Clinical and Research News
Brain Proteins Point to Link Between Parkinson’s, Alzheimer’s
Psychiatric News
Volume 36 Number 20 page 23-23

Scientists from the University of California at San Diego (UCSD) have discovered that two of the proteins associated with Alzheimer’s disease and Parkinson’s disease closely interact to enhance each other’s distinct degenerative effects.

In an early-edition online report posted September 25 on the Proceedings of the National Academy of Sciences Web site, the team suggested that pharmacological therapies that block the production or accumulation of either protein may have broader therapeutic effects than previously thought.

Although Alzheimer’s disease (AD) and Parkinson’s disease (PD) are distinct neurological disorders, previous studies have indicated that as many as 25 percent of patients with AD develop PD-like symptoms, and some PD patients develop signs of AD as well.

Some 4 million patients have AD in the United States, and more than 1 million are currently being treated for PD. Each disorder appears to have a specific group of neurons within specific areas of the brain that it targets. In these specific brain regions, AD is known to be associated with the overproduction or abnormal buildup of the protein beta amyloid into pathological brain changes known as amyloid plaques and PD with a similar pathological accumulation of the protein alpha-synuclein into Lewy bodies. Familial forms of each disease have been associated with genetic mutations leading to the overaccumulation of these proteins.

In the current report, Eliezer Masliah, M.D., a professor of neurology and pathology at UCSD, led a group of researchers from UCSD and the Gladstone Institute of Neurological Disease and department of neurology at the University of California at San Francisco in developing strains of genetically engineered mice that produce the two human proteins. Their work was funded by the National Institutes of Health.

One strain of mice was altered to produce human amyloid precursor protein (hAPP)—the building block of beta amyloid—while a second strain was altered to produce human alpha-synuclein (hSYN). A third strain of mice was engineered to overproduce both proteins.

Reports of human cases with clinical and neuropathological features of both AD and PD led the researchers to hypothesize that hSYN and hAPP have "distinct, as well as convergent, pathogenic effects on the integrity and function of the brain," according to the report. The team suspected that hSYN might affect motor functions more than cognitive ones, while hAPP has the opposite affect. In addition, they believed, the two proteins might interact more directly by engaging in synergistic neurodegenerative pathways.

To explore the possible connection between the two disease processes, Masliah’s team studied the three strains of mice. They followed motor function and ability to learn and used extensive postmortem analysis to determine the end results of the two genetic alterations, either singly or in combination.

The researchers report that mice that produced only one of the proteins developed the symptoms of the disease tied to that respective protein. But when both proteins were produced in the same mouse, the Alzheimer’s-like symptoms of the hAPP mice—including an impaired ability to learn and the pathological degeneration of particular brain cells—were exacerbated by the production of hSYN. The Parkinson-like motor deficits of the hSYN mice also tended to develop sooner in the mice that also expressed hAPP.

An unexpected finding, according to the report, was a direct enhancement of the accumulation of hSYN in brain cells with increasing levels of beta amyloid. The researchers say that because the proteins appear to interact to accelerate and exacerbate the symptoms of their respective diseases, medications could be developed that prevent the accumulation of hAPP or hSYN, leading to benefits for a wider spectrum of neurodegenerative disorders than has previously been thought.

An abstract of the study, "Beta-Amyloid Peptides Enhance Alpha-Synuclein Accumulation and Neuronal Deficits in a Transgenic Mouse Model Linking Alzheimer’s Disease and Parkinson’s Disease," is posted on the Web at www.pnas.org/cgi/content/abstract/211412398v1.

Proc. Natl. Acad. Sci. USA20019812245

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