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.
New gene-regulating enzyme found
Context: The Human Genome Project catalogued our genes, but all that genetic information is useless unless it’s tied to physical traits. One of the biggest remaining questions in biology is simply how genes are turned on and off. Part of the answer lies inside the cell’s nucleus, where DNA is wrapped around spool-like structures called histones. In the late 1990s, researchers found that enzymes placed chemical tags on the spools and that these tags could activate or deactivate genes on the wrapped DNA. What the researchers couldn’t find were enzymes that removed the tags, leading many to conclude that they just didn’t exist. A team at Harvard Medical School and Johns Hopkins School of Medicine led by Yang Shi has now found such an enzyme, and with it a new layer of gene control not previously exploited by medicine.
Methods and Results: Shi’s team was not originally looking for a detagging enzyme. Instead, it was investigating how the enzyme LSD1 (important for embryonic patterning and differentiation), as part of a larger protein complex, manages to suppress huge families of genes. After several experiments, the team realized that when LSD1 wasn’t around, certain genes were expressed because a histone that should not have been tagged in fact was. Closer observation of cells in which LSD1 was present revealed remnants of removed tags, confirming the enzyme’s behavior. It also showed that LSD1 clips tags at very specific spots, thereby exerting control over a discrete set of genes.
Why it Matters: Improperly tagged histones are implicated in several types of cancer. The discovery of this enzyme solves the second half of a mystery in gene regulation. Controlling this and related enzymes could lead to new therapies, particularly for cancers such as leukemia and neurodegenerative diseases. Further off, the enzyme could be used in bioengineered cells to turn large swaths of genes on and off without interfering with other techniques of gene regulation. Shi’s group has submitted a patent application on LSD1. Now, the search begins for more such enzymes.
Source: Shi, Y., et al. 2004. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941–953.
Silicon on the Brain
A chip that reads neurons
Context: The neurons of the mammal brain are hard to study, even when they’re isolated in the lab. For more than a decade, scientists have analyzed the large neurons of leeches and snails by linking them directly to silicon chips that record their electrical activity. But mammalian neurons are smaller, and though they can be grown on silicon, the resulting signals are typically too weak to yield useful data. The electrical activity of mammalian brain cells can be read with electrodes, but that can be imprecise and requires careful preparation steps.
Moritz Voelker and Peter Fromherz at the Max Planck Institute for Biochemistry have now designed the first computer chip that can record the firing of mammalian neurons, though so far only in a petri dish.
Methods and Results: As a neuron fires, the voltage across it changes, so a neuron on a chip affects how transistors underneath it conduct electricity. But in chips with conventional transistor designs, there’s so much naturally occurring noise that it swamps neural signals. So Voelker and Fromherz changed the geometry of the transistors to suit the electrical properties of living neurons. They buried the conducting channels of their transistors a few nanometers deeper than usual, making the transistor more sensitive to the low voltages and firing speeds of neurons. The transistors could detect the signal of an individual rat neuron in a group, without the elaborate sample preparation that conventional electrodes require. What’s more, the transistors are significantly smaller than individual neurons and could in principle provide information on how subsections of a neuron behave.
Why it Matters: Electrodes implanted in human brains have allowed paralyzed patients to move computer cursors and prosthetic limbs (see “Implanting Hope,” March 2005, p. 48). While increased computing power helped enable that breakthrough, so too did the development of hardware suitable for detecting neural signals. A silicon interface could process data more nimbly and is the logical candidate for next-generation devices. Those are still years away; in the nearer term, neuron-silicon interfaces will help explain how groups of neurons communicate with each other and could be particularly helpful for understanding how neuroactive drugs such as antidepressants work.
Source: Voelker, M., and P. Fromherz. 2005. Signal transmission from individual mammalian nerve cell to field-effect transistor, Small 1:206–210.