By Dean A. Haycock
Special To BioWorld Today
At times the threat of Alzheimer's disease (AD) is like a ghost that hovers around whenever we misplace our car keys or forget a phone number. Those are not symptoms of AD but they raise the specter that threatens everyone who values a sharp mind, a good memory and a quick wit. Scientists are just beginning to get a clear idea of the pathological mechanisms behind the threat.
Dennis Selkoe, of the Center for Neurologic Diseases at the Harvard Medical School and Brigham and Women's Hospital, in Boston, reviewed recent research findings on AD in the Jan. 31 issue of Science.
Long a proponent of the view that amyloid ß protein is a necessary but by no mean sufficient factor in the development of AD, Selkoe noted that all four known genetic alterations linked to familial forms of the disease increase the production or deposition of amyloid ß protein in the brain.
Amyloid ß is a fragment of a larger molecule called amyloid-ß precursor protein. It contains between 40 and 43 amino acids. It is sticky, apparently noxious and accumulates in parts of the cerebral cortex in clusters called amyloid plaques. The brains of AD victims are filled with amyloid plaques and most researchers in the field suspect amyloid ß plays an essential role in the sequence of events leading to the cell death responsible for Alzheimer's symptoms. A minority of scientists still view amyloid ß as a consequence of some other, unidentified event that causes AD.
Genetic Research Unlocks Possibilities
In his article, "Alzheimer's disease: genotypes, phenotype, and treatments," Selkoe noted that recent results combined with past studies increase the attractiveness of several therapeutic approaches for eventually treating AD. Much of this support stems from recent genetic research.
Mutations on chromosomes 1, 14, and 21 increase the production of amyloid ß peptides. And variations of a gene on chromosome 19 linked to AD is associated with increased accumulations of amyloid ß, plaques, in the brains of AD victims.
"This is certainly the most parsimonious formulation of the data reviewed in the Science paper," Sam Gandy, a neurologist and Alzheimer disease researcher at Cornell University Medical College, in New York said, "It is possible that APOE and the presenilin mutations [on chromosome 19, 14, and 1] act in exactly the way Dennis describes by promoting amyloid accumulation. But one can't exclude the possibility that the molecules both promote amyloid accumulation and have some other activity that is deleterious to neurons."
Selkoe said the results he reviewed significantly strengthen the rationale for considering amyloid ß as a prime therapeutic target for AD. These potential targets being considered by scientists in academia and in industry can be divided into four categories.
The first approach is to inhibit the enzymes that releases amyloid ß peptide from its precursor molecule.
"We of course know that protease inhibitors have been used for a number of other diseases such as ACE inhibitors in hypertension and HIV protease inhibitor for AIDS," Selkoe told BioWorld Today, "It is my opinion that inhibiting gamma secretase in particular but perhaps also ß secretase, would decrease the production of amyloid peptide."
He compared this approach to the use of the protease inhibitors, Lovostatin or Mevocor which are used to lower cholesterol levels.
"My guess is that will be one of the first if not the first type of new therapeutic agent to come from this emerging synthesis of Alzheimer's disease research," Selkoe said.
A second viable strategic approach would be to inhibit the aggregation of the amyloid peptide.
"That is a particularly attractive therapeutic target and one I would recommend working on because there would be two strong advantages. One, you would be inhibiting a purely pathological event, namely amyloid aggregation . . . The second is that the aggregate is entirely outside of cells in the brain, in the extracellular spaces between cells. The drug would still have to cross the blood brain barrier * that always will be necessary * but you would not have to go into the neuron and therefore you would not be monkeying with cellular metabolism," Selkoe explained.
These drug candidates would be small compounds able to penetrate the blood brain barrier, in Selkoe's view.
Blocking Inflammatory Mechanisms
Anti-inflammatory treatment is the third approach Selkoe described. The rationale is that the accumulation of amyloid in plaques in the brain elicits an inflammatory response from microglial cells. These in turn release cytokines and other inflammatory compounds which damage healthy neurons.
"The idea of anti-inflammatory therapy for AD is to block the action of cytokines or to decrease their release. One would begin by thinking about known anti-inflammatory drugs like NSAIDS but it would be much better to design new molecules that are not for arthritis or peripheral inflammation but are targeted specifically for inflammatory mechanism that come from microglial cells," Selkoe said.
The fourth area worth pursuing in Selkoe's opinion is anti-neurotoxicity. This approach would be directed at blocking the direct effects of amyloid aggregates on neurons.
This strategy obviously assumes that amyloid ß is neurotoxic.
"We don't know yet whether amyloid ß when it accumulates in plaques directly damages neurons or whether it does so via the microglial and astrocytic cells," Selkoe said.
There is some evidence that aggregated amyloid sticks to the surface of neurons in the brain and in tissue cultured cells. And there is evidence it may increase calcium influx, a common mechanism leading to cell death.
"Another way to inhibit neurotoxicity would be the use of antioxidants. Amyloid ß induces oxidative injury in cells studied in culture. Perhaps something as useful as vitamin E which is now being tested in the clinic will be useful," Selkoe said. *