Alzheimer's, aging and acetylcholine.

Alzheimer's, aging and acetylcholine 

Consisting of perhaps no more than 100,000 nerve cells, the basal forebrain takes up very little of the space between our ears. But with evidence that it may play a key role in Alzheimer's disease, this deeply buried clump of cells has captured many neuroscientists' attention in the past two years.

Through long neural branches, the basal forebrain supplies the more highbrow parts of the brain, such as the cortex and hippocampus, with healthy doses of the neurotransmitter acetylcholine, which scientists believe modulates the processes of learning and memory. In Alzheimer's, the basal forebrain usually degenerates, leading to depressed acetylcholine production. Many experimental Alzheimer's therapies have sought to boost acetylcholine, but with little success.

Now, researchers express excitement about the possibility of using a natural hormone, nerve growth factor (NGF), to "rescue" a withering basal forebrain and block the progression of at least some Alzheimer's symptoms. Found in low levels in most animals, NGF dramatically stimulates new outgrowths of acetylcholine-producing ("cholinergic") nerves. Until recently, scientists wanting to work with NGF had to extract it from the salivary glands of male mice--lots of male mice. But now that several laboratories have successfully cloned the NGF gene from several different species, scientists are moving quickly into what some envision as the next big wave in neuroscience research: transplantation of genetically engineered cells that make cell growth factors.

Lars Olson of the Karolinska Institute in Stockholm, Sweden, last week described the first such attempts. Olson and his colleagues inserted into a cultured line of mouse cells the gene for a form of NGF. When transplanted into the brains of rats, these gene-altered cells secreted NGF and stimulated new growth of acetylcholine-producing neurons. Moreover, when the researchers mixed the growth-factor-secreting cells with fetal nerve tissue that was about to be transplanted into adult rats' brains, they enhanced the survival and growth of the fetal tissue graft.

Beyond the possibility of rescuing basal forebrains in Alzheimer's patients, other potential applications of the technique abound. In Parkinson's disease, for example, where Olson and others have experimented with transplants of dopamine-producing fetal cells into patients' brains, gene-altered cells may behave more predictably than fetal cells. "One possibility would be to use these cells rather than fetal tissue, by getting them to make dopamine, for instance," Olson says.

Elsewhere on the Alzheimer's front, scientists report that monkeys, if allowed to live long enough, may be useful models for studying the disease. Alzheimer's research has long been hampered by the lack of a research animal that develops both the behavioral and neurological signs of the disease. Now, Linda C. Cork of the Johns Hopkins School of Medicine in Baltimore and her colleagues report the first identification of a protein called A68 in the brains of old monkeys. In humans, the protein -- whose function remains uncertain -- is uniquely found in Alzheimer's patients (SN: 11/28/87, p.348).

Moreover, Cork's co-worker Donald Price reports the first discovery of neurofibrillary tangles in the brain of a very old monkey who had died after showing symptoms of Alzheimer's. The protein tangles in brain tissue are characteristic of advanced Alzheimer's, and Price speculates that A68 may be a precursor of the tangles.

Along with ongoing, task-oriented studies of a large group of aging monkeys in his lab, he says, analyses of such changes in monkey brains may help scientists understand the connection between neural damage and the behavioral changes seen in Alzheimer's.