Alzheimer’s Disease (AD) is arguably the most feared of the more common (approximately 20 million patients worldwide) neurodegenerative diseases. While there are a number of medications that are thought to help with symptoms at the varying stages of Alzheimer’s, none are curative.
Many physicians and scientists suggest that more advances in understanding the disease at the microscopic level of the genetic control of the metabolism of cells and tissues is the key, in the sense that we can better disrupt the molecular biology of progressive pathological processes once we them understand better. While some rarer, early onset forms of the disease are strongly influenced by well-defined genes, most of the more common types of AD seem to involve the interaction of several genes with many different environmental or personal life history influences possible.
Probably the very most recent discovery of yet another possible pathological pathway to AD appears in a recent issue of Cell (v.133, 1149-1161, June 27, 2008). The team of Drese-Werringloer et al. has found yet another genetic abnormality (polymorphism) that predisposes patients towards the most familiar type of Alzheimer’s, Late Onset AD, or LOAD development.
The discovering team, which was based principally at the North Shore – Long Island Jewish Hospital, worked with tissues from a variety of sites in the brain, but paid special attention to those drawn from the hippocampus, the “library technical services” part of the brain that takes newly arrived input and tags it for future retrieval, before sending it off for permanent storage, and recall on command. It is thought that damage in this area is particularly crucial to the loss of the ability of LOAD patients to make sense of new information and especially new situations, and integrate it with what they should know through appropriate recall.
What the scientists suspected and found, was evidence of a hitherto unexpected gene that regulates calcium ion balance in the brains cells (neurons). Calcium level irregularities had already been shown to be important in disrupting proper processing of A-Beta amyloid proteins. When these A-Beta proteins break down prematurely and incorrectly, they leave waste fragments that build up into plaques, a deposit that is inimical to the healthy nerve cell.
In addition, the material that wrongly goes into the plaque is not available for the protein’s designated job: being a kind of neuron cell “trailer hitch,” which pokes out through the neuron’s cellular membrane, onto which the brain’s cellular repair trucks, neurotrophic factor proteins, can dock and help repair and maintain the cell.
Finally, these amyloid plaques also seem to inhibit the use of glucose, the prime energy fuel, in the mitochondria of the neurons in the hippocampus, further degrading the integration of inputs with memory and appropriate course of action. Ultimately, this leads to hippocampal atrophy.
Does this mean that, having found this particular genetic abnormality, that there will shortly be a quick genetic test for this type of AD? The answer is not at this time. While there are a few genetic tests for AD, they are for those with very strong familial propensities for Early Onset AD, not LOAD, and are still not widely used.
Furthermore, there is increasing evidence that some forms of LOAD are not caused solely by the genetically determined malfunction of A-beta proteins, but by other categories of molecular biological malfunction. Some are traceable though two types of “presenilin” markers, but the most promising involve tau gene mutations, which are already clearly involved in frontotemporal lobar degeneration, a much rarer but swifter and arguably more devastating cause of dementia. Tests for all of these are now also being developed.
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Tony Stankus [email protected] Life Sciences Librarian & Professor
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