflammatory molecule called cyclophilin A (CypA), but ApoE4 does not. Levels of CypA were raised about five-fold in blood vessels of mice that produce only ApoE4.

The excess CypA then activated an enzyme, called MMP-9, which destroys protein components of the blood-brain barrier. Treatment with the immunosuppressant drug cyclosporine A, which inhibits CypA, preserved the integrity of the blood-brain barrier and lessened damage to the brain.

An inhibitor of the MMP-9 enzyme had similar beneficial effects. In prior studies, inhibitors of this enzyme have been shown to reduce brain damage after stroke in animal models.

"These findings point to cyclophilin A as a potential new drug target for Alzheimer's disease," said Suzana Petanceska, Ph.D., a program director at NIH's National Institute on Aging (NIA), which also funded Dr. Zlokovic's study.

"Many population studies have shown an association between vascular risk factors in mid-life, such as high blood pressure and diabetes, and the risk for Alzheimer's in late-life. We need more research aimed at deepening our understanding of the mechanisms involved and to test whether treatments that reduce vascular risk factors may be helpful against Alzheimer's."

Alzheimer's disease is the most common cause of dementia in older adults, and affects more than 5 million Americans. A hallmark of the disease is a toxic protein fragment called beta-amyloid that accumulates in clumps, or plaques, within the brain.

Gene variations that cause higher levels of beta-amyloid are associated with a rare type of Alzheimer's that appears early in life, between age 30 and 60.

However, it is the ApoE4 gene variant that is most strongly tied to the more common, late-onset type of Alzheimer's disease. Inheriting a single copy of ApoE4 from a parent increases the risk of Alzheimer's disease by about three-fold. Inheriting two copies, one from each parent, increases the risk by about 12-fold.

Dr. Zlokovic's study and others point to a complex interplay between beta-amyloid and ApoE4. On the one hand, beta-amyloid is known to build up in and damage blood vessels and cause bleeding into the brain.

On the other hand, Dr. Zlokovic's data suggest that ApoE4 can damage the vascular system independently of beta-amyloid. He theorizes that this damage makes it harder to clear beta-amyloid from the brain.

Some therapies under investigation for Alzheimer's focus on destroying amyloid plaques, but therapies designed to compensate for ApoE4 might help prevent the plaques from forming, he said.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 4,000+ scientific posters on ePosters
  • More Than 5,300+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Exploring the Genome of the River Blindness Parasite
Researchers have decoded the genome of the parasite that causes the skin and eye infection known as river blindness.
Wednesday, December 07, 2016
Gene-Editing Improves Vision in Blind Rats
Scientists developed a targeted gene-replacement technique that can modify genes in both dividing and non-dividing cells in living animals.
Wednesday, December 07, 2016
Uncovering Cerebral Malaria’s Deadly Agents
NIH scientists film inside mouse brains to uncover biology behind the disease.
Wednesday, December 07, 2016
Study to Assess Shorter-Duration Antibiotics in Children
Physicians plan a clinical trial to evaluate whether short course anti-biotics are effective at treating CAP in children.
Wednesday, November 30, 2016
First New HIV Vaccine Study for Seven Years Begins
South Africa hosts historic clinical trial of experimental HIV vaccine aiming to safely prevent HIV infection.
Wednesday, November 30, 2016
Antibody Protects Mice from Zika Infection
Researchers develop human-derived antibody protected pregnant mice and their developing fetuses from Zika infection.
Wednesday, November 23, 2016
Food Additives Promote Inflammation, Colon Cancer
Dietary emulsifiers promoted colon cancer in a mouse model by altering gut microbes and increasing gut inflammation.
Wednesday, November 23, 2016
Protein-Folding Gene Helps Heal Wounds
Researchers identified a protein that dramatically accelerates wound healing in animal models.
Wednesday, November 23, 2016
More Immunotherapy Options Approved for Lung Cancer
The FDA has approved a new immunotherapy drug for certain patients with non-small cell lung cancer.
Monday, November 21, 2016
Big Data for Infectious Disease Surveillance
NIH-led effort examines use of big data from health records and other digital sources for uses in infectious disease surveillance.
Tuesday, November 15, 2016
Potential Therapies Against Drug-Resistant Bacteria Identified
Researchers create new identification method for drug and drug combinations that may combat resistant infections.
Thursday, November 10, 2016
Testing Zika Vaccine in Humans Begins
The first of five planned clinical trials to test ZPIV vaccine in humans has begun.
Tuesday, November 08, 2016
Genetic Markers Predict Malaria Treatment Failure
By comparing 297 parasite genomes to a reference malaria parasite genome, researchers have identified two genetic markers that are strongly associated with the parasites’ ability to resist piperaquine.
Monday, November 07, 2016
Cannabinoid Receptor Structure Revealed
Scientists provided a detailed view of the primary molecule through which cannabinoids exert their effects on the brain. The findings might help guide the design of more targeted medicines with fewer side effects.
Wednesday, November 02, 2016
NIH Researchers Unveil New Wound-Healing Role for Protein-Folding Gene in Mice
The study found that topical treatment of an Hsp60-containing gel dramatically accelerates wound closure in a diabetic mouse model.
Friday, October 28, 2016
Scientific News
Big Genetics in BC: The American Society for Human Genetics 2016 Meeting
Themes at this year's meeting ranged from the verification, validation, and sharing of data, to the translation of laboratory findings into actionable clinical results.
Stem Cells in Drug Discovery
Potential Source of Unlimited Human Test Cells, but Roadblocks Remain.
Automated Low Volume Dispensing Trends
Gain a better understanding of the current and future market requirements for fully automated LVD systems.
Cancer Genetics: Key to Diagnosis, Therapy
When applied judiciously, cancer genetics directs caregivers to the right drug at the right time, while sparing patients of unnecessary or harmful treatments.
Major Neuroscience Initiative Launched
Tianqiao and Chrissy Chen Institute invest $115 million to further expand neuroscience research, while Caltech construct $200 million biosciences complex.
Diabetes Missing Link Discovered
Researchers from the University of Auckland have shown that beta catenin plays a vital role in the control of insulin release from the pancreas.
Study Reveals New Role for Hippo Pathway in Suppressing Cancer Immunity
Hippo pathway signaling regulates organ size by moderating cell growth, apoptosis and stem cell renewal, but dysregulation contributes to cancer development.
Ribosome Recycling as a Drug Target
Researchers explain mechanism that recycles bacterial ribosomes stalled on messenger RNAs that lack termination codons.
How the Brain Recognizes Faces
Machine-learning system spontaneously reproduces aspects of human neurology.
Boosting Effectiveness of Asthma Therapy
A team of scientists from UCSF has developed a new treatment to dampen bronchospasm.
Scroll Up
Scroll Down
Skyscraper Banner

SELECTBIO Market Reports
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
4,000+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
5,300+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!