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Inside Alzheimer’s Disease tangles and plaques directly cause the disease, but they, or their precursors, are believed to Los Alamos neutron and x-ray physicist interfere with normal brain function by sup- Jarek Majewski is at it again. He has used neu- pressing communication between neurons or trons to probe biological structures associated simply disintegrating them. The tau and beta- with illnesses ranging from cholera to vascular amyloid proteins are present in healthy human disease [see the August 2011 and August 2014 brains as well, where they help stabilize micro- issues of 1663, respectively]. To that list, he tubules in the nervous system and participate and his Los Alamos colleague Ann Junghans, in cell growth, respectively. But the question is together with collaborators at the University of what causes them to accumulate into tangles New Mexico, the Max Planck Institute for Neu- and plaques in the brains of those suffering rological Research, and the Center for Neurode- from the disease? In other words, what causes generative Diseases (the latter two in Germany) these proteins to assemble into larger structures now add a mechanism that many researchers that obstruct the cells’ normal activities? believe underlies Alzheimer’s disease. The For atoms or molecules to assemble into disease is America’s sixth-largest killer and larger structures like tangles and plaques, they burdens the nation to the tune of $220 billion must overcome certain energy barriers; when per year—more than 1 percent of GDP—plus the aggregates are too small, they are unstable another 17 billion hours of unpaid care, accord- and will disassemble themselves. Sometimes, ing to the U.S. Centers for Disease Control and however, they receive help from tiny bits of solid Prevention and the Alzheimer’s Association. matter to grow past the unstable phase, such as In the brains of patients suffering from when clouds are seeded with particles to help Alzheimer’s disease—examined post-mortem, raindrops aggregate out of water vapor. Other of course—anomalous tangles of tau proteins times, the help comes from environmental and plaques of beta-amyloid protein fragments conditions, such as fluctuations in temperature, are always present. It is not clear whether these pressure, and electric charge. Something of this sort must be catalyzing the aggregation of beta-amyloid and tau molecules out of solution in Alzheimer’s patients, and a theory that has been gaining traction suggests that electrical charges on neuron cell membranes may provide that catalyst. To investigate the theory, Majewski reflected x-rays and neutrons off of a simplified cell membrane after injecting human tau proteins into the adjacent fluid. He found that when the membrane is comprised of uncharged lipids, as is normally the case with the exteriors of young, healthy brain cells, the proteins do not significantly interact with it. But when the membrane contains negatively charged lipids, as are observed in old or injured cells, the tau proteins fold up into tighter configurations—a necessary first step in the aggregation of tau tangles—and wedge themselves between lipid molecules in the cell membrane. Simi- larly, beta-amyloid proteins anchor into the membrane and begin to aggregate and grow in the presence of the negatively charged lipids. Majewski and his team observed this directly in recent synchrotron x-ray experiments. In other experimentation using graz- ing incidence x-ray diffraction and neutron reflectometry, Majewski revealed that the tau proteins broadly disrupt the lipid organization, creating weak spots and openings in the mem- brane. Such membrane disruptions can impair neuronal signaling and ultimately kill the brain cell—producing (or at least contributing to) the cognitive dysfunction of Alzheimer’s patients. In the absence of the disease, tau proteins bind to microtubules that run the length of the long, wire-like part of neurons, strengthening them and providing convenient roads for other molecules to travel. But if too many phosphate Los Alamos research indicates that neuron membrane disruption may be responsible for the aberrant growths found in the brains of Alzheimer’s patients and the neuronal damage that causes mental decline. 1663 January 2015 27