Five subtypes of muscarinic acetylcholine receptors (mAChRs) are expressed throughout the body, where they exert diverse effects, such as smooth muscle contraction, glandular secretion, thermoregulation, and regulation of behavior, learning, and cognition.  MAChRs have been implicated in schizophrenia and Alzheimer’s disease (AD), making them attractive as candidate drug targets.  Several cholinergic agonists have shown promise for treating these conditions, but most of these drugs bind to the acetylcholine binding site—which is highly conserved across receptor subtypes—and therefore have undesirable side effects.  Because of this, drug developers have recently turned to allosteric agonists, which activate receptors by binding to subtype-specific domains outside the acetylcholine binding site.  Jones et al.  Report that one such agonist, which is highly specific for M1 mAChRs, produced effects in mice similar to effects of atypical antipsychotic drugs, without producing undesirable side effects.  Moreover, the drug regulated processing of amyloid precursor protein, suggesting that it may effectively treat AD.

Marauding molecules cause the tissue damage that underlies heart attacks, sunburn, Alzheimer’s and hangovers.  But scientists at the Stanford University School of Medicine say they may have found ways to combat the carnage after discovering an important cog in the body’s molecular detoxification machinery.

The culprit molecules are oxygen byproducts called free radicals.  These highly unstable molecules start chain reactions of cellular damage an escalating storm that ravages healthy tissue.

“We’ve found a totally new pathway for reducing the damage caused by free radicals, such as the damage that happens during a heart attack,” said Daria Mochly-Rosen, PhD, professor of chemical and systems biology and the senior author of a study reporting the new findings.  The research will appear in the Sept. 12 issue of Science.

Before the study, scientists knew that heart muscle could be preconditioned to resist heart attack damage for instance, moderate drinkers tend to have smaller, less severe heart attacks than teetotalers.  But scientists didn’t understand how pre-conditioning worked.

To figure out how alcohol protects heart muscle from free-radical damage, Mochly-Rosen’s team tested alcohol pretreatment in a rat heart-attack model.  They compared the enzymes activated during the attacks to those switched on with no alcohol.  Enzymes are the “doers” of the cellular machinery, catalyzing all of the biochemical reactions that form the basis of life.

Surprisingly, the treatment activated aldehyde dehydrogenase 2 (ALDH2), an obscure alcohol-processing enzyme.  Alcohol pretreatment increased the enzyme’s activity during heart attack by 20 percent, leading to a 27 percent drop in the associated damage.

“Although this enzyme was discovered a long time ago, my research group knew nothing about the enzyme except that it helps remove alcohol when people drink,” said Mochly-Rosen, who is also the senior associate dean for research in the School of Medicine and the George D. Smith Professor in Translational Medicine.

ALDH2 wasn’t one of the well-studied antioxidant players that the scientists expected to find fighting free-radical damage.  The enzyme neutralizes an aldehyde molecule, a toxic byproduct of the ethanol in alcoholic beverages.  But aldehydes are also formed in the body when free radicals react with fat molecules.

The body’s cells contain a lot of fat, Mochly-Rosen noted.  “It’s very easy for free radicals to find fat and oxidize it to aldehydes.”

Inside cells, the accumulating aldehydes permanently bind and damage cellular machinery and DNA.  Such damage occurs in many diseases, from heart attack and Parkinson’s to sun-induced aging of the skin.

After learning of ALDH2’s novel role in reducing the damage, the researchers searched for a molecule that could make the enzyme function even better.  They enlisted the Stanford High Throughput Bioscience Center, directed by David Solow-Cordero, PhD, to find a molecule that heightened the enzyme’s activity.

The winner of this contest was a tiny molecule that reduced heart attack damage by 60 percent in the rat model.  The molecule, Alda-1, has a surprising mode of action: it protects ALDH2 itself from aldehyde attack.  The enzyme, it turns out, was being hobbled by the very chemical it removes.

Because Alda-1 is small, it should be easy to adapt for pharmacological use, Mochly-Rosen said.  She expects the new molecule to have many possible drug applications.

