Research shows the success of a bacterial community depends on its shape.
Compounds now under development might eventually slow the progression of Alzheimer's disease, although it will be difficult to cure the age-related illness, Professor of Biology Vernon Ingram said in an IAP talk.
One such compound under development in Professor Ingram's laboratory is DP-8, a decoy peptide (a short chain of amino acids) that he said is particularly promising in derailing the formation of the fibrils that kill brain cells in Alzheimer's patients.
"If we only understood the process of Alzheimer's a little better, we could deal with slowing it down, but not reversing it," said Professor Ingram, who also is director of the Experimental Study Group at MIT. "This is the first time we can say we understand the process of Alzheimer's better, and hopefully compounds [like DP-8] will interfere with it."
Professor Ingram presented "Alzheimer's Disease: Present and Future Research," the last in a series of IAP lectures by the Department of Biology, on January 31. He has been researching the disease for the past seven years to better understand the biochemical basis of the disease and, more recently, to develop new diagnostic techniques and treatments for it.
Alzheimer's will be difficult to cure because so many brain cells are killed as the disease progresses, Professor Ingram said. Alzheimer's, which strikes after age 50, impairs memory and progresses to the loss of the ability to write, speak and orient oneself. It was first described by Alois Alzheimer, a professor in Wurzburg, Germany, about 90 years ago.
The disease first affects the locus ceruleus--neurons at the base of the brain that are part of the system that alerts or awakens the brain to signals and information. "If you're going to remember something, you must first perceive it, and then store it in such a way that you can retrieve it again," said Professor Ingram.
The locus ceruleus neurons are particularly affected in Alzheimer's. Each neuron is connected to about 3,000 cells, which in turn are connected to other cells in the brain in an intercommunicating three-dimensional network. So if important groups of cells disappear or become nonfunctional, other parts of the brain are affected as well.
The first disease case that Professor Alzheimer identified was a 52-year-old woman whose brain showed two unique characteristics upon autopsy. One was senile plaques, which are spherical, crystallized fibrils outside of cells. The other was tangles--fibrils that accumulate inside nerve cells, preventing them from functioning properly and eventually killing them.
Senile plaques are composed of an abnormal protein called a beta amyloid, which is toxic to nerve cells. Alzheimer's patients have an abnormally high production of beta amyloid. That results in enormous numbers of killed cells that are regionalized in the hippocampus of the brain (in the temporal lobe), where memories are stored.
Senile plaques are impervious to the body's normal clean-up processes in the body. Beta amyloids also accumulate in normal brains as people age, but at a much slower rate.
Calcium is a vital mineral in the human body that is present in each cell to regulate cell activities. A normal, healthy cell keeps its internal calcium concentration very low, Professor Ingram explained. But calcium levels outside the cell are more than 1,000 times higher than inside the cell.
When a cell receives a message from another cell, its calcium content is raised dramatically. Then the cell automatically readjusts itself to a low calcium level, readying itself for the next signal.
When the beta amyloid fibrils touch the cell surface, they open a "gate" in the cell wall that admits the external calcium. However, instead of closing, the gate stays open. This calcium flooding causes TAU hyperphosphorylation, which causes tangles (fibrils) to form inside the cell, and those fibrils cause apoptosis (cell death).
Professor Ingram said he and his colleagues are studying how to solve this flooding problem. "We have done research to interfere with the fibrils and we've succeeded. And we are also working on interfering with the open channel [gate] and blocking it. We now know of a number of compounds that can do this.
"We think decoy peptides derail the fibril formation process," he said. "We have evidence that DP-8 specifically blocks the toxic formation so the fibril can't properly interact with the cell surface and the calcium level will stay low."
Professor Ingram said he would like to see animal and clinical studies done on DP-8 and other decoys to make sure they don't interfere with normal cell signaling or have undesirable side effects.
"DP-8 and other decoys like it will be developed and will have highly specific interactions," he predicted. "The important thing about Alzheimer's is there are a number of paths that come together and result in a calcium increase, and thus there are a number of parts of the pathway you can interfere with. I'm firmly convinced that ultimately, as with HIV, there will be more than one drug that will act on different parts of this pathway" in Alzheimer's.
He pointed to broader applications of such promising therapeutics in the future. They might, for example, be applied to slowing the normal aging process, so that older people can have a better quality of life, remaining independent and mentally and physically functional.
A version of this article appeared in MIT Tech Talk on February 5, 1997.