Naturally occurring protein fragment found in brain inhibits key enzyme implicated in Alzheimer's

July 29, 2015
Diagram of the brain of a person with Alzheimer's Disease. Credit: Wikipedia/public domain.

For the first time, UCLA researchers have shown that a natural protein fragment produced in the brain can act as an inhibitor of a key enzyme implicated in the onset of Alzheimer's disease, a finding that could lead to the development of new drugs to treat the disease.

The study found that the , sAPPα, inhibits the proteolytic enzyme BACE1. Increased BACE1 activity contributes to production of the amyloid beta aggregates and plaques that are the hallmark of Alzheimer's.

"Because sAPPα inhibits the BACE1 enzyme, it may be possible that it can be used to help prevent potentially dangerous increases in BACE1 activity, and thus prevent the onset of Alzheimer's disease," said senior study author Varghese John associate professor of neurology and principle investigator of the Drug Discovery Lab in the Mary S. Easton Center for Alzheimer's Disease Research at UCLA.

The findings appear July 28, 2015 in the peer-reviewed Journal of Alzheimer's Disease.

The protein fragment sAPPis normally produced by neurons and is involved in maintenance of memory. UCLA researchers have shown that this normal brain fragment is also a potent inhibitor of the proteolytic enzyme BACE1. The new finding sheds light on brain regulation of amyloid beta production and could lead to development of new therapeutics.

The need for a new approach to treatment of Alzheimer's disease is urgent. Alzheimer's is the most common age-related dementia and the number of cases in the United States is expected to increase from the current number of about five to six million to 15 million by 2050. The costs to family life and on the health care system are enormous. Alzheimer's and other dementias are projected to cost the United States $226 billion in 2015 alone, with that number rising to as high as $1.1 trillion in 2050.

There currently are no truly effective treatment or prevention strategies for Alzheimer's, and the available drugs only reduce symptoms temporarily.

John and his team employed a technique called small-angle X-ray scattering, or SAXS, and found that the sAPPα inhibition of BACE1 activity is likely due to the unique, three-dimensional structure of the protein fragment itself. Going forward, John and his team are determining the binding site of sAPP to BACE1 using X-ray crystallography and other techniques.

"Our study suggests that developing sAPPα itself as a biologic, finding a smaller protein or peptide fragment that has similar effects, or identifying a chemical compound that increases levels of this beneficial protein fragment could be new and effective therapeutic strategies for mild cognitive impairment and Alzheimer's patients," John said. "These strategies could help normalize brain function and either restore memory and cognitive function, or prevent its decline."

The protein fragment is critical to normal brain function, and creation of a new class of CNS therapeutics that enhance sAPPα may be of benefit beyond Alzheimer's. The potential drug could also help those who have suffered stroke or traumatic injury. Increasing levels of sAPPα may also be beneficial in treatment of ALS (Lou Gehrig's disease).

Explore further: Beta secretase inhibitors to treat Alzheimer's disease

Related Stories

Beta secretase inhibitors to treat Alzheimer's disease

April 2, 2015
With each new amyloid-targeting treatment for Alzheimer's disease that has been developed, there has been a corresponding concern. For example, antibodies targeting amyloid-β peptide (Aβ) produce inflammation in the brain ...

Specific protein as missing link for earliest known change in Alzheimer's pathology

July 21, 2015
A recent study conducted at Nathan S. Kline Institute for Psychiatric Research (NKI) and NYU Langone Medical Center implicates a new culprit in Alzheimer's disease development. The research reveals that ßCTF—the precursor ...

Brain enzyme is double whammy for Alzheimer's disease

August 20, 2012
The underlying causes of Alzheimer's disease are not fully understood, but a good deal of evidence points to the accumulation of β-amyloid, a protein that's toxic to nerve cells. β-amyloid is formed by the activity ...

Researchers identify new enzyme to fight Alzheimer's disease

September 17, 2012
An enzyme that could represent a powerful new tool for combating Alzheimer's disease has been discovered by researchers at Mayo Clinic in Florida. The enzyme—known as BACE2—destroys beta-amyloid, a toxic protein fragment ...

Team finds regulator of amyloid plaque buildup in Alzheimer's disease

January 23, 2014
Scientists from the Florida campus of The Scripps Research Institute have identified a critical regulator of a molecule deeply involved in the progression of Alzheimer's disease.

Poor recycling of BACE1 enzyme could promote Alzheimer's disease

November 21, 2011
Sluggish recycling of a protein-slicing enzyme could promote Alzheimer's disease, according to a study published online on November 21 in The Journal of Cell Biology.

Recommended for you

Is the Alzheimer's gene the ring leader or the sidekick?

September 15, 2017
The notorious genetic marker of Alzheimer's disease and other forms of dementia, ApoE4, may not be a lone wolf.

Potential noninvasive test for Alzheimer's disease

September 6, 2017
In the largest and most conclusive study of its kind, researchers have analysed blood samples to create a novel and non-invasive way of helping to diagnose Alzheimer's disease and distinguishing between different types of ...

Researchers unlock the molecular origins of Alzheimer's disease

September 6, 2017
A "twist of fate" that is minuscule even on the molecular level may cause the development of Alzheimer's disease, VCU researchers have found.

Is dementia declining among older Americans?

September 5, 2017
(HealthDay)—Here's some good news for America's seniors: The rates of Alzheimer's and other forms of dementia have dropped significantly over the last decade or so, a new study shows.

Which genetic marker is the ring leader in the onset of Alzheimer's disease?

September 4, 2017
The notorious genetic marker of Alzheimer's disease and other forms of dementia, ApoE4, may not be a lone wolf.

A decline in navigational skills could predict neurodegenerative disease

August 30, 2017
Changes in how humans map their surroundings and construct and follow directions as they age have been understudied compared to effects on memory and learning. However, age-related declines in navigational ability are independent ...


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.