“It has a huge potential use,” she said.  So far, Alda-1 has been tested only in the rat model, but Mochly-Rosen’s lab is investigating other possible applications, such as fighting neurodegenerative disease and sun damage on the skin.  The team also hopes to interest drug companies in human trials.

In addition to its lofty medical applications, Alda-1 could also have a much lowlier use: fighting hangovers.  Many nasty hangover symptoms are due to aldehyde buildup.

The tiny molecule may also improve alcohol tolerance and reduce susceptibility to free-radical diseases in people with a common ALDH2 mutation.  The mutation affects 40 percent of people of Asian descent and causes an intolerance for alcohol.

Blocking a common immune system response cleared up plaques associated with Alzheimer’s Disease and enabled treated mice to recover some lost memory, Yale University researchers report Friday in the journal Nature Medicine.Researchers hope the new approach may one day overcome one of the biggest obstacles to development of new dementia medications – the difficulty in finding drugs that can safely cross the blood-brain barrier.

The results of the research surprised the scientists working in the lab of Richard Flavell, senior author of the paper, chairman of the Department of Immunobiology at Yale and investigator with the Howard Hughes Medical Institute. Flavell’s team originally thought that blocking the immune system molecule TGF-β(or transforming growth factor), might actually increase the buildup of amyloid plaques associated with Alzheimer’s Disease

Earlier studies had shown that Alzheimer’s patients tend to have elevated amounts of TGF-β, which plays a key role in activating immune system response to injury. Some had thought the presence of the molecule was simply an attempt to quiet the inflammatory response caused by a buildup of plaque.

Instead, the team found that as much as 90 percent of the plaques were eliminated from the brains of mice genetically engineered to block TGF-β in the peripheral immune cells.

It was like a vacuum cleaner had removed the plaques,” Flavell said.

When the TGF-β pathway was interrupted in mice engineered to have Alzheimer’s, the mice showed an improved ability to perform some tests, including navigating mazes when compared to mice without TGF-β blocked. Scientists also found lower levels of other biological markers associated with the dementia.

When TGF-β was blocked, the immune system seemed to unleash immune cells known as peripheral macrophages. The macrophages passed through the blood-brain barrier and surrounded the neurons and plaques in the brains of mice. “If results from our study in mice engineered to develop Alzheimer’s-like dementia are supported by studies in humans, we may be able to develop a drug that could be introduced into the bloodstream to cause peripheral immune cells to target the amyloid plaques,” said Terrence Town, lead author of the study.

Different types of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and aspirin, appear to be equally effective in lowering the risk of Alzheimer’s disease, according to the largest study of its kind published in the May 28, 2008, online issue of Neurology®, the medical journal of the American Academy of Neurology. Experts have debated whether a certain group of NSAIDs that includes ibuprofen may be more beneficial than another group that includes naproxen and aspirin.Using information from six different studies, researchers examined data on NSAID use in 13,499 people without dementia. Over the course of these six studies, 820 participants developed Alzheimer’s disease.

Researchers found that people who used NSAIDs had 23 percent lower risk of developing Alzheimer’s disease compared to those who never used NSAIDs. The risk reduction did not appear to depend upon the type of NSAID taken.

“This is an interesting finding because it seems to challenge a current theory that the NSAID group which includes ibuprofen may work better in reducing a person’s risk of Alzheimer’s,” said study author Peter P. Zandi, PhD, with Johns Hopkins Bloomberg School of Public Health in Baltimore, MD. “The NSAID group that includes ibuprofen was thought to target a certain type of plaque in the brain found in Alzheimer’s patients. But our results suggest there may be other reasons why these drugs may reduce the risk of Alzheimer’s.”

The study’s lead author Chris Szekely, PhD, with Cedars Sinai Medical Center in Los Angeles, says the discrepancy between studies such as this one and the negative clinical trials of NSAIDs in treatment or prevention of Alzheimer’s need to be further explored.