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Old Drugs, New Tricks
Cholesterol and cancer drugs may fight Alzheimer’s

Context: Often a drug that treats one disease works for another, apparently unrelated disease. Two early antidepressants began their careers as an antibiotic (iproniazid) and an antihistamine (imipramine). The impotence drug Viagra was designed to prevent heart failure. Now, two recent papers report that drugs already on the market may help prevent Alz­heimer’s disease.

Methods and Results: Some studies have found that patients taking statins, a class of cholesterol-lowering drugs, are less likely to develop Alzheimer’s disease. A team led by Sam Gandy at the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia sought an explanation of this finding. It turns out that when statins are added to cultures of neurons, the neurons more quickly destroy a precursor of the protein amyloid that goes on to form the plaques characteristic of Alz­heimer’s. To determine exactly what statins do in neurons, Gandy’s team both blocked and mimicked their effects by manipulating proteins—and so showed which proteins the statins affect.

Taking a different tack, a University of Pennsylvania School of Medicine team led by John Troja­nowski, in collaboration with Angiotech Pharmaceuticals, tested the cancer drug paclitaxel in mice genetically designed to have neurodegenerative disease. Paclitaxel halts cell division, causing cells to die. It does so by binding to and preventing the movement of microtubules, structures that form cells’ support and transport infrastructure. For diseased neurons, however, this stabilizing effect proved beneficial. In mice, the drug partially restored nerve function, apparently substituting for a protein, tau, that normally stabilizes microtubules in nerve cells but malfunctions in Alzheimer’s disease.

Why it Matters: Alzheimer’s disease is the leading cause of dementia in the elderly, but current treatments do nothing to halt the disease; they simply alleviate its symptoms, often insignificantly. Other experimental therapies directly target amyloid or closely related molecules.
The Penn and Jefferson researchers’ results point to possible new approaches to combatting the disease, ones that might prevent plaques from forming in the first place. Though this research is still in its early stages, its basis in widely used and studied drugs should help speed its progress.

Sources: Zhang, B., et al. 2005. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proceedings of the National Academy of Sciences 102: 227–231.

Pedrini, S., et al. 2005. Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK. PLoS Medicine 2: 69–78.

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Tagged: Biomedicine

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