Dec. 16, 1997 A research team based at the Massachusetts General Hospital (MGH) has discovered a new gene that appears to play a role in Alzheimer's disease. The gene produces a protein in nerve cells, and the researchers found excessive quantities of this protein in brain tissue and cerebrospinal fluid (CSF) of people with Alzheimer's. They also showed that accumulation in nerve cells of this protein, called AD7c-NTP, causes changes similar to those seen in Alzheimer's, including cell death. Published in the December issue of the Journal of Clinical Investigation, the study additionally describes a highly sensitive and specific assay for AD7c-NTP, developed by scientists from the Nymox Corporation.
"There are many questions about the role this protein may actually play in Alzheimer's, but we're very excited about how closely its effects mimic the damage seen in Alzheimer's and how consistently excessive levels are seen in people with this terrible disease," says Suzanne de la Monte, MD, the MGH neuropathologist who is the paper's first author.
Alzheimer's is the most common cause of dementia in the Western hemisphere and currently affects more than 4 million Americans. In a small proportion of cases — 5 to 10 percent — the disease runs in families. Three genes have been discovered that cause familial Alzheimer's, and MGH researchers contributed to the discovery of all three genes. In most instances, however, Alzheimer's appears in people without a family history of the disease. The current study focuses on this common sporadic form of Alzheimer's.
De la Monte isolated the gene for AD7c-NTP and determined its sequence of nucleotides, the genetic building blocks that define a specific protein. She then showed that the gene's protein was produced in brain tissue but not in tissues from numerous other organs and that significantly higher levels of the protein were seen in tissue samples from people with Alzheimer's compared with samples from elderly people with no neurological disorder. In addition, elevated AD7c-NTP was seen much earlier in the course of the disease than several other proteins associated with Alzheimer's are known to appear. When the gene was introduced into cultured nerve cells and its protein was expressed, the cells grew abnormally long branches or processes and died, a phenomenon seen in Alzheimer's.
The researchers from Nymox, led by Hossein Ghanbari, PhD, developed a very sensitive test to measure levels of the protein in cerebrospinal fluid. They then examined samples from people who had died with Alzheimer's (confirmed by postmortem examination), who had early Alzheimer's, who had other neurologic diseases (multiple sclerosis or Parkinson's disease), or who had no neurologic disorders. The Nymox researchers, who did not know beforehand which diagnostic categories individual samples represented, found elevated AD7c-NTP levels in 84 percent of the confirmed Alzheimer's cases. Levels that could be considered elevated also were seen in 89 percent of the early Alzheimer's cases, compared with 11 percent of elderly individuals with no neurologic disease. In those with other neurologic disorders, levels were slightly higher than those seen in healthy controls.
"AD7c-NTP levels were uniquely elevated in patients with Alzheimer's," Ghanbari says. "We were particularly surprised to see this protein was present in very early Alzheimer's cases and that its level generally increased as patients got worse."
The researchers stress that they do not yet know whether the gene itself is abnormal or whether it is a normal gene that is overactivated by some other factor. However, nerve cells stimulated to produce AD7c-NTP can be used to screen possible Alzheimer's drugs for effectiveness. The protein assay could be helpful in determining whether an individual with dementia has Alzheimer's or another condition as well as for tracking the success of clinical Alzheimer's therapies.
Additional coauthors of the study are senior author Jack R. Wands, MD, of the MGH; Kasra Ghanbari, Iraj Beheshti, PhD, and Paul Averback, MD, of Nymox; William Frey, PhD, of the Ramsey Alzheimer's Treatment and Research Center in St. Paul, Minn.; and Stephen Hauser, MD, of the University of California Medical Center in San Francisco. The research was supported by grants from the National Institutes of Health, the American Cancer Society, Nymox Corporation and the Tan Yan Lee Foundation.
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