Brain Starvation as We Age Appears to Trigger Alzheimer's

A slow, chronic starvation of the brain as we age appears to be one of the major triggers of a biochemical process that causes some forms of Alzheimer's disease.

A new study from Northwestern University's Feinberg School of Medicine has found when the brain doesn't get enough sugar glucose -- as might occur when cardiovascular disease restricts blood flow in arteries to the brain -- a process is launched that ultimately produces the sticky clumps of protein that appear to be a cause of Alzheimer's.

Robert Vassar, lead author, discovered a key brain protein is altered when the brain has a deficient supply of energy. The altered protein, called elF2alpha, increases the production of an enzyme that, in turn, flips a switch to produce the sticky protein clumps. Vassar worked with human and mice brains in his research.

The study is published in the December 26 issue of the journal Neuron.

"This finding is significant because it suggests that improving blood flow to the brain might be an effective therapeutic approach to prevent or treat Alzheimer's," says Vassar, a professor of cell and molecular biology at the Feinberg School.

A simple preventive strategy people can follow to improve blood flow to the brain is getting exercise, reducing cholesterol and managing hypertension.

"If people start early enough, maybe they can dodge the bullet," Vassar says. For people who already have symptoms, vasodilators, which increase blood flow, may help the delivery of oxygen and glucose to the brain, he added.

Vassar said it also is possible that drugs could be designed to block the elF2alpha protein that begins the formation of the protein clumps, known as amyloid plaques.

An estimated 10 million baby boomers will develop Alzheimer's in their lifetime, according to the Alzheimer's Association. The disease usually begins after age 60, and risk rises with age. The direct and indirect cost of Alzheimer's and other dementias is about $148 billion a year.

The initial trigger of Alzheimer's has long been a mystery.

Ten years ago, it was Vassar who discovered the enzyme, BACE1, that was responsible for making the sticky, fiber-like clumps of protein that form outside neurons and disrupt their ability to send messages.

But the cause of the high levels of the protein in people with the disease has been unknown. Vassar's study now shows that energy deprivation in the brain might be the trigger starting the process that forms plaques in Alzheimer's.

Vassar said his work suggests that Alzheimer's disease may result from a less severe type of energy deprivation than occurs in a stroke. Rather than dying, the brain cells react by increasing BACE1, which may be a protective response in the short term, but harmful in the long term.

"A stroke is a blockage that prevents blood flow and produces cell death in an acute, dramatic event," Vassar says. "What we are talking about here is a slow, insidious process over many years where people have a low level of cardiovascular disease or atherosclerosis in the brain. It's so mild, they don't even notice it, but it has an effect over time because it's producing a chronic reduction in the blood flow."

Vassar says when people reach a certain age, some may get increased levels of the enzymes that cause a build-up of the plaques. "Then they start falling off the cliff," he says.

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Rat Whiskers Yields Insight Into Sensing Machinery

High-speed video of rats using their whiskers to explore different surfaces has given researchers significant insights into the subtle mechanics of their tactile sensory system. Such information is important because the rat tactile machinery is a widely used laboratory model for studying how energy from sound or touch is translated into neural activity. Thus, basic insights from studying the rat system could aid in understanding the senses of hearing and touch in all mammals, including humans.

Christopher Moore and colleagues published their findings in the Feb. 28, issue of the journal Neuron, published by Cell Press.

Previous studies of the mechanics of rat whiskers had analyzed the motions and neural signals generated by isolated rat whiskers, rather than the complex, subtle “micromotions” of the array of whiskers, called vibrissae, in a behaving animal.

“Research has proceeded without a thorough understanding of these signals because the inherent challenges in tracking high-speed, small-amplitude motion of thin vibrissae in a freely behaving animal precluded direct measurement of micromotions,” wrote the researchers.

In their experiments, the researchers trained rats to use their whiskers to discriminate between rough and smooth surfaces in a darkened chamber. Their reward for performing correctly was a sip of chocolate milk.

Using high-speed videography, the researchers recorded the subtle vibrations of the whiskers as the animals probed the surfaces with their characteristic “whisking” motion.

Detailed analysis of these vibrations revealed how the different surfaces produced different micromotions. The rough surfaces produced what the researchers termed “stick-slip-ring” events—a kind of twanging of the whiskers. In contrast, smooth surfaces generated a stream of infinitesimal “stick-slip” oscillations.

The analysis also revealed how the different-length whiskers on the animals’ snouts exhibited different resonance characteristics, contributing to the animals’ acute ability to “see” their environment with their whiskers.

“The present findings provide the first description of what is believed to be an essential surface cue, micromotions of the vibrissae,” conclude the researchers. “In so doing, they address fundamental questions that had until this point remained unanswered, such as whether intrinsic biomechanics would impact transduction meaningfully during active sensation and what range of velocities are produced during free behavior.”

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