Scientists develop a new way to target Alzheimer's disease

December 4, 2006

The pathological embrace between two proteins plays a key role in the development of Alzheimer's disease by triggering the formation of neuron-killing plaques of amyloid beta protein. Now a group of scientists at NYU School of Medicine have devised a way to reduce amyloid beta deposition by interfering with the deadly embrace of these proteins.

Researchers hope to slow or even prevent the development of Alzheimer's by reducing or preventing the aggregation of amyloid beta. These deposits are one of the defining characteristics of Alzheimer's disease. Although scientists still aren't sure whether plaques are the initial trigger for the disease or are a consequence of it, the clumps can appear years before the onset of clinical symptoms. By the time dementia emerges, the plaques litter the brain.

In a new animal study, the NYU School of Medicine researchers report that they have reduced by around 50 percent the aggregation of toxic amyloid protein in the brains of mice by blocking the interaction between a protein called apolipoprotein E (apo E) and amyloid. Apo E acts as a sort of biological chaperone, ferrying cholesterol and fats around the brain.

The researchers, led by Martin Sadowski, M.D., Ph.D., Assistant Professor of Neurology and Psychiatry and Dr. Thomas Wisniewski, M.D., Professor of Neurology, Pathology and Psychiatry, created a nontoxic, synthetic protein fragment or peptide that binds to apo E, preventing it from latching onto amyloid. Deprived of its biochemical chaperone, amyloid won't form deadly plaques.

In a series of studies in transgenic mice, the peptide reduced the amount of plaque in the brain and the amount of amyloid in the brain's blood vessels. It did not cause any apparent inflammation or leaks in blood vessels in the animals' brains, according to the study. Finally, in another set of experiments, the treated mice did not exhibit any memory decline when they were put into a radial arm maze, which evaluates working memory based on the animals' behavior. The peptide, which crosses the blood-brain barrier, was injected into the animals' abdomens.

It is the first time apo E has been manipulated in this way, according to Dr. Wisniewski. The study is published in the December 5, 2006, issue of the Proceedings of the National Academy of Sciences.

"Our approach opens up a completely new avenue for therapy," says Dr. Wisniewski. "There is a lot of data showing that apo E is important in sporadic Alzheimer's disease. But until now no one has really addressed how you can manipulate its interaction with amyloid beta." Alzheimer's affects some 4.6 million people in the United States, and the devastating neurodegenerative disease occurs most commonly as "sporadic," meaning it affects individuals who do not have rare genetic mutations.

Amyloid beta is a shape-changing chameleon. It normally exists as a nontoxic linear chain of amino acids. But the protein becomes a killer of neurons when it transforms itself into a spiral-like form that aggregates into plaques in the brain.

Apo E is a key player in the deadly transformation of amyloid. Dr. Wisniewski, who is among the scientists who first described the role of apo E in amyloid deposition, describes the lipoprotein as a "pathological chaperone." A string of amino acids on amyloid beta binds to apo E, and this deadly embrace triggers the transformation of amyloid. The NYU researchers stitched together the string of amino acids on amyloid beta to create their synthetic peptide "mimic."

In a recent review article in the journal Science, scientists enumerated several approaches that are being pursued to reduce amyloid in the brain. One of the most promising is to inhibit an enzyme that shears off amyloid beta from a larger protein. However, this enzyme plays a variety of roles in the body, and concerns have arisen about the deleterious systemic affects of inhibiting it. Concerns also have emerged about vaccines to amyloid beta, and a clinical trial of one vaccine had to be halted because 6 percent of patients developed brain inflammation. In addition, studies in Alzheimer animal models and in the few vaccinated individuals who have had autopsies have suggested that vaccination can produce bleeding in the brain.

The NYU researchers said they were encouraged that their synthetic peptide did not appear to cause inflammation or bleeding in the brains of the animals tested. "In order for a peptide like this to be used in humans it would have to be taken for many years, much like statin medications for cholesterol," said Dr. Sadowski, whose research has been supported by a Paul B. Beeson Career Development in Aging a grant jointly funded by the American Federation of Aging Research and the National Institute on Aging. "Our ongoing research is now focusing on transforming the peptide used in the study into an agent that could be used clinically. It would have to be taken for a very long period of time without causing toxicity."

Source: New York University Medical Center and School of Medicine

Explore further: Newly ID'd role of major Alzheimer's gene suggests possible therapeutic target

Related Stories

Newly ID'd role of major Alzheimer's gene suggests possible therapeutic target

September 20, 2017
Nearly a quarter century ago, a genetic variant known as ApoE4 was identified as a major risk factor for Alzheimer's disease—one that increases a person's chances of developing the neurodegenerative disease by up to 12 ...

New perspective needed for role of major Alzheimer's gene

May 7, 2013
(Medical Xpress)—Scientists' picture of how a gene strongly linked to Alzheimer's disease harms the brain may have to be revised, researchers at Washington University School of Medicine in St. Louis have found.

New research adds evidence on potential treatments targeting amyloid beta in Alzheimer's

July 28, 2016
New research findings from the Center for Cognitive Neurology at NYU Langone Medical Center could provide additional clues for future treatment targets to delay Alzheimer's disease and related dementias. This is according ...

Possible biological function for the Alzheimer protein amyloid-beta

November 4, 2015
A new study from Karolinska Institutet shows that amyloid-β-peptides, which are thought to be toxic and a suspected cause of Alzheimer's disease, actually have a biological function. The discovery, which is published in ...

Researchers identify new gene linked to amyloid beta plaque buildup in Alzheimer's disease

October 5, 2015
In a newly published study, a multi-institutional team led by scientists at the Indiana University School of Medicine have discovered an immune system gene associated with higher rates of amyloid plaque buildup in the brains ...

Anxiety moderates amyloid-beta association with cognition

January 29, 2015
(HealthDay)—For older adults, elevated amyloid-β (Aβ) levels correlate with cognitive decline, and elevated anxiety moderates these associations, according to a study published online Jan. 28 in JAMA Psychiatry.

Recommended for you

Anti-malaria drug shows promise as Zika virus treatment

November 17, 2017
A new collaborative study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) and UC San Diego School of Medicine has found that a medication used to prevent and treat malaria may also be effective ...

Decrease in sunshine, increase in Rickets

November 17, 2017
A University of Toronto student and professor have teamed up to discover that Britain's increasing cloudiness during the summer could be an important reason for the mysterious increase in Rickets among British children over ...

Scientists identify biomarkers that indicate likelihood of survival in infected patients

November 17, 2017
Scientists have identified a set of biomarkers that indicate which patients infected with the Ebola virus are most at risk of dying from the disease.

Research team unlocks secrets of Ebola

November 16, 2017
In a comprehensive and complex molecular study of blood samples from Ebola patients in Sierra Leone, published today (Nov. 16, 2017) in Cell Host and Microbe, a scientific team led by the University of Wisconsin-Madison has ...

Study raises possibility of naturally acquired immunity against Zika virus

November 16, 2017
Birth defects in babies born infected with Zika virus remain a major health concern. Now, scientists suggest the possibility that some women in high-risk Zika regions may already be protected and not know it.

A structural clue to attacking malaria's 'Achilles heel'

November 16, 2017
Researchers from The Scripps Research Institute (TSRI) and PATH's Malaria Vaccine Initiative (MVI) have shed light on how the human immune system recognizes the malaria parasite though investigation of antibodies generated ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.