New Alzheimer's research suggests possible cause: The interaction of proteins in the brain

(Press-News.org) PORTLAND, Ore. — For years, Alzheimer's researchers have focused on two proteins that accumulate in the brains of people with Alzheimer's and may contribute to the disease: plaques made up of the protein amyloid-beta, and tangles of another protein, called tau.

But for the first time, an Alzheimer's researcher has looked closely at not the two proteins independently, but at the interaction of the two proteins with each other — in the brain tissue of post-mortem Alzheimer's patients and in mouse brains with Alzheimer's disease. The research found that the interaction between the two proteins might be the key: as these interactions increased, the progression of Alzheimer's disease worsened.

The research, by Hemachandra Reddy, Ph.D., an associate scientist at the Oregon National Primate Research Center at Oregon Health & Science University, is detailed in the June 2013 edition of the Journal of Alzheimer's Disease.

Reddy's paper suggests that when the interaction between the phosphorylated tau and the amyloid-beta — particularly in its toxic form — happens at brain synapses, it can damage those synapses. And that can lead to cognitive decline in Alzheimer's patients.

"This complex formation between amyloid beta and tau — it is actually blocking the neural communication," Reddy said. "If we could somehow find a molecule that could inhibit the binding of these two proteins at the synapses, that very well might be the cure to Alzheimer's disease."

To conduct the research, Reddy and his team studied three different kinds of mice, who had been bred to have some of the brain characteristics of Alzheimer's disease, including having amyloid-beta and phosphorylated tau in their brains. Reddy also analyzed postmortem brain tissue from people who had Alzheimer's disease.

Using multiple antibodies that recognize amyloid-beta and phosphorylated tau, Reddy and Maria Manczak, Ph.D., a research associate in Reddy's laboratory, specifically looked for the evidence of the amyloid beta and phosphorylated tau interactions. They found amyloid-beta/tau complexes in the human Alzheimer's brain tissue and in the Alzheimer's disease mouse brains. The Reddy team also found much more of those amyloid-beta/tau complexes in brains where Alzheimer's disease had progressed the most.

Reddy found very little or no evidence of the same interaction in the "control" subjects — mice that did not have the Alzheimer's traits and human brain tissue of people who did not have Alzheimer's.

"So much Alzheimer's research has been done to look at amyloid-beta and tau," Reddy said. "But ours is the first paper to strongly demonstrate that yes, there is an amyloid-beta/phosphorylated tau interaction. And that interaction might be causing the synaptic damage and cognitive decline in persons with Alzheimer's disease."

Reddy and his lab are already working on the next crucial questions. One is to define the binding site or sites and exactly where within the neuron the interaction of amyloid-beta and tau first occurs. The second is to find a way to inhibit that interaction — and thus maybe prevent or slow the progression of Alzheimer's.

### Manczak was a co-author on the Journal of Alzheimer's Disease article.

The research was funded by the following grants from the National Institutes of Health: AG028072, AG042178, RR000163 and P30-NS061800. It was also funded by a grant from the Medical Research Foundation of Oregon.

About ONPRC The ONPRC is one of the eight National Primate Research Centers supported by NIH. ONPRC is a registered research institution, inspected regularly by the United States Department of Agriculture. It operates in compliance with the Animal Welfare Act and has an assurance of regulatory compliance on file with the National Institutes of Health. The ONPRC also participates in the voluntary accreditation program overseen by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC).

About OHSU Oregon Health & Science University is a nationally prominent research university and Oregon's only public academic health center. It serves patients throughout the region with a Level 1 trauma center and nationally recognized Doernbecher Children's Hospital. OHSU operates dental, medical, nursing and pharmacy schools that rank high both in research funding and in meeting the university's social mission. OHSU's Knight Cancer Institute helped pioneer personalized medicine through a discovery that identified how to shut down cells that enable cancer to grow without harming healthy ones. OHSU Brain Institute scientists are nationally recognized for discoveries that have led to a better understanding of Alzheimer's disease and new treatments for Parkinson's disease, multiple sclerosis and stroke. OHSU's Casey Eye Institute is a global leader in ophthalmic imaging, and in clinical trials related to eye disease.