Gladstone/UCSF team discovers interaction of two brain proteins may be key factor in development of Alzheimer's disease

June 22, 1999

A team of San Francisco scientists studying Alzheimer's disease has found the interaction of two brain proteins may be a critical factor in development of the debilitating disorder.

Both proteins have been the focus of intense scientific scrutiny because of their independent roles in different diseases and basic cell biology. The current study reveals a novel interaction between the two that could help explain the death of nerve cells associated with Alzheimer's disease, or AD. Understanding this process could lead to development of better treatments to prevent or slow the degeneration of nerve cells that causes memory loss or disturbed thinking that are symptoms of the illness.

The research, conducted by researchers from the Gladstone Institute of Neurological Disease (GIND) and the University of California San Francisco, is reported in the new issue (June 22) of the Proceedings of the National Academy of Sciences.

One of the proteins, amyloid precursor protein, or APP, is normally found at high levels in the brain, but its function is largely unknown. The second protein is p53, which under certain conditions turns on an internal cell suicide process that leads to the death of the cell. In the case of nerve cells, this process can be devastating to the brain because most of these cells are irreplaceable.

Mutant forms of APP are associated with certain forms of AD, but how they cause the death of brain cells has been a mystery. Now the new research findings provide some clues.

The researchers, led by Gladstone staff research scientist Xiao Xu, MD, PhD, and Lennart Mucke, MD, director of the GIND and associate professor of neurology and neuroscience at UCSF, found that normal APP--known as "wild-type" APP--provides a protective function against nerve cell death, inhibiting the p53-induced suicide process in cell cultures. Findings showed mutant forms of APP do not provide this protection.

AD is a disorder of the central nervous systems that affects some four million Americans and is the fourth leading cause of death among adults in the U.S. It causes progressive mental deterioration that culminates in dementia, robbing people of their ability to think and share thoughts with others. There is no cure, and current treatments offer only limited hope of alleviating the devastating effects of the disease.

The cells in this study were neurons, which are necessary for the processing and storage of information in the brain. They had been genetically altered to express wild-type human APP or a mutant APP found in a type of early-onset AD that runs in families. When the neurons were exposed to stimuli that induce cell death, wild-type APP--but not mutant APP--protected the cells by inhibiting the ability of p53 to switch on the cell suicide machinery. "The inability of mutant APP to control p53 activation may help to explain, at least in part, why Alzheimer's-linked APP mutations result in the early onset of neurodegenerative disease," Mucke said. "The next step will be to determine if the APP mutations directly impair the protective function of APP or rather counteract it by increasing a neurotoxic APP breakdown product."

The new research findings relate to an earlier study by Mucke, Roger Nicoll, MD, UCSF professor of pharmacology and physiology, and their colleagues in the UCSF neuroscience program. Published in the March 1999 issue of PNAS, it focused on the amyloid-beta peptide, or A-beta, a breakdown product of APP.

Production of A-beta is increased by AD-linked APP mutations. The peptide accumulates in the brains of Alzheimer's victims, forming roundish deposits, called plaques, which have long been suspected of causing the memory loss and disturbed thinking that characterize the disease.

A correlation between cognitive decline and accumulation of A-beta in brain plaques has been reported by some researchers, but many other scientists have failed to find such a relationship. The Gladstone and UCSF researchers found that high levels of A-beta can be neurotoxic even without plaque formation. Mucke noted, "These results could provide a circuit-level explanation for the discrepancies observed between plaque load and functional deficits in people with AD."

In this earlier study, Mucke and his collaborators used genetic engineering to produce transgenic mice with mutant human APP and A-beta in the brain. Their findings showed that high levels of A-beta disrupted the structure and function of nerve cell circuits in the hippocampus, a brain region that is essential for the formation of memories. In addition, they found that amyloid proteins induced degeneration of synaptic connections and impeded the ability of neurons to transmit nerve impulses. These abnormalities increased with age, similar to the pattern in AD.

"Remarkably, the amyloid-induced disruption of memory circuits was found in the transgenic mice even before they developed AD-like amyloid plaques. This demonstrates that plaque formation is not required for amyloid peptides to impair the communications between nerve cells in the brain," said Nicoll, who directed the electrophysiological analysis of the mice.

According to Mucke, the findings have important implications for the design of new treatments for AD. "Inhibiting plaque formation alone may not be enough to prevent A-beta toxicity in the brain. Inhibition of A-beta production may be required to achieve this therapeutic goal," he said.

In addition to Mucke and Xu, co-investigators of the June 22 PNAS paper are Daseng Yang, PhD; Tony Wyss-Coray, PhD; Jim Yan, BS; and Li Gan, PhD, all from the Gladstone Institute of Neurological Disease and UCSF Department of Neurology, and Yi Sun, MD, PhD, of Parke-Davis Pharmaceutical Research. This research was supported by grants from the National Institute on Aging and from the Alzheimer's Disease Program of the State of California.

Co-investigators with Mucke and Nicoll on the March 1999 PNAS paper were lead author Albert Y. Hsia, PhD, a UCSF neuroscience graduate student; Robert Malenka, MD, PhD, UCSF Department of Physiology and now with Stanford University; Eliezer Masliah, MD, UC San Diego Departments of Neurosciences and Pathology; and Lisa McConglogue, PhD; Gwen Tatsuno, MS; Kang Hu, BS, and Dora Kholodenko, MS, of Elan Pharmaceuticals. This research was supported by grants from the National Institutes of Health, the Human Frontiers Science Program, the McKnight Endowment Fund for Neuroscience, and the Office of Naval Research.
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The Gladstone Institute of Neurological Disease, established in 1998, focuses on research directed at understanding the biological mechanisms of AD and other major diseases of the central nervous system. The Institute is one of three that make up the J. David Gladstone Institutes, a private biomedical research institute affiliated with UCSF.



University of California - San Francisco

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