New Advances Dissolve Brain-Destroying Alzheimer's Plaques

When Gene Wilder died Monday of Alzheimer's disease, his fans were shocked and saddened to learn that such a brilliant comic mind had been taken by such a cruel disease. Wilder kept his condition secret for three years, not out of fear of the stigma sometimes associated with Alzheimer's, but for fear of disappointing his young fans who brightened when they spotted "Willie Wonka."

Wilder wasn't alone in his fight against the brain-robbing condition. Currently, Alzheimer's, which has no known treatment, affects 5.4 million Americans.

Characteristics of Alzheimer’s include amyloid plaque deposits — abnormal clusters of "sticky" protein fragments — and the formation of neurofibrillary tangles in the brain, which are comprised of another protein called tau. As the disease progresses, plaques and tangles build, leading to the loss of connections between nerve cells. The cells die, causing the loss of brain tissue.

Two recent studies have given a beacon of hope, perhaps to those who already have the disease, but especially for those who live in fear of Alzheimer's, and whose numbers are projected to triple by 2050. Both focus on increasing the amount of a brain enzyme called neprilysin.

The first study tested a protein called IL-33 which reversed Alzheimer's-like disease in mice in only one week.

"IL-33 is a protein produced by various cell types in the body and is particularly abundant in the central nervous system — brain and spinal cord," said Professor Eddy Liew of the University of Glasgow. "We carried out experiments in a strain of mice (APP/PS1) which develop progressive AD-like disease with aging.

"We found that injection of IL-33 into aged APP/PS1 mice rapidly improved their memory and cognitive function to that of the age-matched normal mice within a week."

Researchers believe that IL-33 works by activating the immune cells in the brain, called microglia, which surround amyloid plaques. IL-33 produces an enzyme called neprilysin, which destroys plaques by digesting them.

In addition to destroying plaques, IL-33 reduces inflammation in brain tissue, which previous studies found encouraged plaque and tangle formation. Therefore, IL-33 helps to clear the amyloid plaque already formed and also prevents the formation of new plaques and tangles.

"There is some distance between laboratory findings and clinical applications," says Liew. "Nevertheless, this is a good start."

IL-33 will begin human trials this year.

The second study, conducted at the Salk Institute, also involved treating Alzheimer's by increasing the amount of neuregulin-1 in the brain. Similar to the Glasgow study, neuregulin-1 also increased levels of neprilysin which fought the buildup of plaque in the brains of mice bred to develop Alzheimer's.

Researchers aren't sure how neuregulin-1 works and all of the ways it affects the brain. However, said professor Kuo-Fen Lee, "We've shown that it promotes metabolism of the brain plaques that are characteristic of Alzheimer's disease."

Previous studies had found that treating cells with neuregulin-1 lowered brain levels of amyloid precursor protein, a molecule that generates amyloid beta. So, Lee and his team decided to raise the levels of two forms of neuregulin-1 in the hippocampus, an area of the brain responsible for learning and memory. Both forms of the protein improved memory in the mice.

In addition, the levels of amyloid beta and plaques were noticeably lower in mice with more neuregulin-1 compared to controls.

The study suggested that neuregulin-1 breaks up plaques by raising levels of neprilysin, an enzyme that has been shown to degrade amyloid-beta. (Neprilysin is the same enzyme the Glasgow researchers found effective.) The Salk researchers are also exploring whether or not the protein improves signaling between neurons, a function which is damaged in Alzheimer's.

Although supplemental neuregulin-1 isn't available to the public, Lee and his team have created a method of raising existing levels of neuregulin-1, which could help prevent plaque from forming.

"There's much more work ahead before neuregulin-1 could become a treatment, but we are excited about its potential," Lee said.