Fighting Alzheimer's Disease: The One-Two Punch

An experimental drug called AF267B has been shown to curb both the intracellular (neurofibrillary tangles) and extracellular (amyloid plaque) manifestations of Alzheimer's disease.

What's more, AF267B also appeared to reverse cognitive declines in mice genetically designed to mimic Alzheimer's disease. Mice appeared to gain renewed powers of memory and learning after treatment, the researchers report in the March 2 issue of Neuron.

AF267B "does exactly what one would hope a drug for Alzheimer's is going to do -- it's a disease-modifying compound that's not only able to treat symptoms, but was able to reverse the onslaught of the pathology in these mice," said study senior author Frank LaFerla, a professor of neurobiology at the University of California, Irvine (UCI).

He explained that AF267B is an "M1 agonist" -- a drug that acts by stimulating the muscarinic receptor lying on the surface of nerve cells.

"It's been known for about 30 years that there's a selective loss of neurons in the brains of Alzheimer's patients, neurons that produce a neurotransmitter chemical called acetylcholine," LaFerla explained.

One way to boost flagging acetylcholine activity is to stimulate the M1 receptor, which is designed to interact with the neurotransmitter.

AF267B does just that. It was developed by noted Alzheimer's researcher and study co-author Abraham Fisher, of the Israel Institute for Biological Research, in Ness-Ziona, Israel.

....About two years ago, LaFerla's team developed a genetically engineered mouse model that mimics human Alzheimer's disease more closely than any previous rodent strain. That's because these mice develop both plaques and tangles.

"Models used up till now have only developed the plaques," LaFerla pointed out.

"It's a model that a lot of people are excited about," added William Thies, vice president of medical and scientific affairs at the Alzheimer's Association. Because it so closely resembles human disease, the new mouse model "shows promise for broadening what we can measure in animal studies," he added.

The UCI team tested AF267B in the new mouse model.

"We found that when we stimulated the muscarinic receptor, we were able to reduce the two major neuropathological lesions -- plaques and tangles," LaFerla said.

What's more, mice given AF267B began to perform much better in tests meant to assess memory and learning, reversing previous Alzheimer's-linked cognitive dysfunction. Later examination of brain tissue confirmed that the drug appears to target neurons in exactly those brain centers affected by the disease.

....Although many experimental drugs are being targeted to remove plaques, "we know that tangles, by themselves, can clearly cause dementia and neurological disease," La Ferla said. "So, the sooner you can get rid of both lesions, the better."

Thies said he's cautiously optimistic about AF267B. "In this case, you have some evidence that the agent modifies both amyloid and tau -- that's something you want to see in a therapeutic agent," he said.

But he also cautioned that animal findings don't always translate to humans. "A mouse is never a person, even when you put in a lot a human genes," he said.

Read the entire article here. Or go to HealthDay News, the original source. Hat tip to Mental Health Net.

I am skeptical that simply stimulating muscarinic receptors will abolish the histological and neurological manifestations of Alzheimer's disease. If these promising results are replicated in human trials, I would begin looking for other additional sites of action for AF267B.