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Blocking the Molecular Processes Leading to Alzheimer's
As the population of the United States and much of the developed world ages, rates of Alzheimer's disease, discovered by German neurologist Alois Alzheimer in 1906, are increasing. About three percent of men and women ages 65 to 74 have Alzheimer's disease, and nearly half of those age 85 and older may have the disease, according to the National Institutes of Health (NIH). Altogether, about four million Americans are currently affected.
During an autopsy of the brain, Alzheimer identified two key features of the disease in the early twentieth century: plaques and tangles of proteins in the cerebral cortex and limbic system, areas of the brain responsible for higher brain functions. The plaques are deposits found outside the neurons and are composed mostly of a protein called amyloid-beta (A-beta). The tangles are formed inside neurons and are made of filaments of a protein called tau. Although medical researchers have known for 100 years about these plaques and tangles, the ways in which they develop and the process by which the disease causes relentless mental decline has remained a mystery since its discovery. Scientists have been divided regarding whether the growth of these plaques and tangles actually cause the death of neurons or are simply the detritus of brain neurons that have been destroyed by some other process.
According to Michael S. Wolfe, Associate Professor of Neurology at Brigham and Women's hospital and Harvard Medical School, the weight of evidence has shifted toward what he calls the "amyloid cascade" hypothesis, which holds that A-beta and tau are closely involved in causing Alzheimer's disease, and that A-beta initiates the disease process.
A-beta is actually a piece of a normally occurring protean called the amyloid-beta precursor protein (APP). Molecules of APP stick through the cellular membranes of brain neurons and nearly all other cells in the body, with one part of the molecule inside the cell and the other part sticking outside. Two protein cutting enzymes called beta- and gamma-secretase respectively carve A-beta from APP, again a normal process. No one yet knows what A-beta's normal purpose is, although scientists speculate that it is part of an intercellular signaling pathway within the body.
Laboratory experiments have replicated the formation of protein tangles from high concentrations of A-beta, and these tangles have been shown to be toxic to neurons cultured in test tubes and interfere with learning and memory in mice. However the amyloid-cascade hypothesis has received its strongest support from studies of families at high genetic risk for Alzheimer's. These families carry rare genetic mutations that predestine them for the early-onset form of the disease, often before the age of 60. These mutations are expressed in the genes that code for APP, affecting the areas of the protein in and around the A-beta region. They increase the formation of either A-beta in general or a type of A-beta that is particularly prone to forming deposits. People with Down syndrome, who carry three copies of the chromosome that carries the APP gene, have a much higher incidence of Alzheimer's disease in middle age. People with Down syndrome produce higher levels of A-beta from birth, and often exhibit amyloid deposits in their brains in adolescence. Other genetic abnormalities that lead to the increased production of a form of A-beta that is prone to clumping produce a very early and aggressive form of Alzheimer's. Thus, the three genes known to cause Alzheimer's early in life all affect the production and type of A-beta.
The way in which assemblies of A-beta disrupt and kill neurons is still not understood. However researchers have found evidence that aggregates of A-beta outside of a neuron can start a cascade of events that leads to changes in the tau protein inside the cell. These aggregates apparently alter the molecular structure of tau so that it begins to form intracellular tangles. Wolfe speculates that the altered tau proteins ultimately kill the neuron, possibly by disrupting the microtubules that transport proteins and other large molecules along the axons and dendrites. He notes that mutations affecting the tau gene are associated with various types of neurogenerative diseases, indicating that the formation of tau filaments is a more general event leading to neuronal death, while A-beta initiates the process in the case of Alzheimer's disease.
Since A-beta plays an apparent key role in the development of Alzheimer's disease, inhibiting the enzymes called proteases ("beta" and "gamma" secretase) that produce it by cutting APP could result in potential treatments. One requirement for such treatments is that they be based on molecules small enough to get through the tiny capillaries that constitute the "blood-brain barrier." Wolfe and colleagues have found that the inhibitors of gamma-secretase are relatively small molecules that could penetrate this barrier.
However, gamma secretase is an essential agent in the maturation of undifferentiated stem cells in various tissues such as bone marrow. It cuts a cell-surface protein called the Notch receptor which signals surrounding cells regarding how the area of undifferentiated tissue as a will differentiate and form particular organ tissue. Inhibiting the Notch receptor produces severe toxic reactions in mice. Nevertheless a gamma-secretase inhibitor has passed a safety test and is currently a candidate being tested in phase I (safe dose finding), and will soon be further tested on patients with early Alzheimer's in phase II (efficacy) drug trials.
Another promising drug that targets the type of A-beta that tends to clump in aggregates is already entering phase III (comparative efficacy) advanced clinical trials. Yet another approach is to stimulate an immune response to amyloid plaques as they are being formed. Although some of the test patients using this approach developed severe encephalitis in a runaway inflammation response to A-beta, others simply formed antibodies to the peptide and showed signs of improved memory and concentration.
Scientists have long wrestled with the perplexities of Alzheimer's and are loath to raise their expectations for an effective treatment in the near future. Still, the enhanced understanding of the disease process combined with the multiplicity of new avenues for potential therapies that have recently opened give researchers new optimism. Optimism is a commodity that Wolfe notes has long been in short supply in the fight against Alzheimer's disease.
Further Reading
- National Institutes of Health. SeniorHealth website. http://nihseniorhealth.gov/alzheimersdisease/toc.html. (Accessed July 16, 2006.)
- Tanzi, R.E., and Parson, A.B. Decoding Darkness. Perseus Books Group, 2000.
- Wolfe, M.S. "Shutting down Alzheimer's." Scientific American (May 2006): 73-79.
- Wolfe, M.S. "Therapeutic Strategies for Alzheimer's Disease." In Nature Reviews Drug Discovery, vol. 1, pp. 859-866; November, 2002.