UCLA researchers have found that a natural protein fragment produced in the brain can inhibit of a key enzyme implicated in the development of Alzheimer’s disease. The finding could lead to the development of new medications to treat the disease. The study appears on July 29 in the Journal of Alzheimer’s Disease.
The investigators found that the protein fragment sAPPα inhibits the enzyme BACE1. Increased activity of the enzyme leads to the 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,” explained senior study author Varghese John. PhD, 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 protein fragment sAPPα is normally produced by neurons and is involved in the maintenance of memory. The researchers have found that this normal brain fragment is also a powerful inhibitor of the proteolytic enzyme BACE1. The new finding adds to the understanding of the brain regulation of amyloid beta production and could lead to development of new therapeutics.
The study authors stress that an urgent need exists for a new approach to treatment of Alzheimer’s disease. The disease 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 approximately 5-6 six million to 15 million by 2050. The costs to family life and on the healthcare system are huge. Alzheimer’s and other dementias are projected to cost the US $226 billion in 2015 alone, with that number rising to as high as $1.1 trillion in 2050.
At present, there are no truly effective treatment or prevention methods for Alzheimer’s disease, and the available drugs merely temporarily reduce the symptoms. The researchers used a technique called small-angle X-ray scattering (SAXS), and found that the sAPPα inhibition of BACE1 activity is probably due to the unique, three-dimensional structure of the protein fragment itself. The investigators next plan to locate the binding site of sAPPα 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,” explained Dr. John. He added, “These strategies could help normalize brain function and either restore memory and cognitive function, or prevent its decline.”
The protein fragment is essential for normal brain function, and creation of a new class of CNS therapeutics that enhance sAPPα may be of benefit beyond Alzheimer’s disease treatment. The potential drug could also help individuals who have suffered stroke or traumatic brain injury. Increasing levels of sAPPα may also benefitcial in treatment of amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease).
