Reduced Blood Flow to Brain a Possible Alzheimer’s Trigger

Gradual, chronic starvation of the brain as it ages seems to be a trigger of Alzheimer’s, according to a new study from Northwestern University’s Feinberg School of Medicine.

In fact, 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.

The study, in the December 26 issue of Neuron, found that when the brain does not receive enough glucose, such as might happen when a cardiovascular disease restricts blood flow in arteries to the brain, then a particular process is begun that eventually produces the sticky lumps of protein known as amyloid plaques that are a suspected cause of Alzheimer’s disease.

The lead author, professor of cell and molecular biology Robert Vassar, discovered that a key brain protein- elF2alpha – is changed when the brain has a deficient supply of energy. This altered protein increases production of an enzyme that, in turn, activates a pathway for producing the sticky protein clumps.

“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,” said Vassar.

Improving Blood Flow to Brain Preventive Strategy

One easy preventive strategy people could follow to raise blood flow to the brain is getting exercise, managing hypertension and lowering cholesterol levels.

“If people start early enough, maybe they can dodge the bullet,” Vassar said.

For individuals already having symptoms, vasodilator medications, which increase blood flow, might help the delivery of oxygen and glucose to the brain. He added that drugs could possibly be designed which block the elF2alpha protein that begins formation of the protein clumps.

Initial trigger of Alzheimer’s Longstanding Mystery

It was Vassar who, ten years ago, 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.

However, the cause of the high levels of the protein in people with the disease was 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 said. “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 said 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.”

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 coming debates on ethical issues surrounding treatment for Alzheimer’s are hinted at in an interesting recent post at the blog The Tangled Neuron- Who Should Get Alzheimer’s Drugs?

Phosphorylation of the Translation Initiation Factor eIF2 Increases BACE1 Levels and Promotes Amyloidogenesis
Tracy O’Connor ,Katherine R. Sadleir,Erika Maus,Rodney A. Velliquette ,Jie Zhao,Sarah L. Cole,William A. Eimer,Brian Hitt,Leslie A. Bembinster,Sven Lammich,Stefan F. Lichtenthaler,Sebastien S. Hebert,Bart De Strooper,Christian Haass,David A. Bennett and Robert Vassar
1016/j.neuron.2008.10.047

Image by Chris Nurse, Wellcome Images: Creative Commons License.

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