The Salk team expanded upon their previous development of a drug candidate J147, which takes a different tack by targeting Alzheimer’s major risk factor—old age. In the new work, the team showed that the drug candidate worked well in a mouse model of aging not typically used in Alzheimer’s research. When these mice were treated with J147, they had better memory and cognition, healthier blood vessels in the brain and other improved physiological features.
“Initially, the impetus was to test this drug in a novel animal model that was more similar to 99% of Alzheimer’s cases,” says Prof Antonio Currais. “We did not predict we’d see this sort of anti-aging effect, but J147 made old mice look like they were young, based upon a number of physiological parameters.”
Alzheimer’s is the 3rd leading cause of death in the US and affects > 5 million Americans. It is also the most common cause of dementia in older adults. “While most drugs developed in the past 20 years target the amyloid plaque deposits in the brain (which are a hallmark of the disease), none have proven effective in the clinic,” says Schubert, senior author of the study. Rather than target amyloid, the lab decided to zero in on the major risk factor for the disease—old age. Using cell-based screens against old age-associated brain toxicities, they synthesized J147.
Previously, they found J147 could prevent and even reverse memory loss and Alzheimer’s pathology. However, this form of the disease only ~1% of Alzheimer’s cases. For everyone else, old age is the primary risk factor, says Schubert.They used a set of assays to measure the expression of all genes in the brain, as well as over 500 small molecules involved with metabolism in the brains and blood of three groups of the rapidly aging mice. The 3 groups of rapidly aging mice included one set that was young, one old and one set old but fed J147 as they aged.
RESULTS The old mice that had J147 performed better on memory and other tests for cognition and also displayed more robust motor movements. The mice treated with J147 also had fewer pathological signs of Alzheimer’s in their brains. Many aspects of gene expression and metabolism in the old mice fed J147 were very similar to those of the young animals. These included markers for increased energy metabolism, reduced brain inflammation and oxidized fatty acids in the brain.
J147 also prevented the leakage of blood from the microvessels in the brains of old mice. “Damaged blood vessels are a common feature of aging in general, and in Alzheimer’s, it is frequently much worse,” says Currais.
The team aims to begin human trials next year. http://www.salk.edu/news/pressrelease_details.php?press_id=2130
As mice age, those treated with J147 (right) showed improved physiology, memory and appearance that more closely resembled younger mice. Credit: Courtesy of the Salk Institute for Biological Studies
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