June 2007

Shedding New Light on Alzheimer's Brain Plaque

It's long been known that deposition of plaque in the brain is one of the major features of early-stage Alzheimer's disease, the most common age-related neurodegenerative disorder. What hasn't been fully understood is what chain of events contributes to this plaque formation.

Institute researchers may have found a key to the process.

A tell-tale characteristic of Alzheimer's disease (AD) is the presence of neuritic plaques. These plaques contain deposits of beta-amyloid peptides (AB) surrounded by inflammatory glia (the network of cells that support the nervous system) and abnormal or swollen nerve cell extensions called dystrophic neurites.

What hasn't been known definitively is what role, if any, is played by these dystrophic neurites. Are they a by-product of the formation of AB? Or could they influence the development of AB or even contribute directly to the dysfunction associated with AD?

Riqiang Yan, Ph.D., Neurosciences, and his colleagues found that increased levels of the protein reticulon 3 (RTN3) cause the formation of dystrophic neurites and that having dystrophic neuritis impairs spatial learning and memory – even without deposition of AB.

“The presence of dystrophic neurites has been identified as one of the distinguishing features in the brains of patients with AD. However, the molecular nature wasn't understood, until now” Dr. Yan said.

Dr. Yan's research shows that even a modest increase in RTN3 – perhaps only one- or two-fold – is sufficient to cause formation of dystrophic neurites. And when these neurites are created even absent aggregation of AB, cognitive impairment still results.

“Now, we are able to link, for the first time, the presence of dystrophic neurites to cognitive failure, and we show that over-expression of RTN3 early and under abnormal circumstance can cause AD,” Dr. Yan said. “RTN3 isn't just another protein trapped within dystrophic neurites, but is actively involved in their formation.”

The understanding could lead to new therapies for Alzheimer's disease.

“The research suggests that suppressing RTN3 aggregation may not only delay dysfunction, but also inhibit the BACE1 enzyme that creates the AB plaque,” he said. “RTN3 could be a new therapeutic target.”

Dr. Yan was assisted by Xiangyou Hu, M.D., Ph.D., Qi Shi, M.D., Ph.D., Xiangdong Zhou, Ph.D., Wanxia He , and Xinghua Yin, M.D., of the Institute's Department of Neurosciences; and Hong Yi, Marla Gearing, Ph.D., and Allan Levey, M.D., Ph.D., of the Emory University School of Medicine. The research was published in the EMBO Journal (www.nature.com/emboj/ 3 May 2007.).