Targeting Alzheimer's disease through anti-aging

Salk Institute researchers have found an experimental drug aimed at Alzheimer's which ends up having anti-aging effects in mice.

The Salk team is expanding on their previous development of the drug candidate J147, which takes a different tack in targeting Alzheimer's — it targets old age.

In their new work, the team shows that J147 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 their brains and other improved physiological features.

The work is detailed November 12, 2015 in the journal Aging.

"The impetus was to test this drug in a new animal model more similar to 99 percent of Alzheimer's cases. We did not predict we'd see this sort of anti-aging effect, but J147 made old mice look like they were young, based on a number of physiological parameters."

Antonio Currais PhD, lead author, member of Professor David Schubert's Cellular Neurobiology Laboratory, Salk Institute, California.

Alzheimer's disease is a progressive brain disorder, recently ranked as the third leading cause of death in the United States and affecting more than five million Americans. It is also the most common cause of dementia in older adults, according to the National Institutes of Health.

"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.

Several years ago, Schubert and his colleagues began to approach the treatment of the disease from a new angle. Rather than target amyloid, the lab decided to zero in on the major risk factor for the disease — old age. Based on cell-based screens against brain toxicity associated with old age — they synthesized J147.

Previously, J147 had been found to prevent — even reverse — memory loss and Alzheimer's pathology in mice with a version of inherited Alzheimer's. However, this form is only about 1 percent of all cases. For everyone else, old age is the primary risk factor.

The team then explored the effects of J147 on a breed of mice that age rapidly and experience a version of dementia closely resembling Alzheimer's.

In this work, they used comprehensive assays to measure the expression of all genes in the mice brains, including over 500 small molecules in the brain and blood involved in metabolism. The rapidly aging mice were divided into three groups: [1] one set that was young, [2] one set that was old, and [3] one set that was old, yet fed J147 as they aged.

Old mice that were fed J147 performed better on memory and cognition tests and also displayed more robust muscle movement. They also had fewer pathological signs of Alzheimer's in their brains.

Importantly, the large amount of data collected revealed that in the old mice fed J147, many aspects of gene expression and metabolism were very similar to young animals. This included increased energy, reduced brain inflammation, and reduced levels of oxidized fatty acids in the brain.

J147 also prevented leakage of blood from 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," adds Currais.

Currais and Schubert note that while these studies represent a new and exciting approach to Alzheimer's drug discovery and animal testing on aging, the only way to demonstrate the work's relevance is to use J147 in human clinical trials for Alzheimer's disease.

David Schubert: "If proven safe and effective for Alzheimer's, the apparent anti-aging effect of J147 would be a welcome benefit."

The team aims to begin human trials next year.

Abstract
AIMS: Accurate biomarkers for early diagnosis of Alzheimer's disease (AD) are badly needed. Recent reports suggest that dysfunctional mitochondria and DNA damage are associated with AD development. In this report, we measured various cellular parameters, related to mitochondrial bioenergetics and DNA damage, in peripheral blood mononuclear cells (PBMCs) of AD and control participants, for biomarker discovery.

METHODS: PBMCs were isolated from 53 patients with AD of mild to moderate degree and 30 age-matched healthy controls. Tests were performed on the PBMCs from as many of these participants as possible. We measured glycolysis and mitochondrial respiration fluxes using the Seahorse Bioscience flux analyzer, mitochondrial ROS production using flow cytometry, dNTP levels by way of a DNA polymerization assay, DNA strand breaks using the Fluorometric detection of Alkaline DNA Unwinding (FADU) assay, and APE1 incision activity (in cell lysates) on a DNA substrate containing an AP site (to estimate DNA repair efficiency).

RESULTS: In the PBMCs of AD patients, we found reduced basal mitochondrial oxygen consumption, reduced proton leak, higher dATP level, and lower AP endonuclease 1 activity, depending on adjustments for gender and/or age.

CONCLUSIONS: This study reveals impaired mitochondrial respiration, altered dNTP pools and reduced DNA repair activity in PBMCs of AD patients, thus suggesting that these biochemical activities may be useful as biomarkers for AD.

Other authors on the paper include Oswald Quehenberger of the University of California, San Diego; and Joshua Goldberg, Catherine Farrokhi, Max Chang, Marguerite Prior, Richard Dargusch, Daniel Daugherty and Pamela Maher of the Salk Institute.

This study was supported by the Salk Institute Pioneer Fund Postdoctoral Scholar Award and the Salk Nomis Fellowship Award, fellowships from the Hewitt Foundation and Bundy Foundation, and grants from the Burns Foundation and NIH.

About the Salk Institute for Biological Studies:
The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probes fundamental life science questions in a unique, collaborative and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes and infectious diseases by studying neuroscience, genetics, cell and plant biology and related disciplines.

Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, MD, the Institute is an independent nonprofit organization and architectural landmark.

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Alzheimer's disease is a progressive brain disorder, recently ranked as the third leading
cause of death in the United States and affecting more than five million Americans.

Image Credit: Public Domain