By David N. Leff
Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.
By now, it¿s common, lay knowledge that the unique hallmark of Alzheimer¿s disease (AD) is the senile, neuritic amyloid plaque. This peptide, visible in brain autopsy, enwraps the neurons assailed by AD.
The plaque exists in two persuasions, one 42 amino acids long (Ab42), the other 40 in length (Ab40). Both are proteolytic fragments cleaved off from a much lengthier mother molecule called APP ¿ amyloid precursor protein. The 42 amyloid peptide is regarded as more harmful than the 40. Notably, in most APP mutations that cause early onset familial AD, the amyloid-beta species initially deposited in brain is particularly prone to aggregation in cell culture.
Neuroscientists at the University of California at San Diego report that three well-known nonsteroidal anti-inflammatory drugs (NSAIDs), widely prescribed as pain relievers, reduce AD symptoms in mice. But not any old NSAIDs. They found the AD-ameliorating effect in only three products ¿ ibubrofen (Motrin), indomethacin (Indocin) and sulindac (Clinoril). Curiously, equally popular NSAIDs painkillers ¿ aspirin, celecoxib (Celebrex) and naproxen (Aleve) ¿ showed no such Alzheimer¿s palliation.
For that in vivo study, the team dosed 15 3-month-old female mice with ibuprofen, seven animals with naproxen; 18 controls got mock treatment. Ibuprofen netted a 39 percent decrease in Ab42, whereas naproxen did not alter that deleterious peptide level. Epidemiological studies had documented a reduced prevalence of Alzheimer¿s disease among users of the nonsteroidal anti-inflammatory drugs ¿ but no one knew why.
The co-authors¿ research appears in Nature dated Nov. 8, 2001, under the title: ¿A subset of NSAIDs lower amyloidogenic Ab42 independently of cyclooxygenase activity.¿ Cox for short, cyclooxygenase is the key principle of anti-inflammatory drugs, beginning with aspirin. The three NSAIDs that eased AD symptoms did so expressly by inhibiting the more harmful plaque-forming peptide. Short-term administration of ibuprofen to mice that produce mutant b-amyloid precursor protein lowered their brain levels of Ab42. What¿ s more, it did so without relevance to the drugs¿ anti-inflammatory properties.
The Nature paper concluded: ¿Because not all NSAIDs lower Ab42 levels, this Ab42 activity may be an important criterion to consider in clinical trials of NSAIDs for the treatment of Alzheimer¿s disease.¿ An accompanying editorial commented: ¿If the findings can be extended to people, these drugs could join the Ivy League of potential treatments for the devastating neurodegenerative disorder.¿
Alcohol¿s Effects On Brain Areas Controlling Mentation, Addiction Charted In 38 Rats
Cocaine and heroin are addictive, illicit, controlled substances. Why then is ethanol ¿ beverage alcohol ¿ licit and uncontrolled? Scientists have known for years that the illicit drugs interact with specific proteins in the brain, while traditionally they thought alcohol had no such pointed effects. Now, 38 ethanol-downing rats give them cause to think again.
A paper in the November 2001 issue of the journal Alcoholism: Clinical & Experimental Research reports: ¿Regional specificity of ethanol and NMDA action in brain revealed with Fos-like immunohistochemistry and differential routes of drug administration.¿ Its lead author is psychiatrist Darin Knapp at the University of North Carolina¿s Bowles Center for Alcoholic Studies in Chapel Hill.
¿NMDA receptors in the brain,¿ Knapp pointed out, ¿are key sites of action of the neurotransmitter glutamate, which increases the activity of brain neurons. Alcohol-NMDA interactions influence many features of alcohol exposure, including effects on fetal development, seizures, gene expression in brain, intoxication, tolerance to ethanol and alcohol dependence.¿
Fos proteins in the brain regulate gene activity. ¿Their measurement,¿ Knapp explained, ¿is a form of brain mapping that allows researchers to identify brain regions that change their activity after challenges such as alcohol consumption.¿
Two hours after consuming quantities of ethanolic spirits, rats were injected with NMDA, and their behavioral responses noted. They duly assumed a typical drunken staggering gait and flat body posture. Their brains were then removed and analyzed for Fos-like responses. The co-authors found a significant increase of Fos in 24 of 38 brain regions quantified after intraperitoneal NMDA injection, and in 32 of 38 brain regions after intravenous NMDA injection.
¿These results,¿ their paper concludes, ¿provide new evidence for the regionally specific functional interactions of ethanol on NMDA receptors in vivo [and] support efforts to identify brain region-specific targets for ethanol and ethanol-induced changes in gene expression.¿
New Gig For Cholesterol-Lowering Drugs: Foiling AIDS Virus Replication
In recent years, cholesterol has acquired a bad rep as a co-conspirator in atherosclerosis and heart disease. Hence, a number of cholesterol-reducing agents have emerged, not only in the cardiology drug arsenal but on TV commercials urging viewers to ¿ask your doctor¿ if Lipitor, Mevacor, Pravachol or Zocor is ¿right for you.¿
But cholesterol in the body wears a white hat, too. In fact, it¿s a major molecule in forming cell membranes. These plasma membranes, recent research shows, are studded with discrete patches of cholesterol-rich microdomains known as ¿rafts.¿ A paper in the Proceedings of the National Academy of Sciences (PNAS), dated Nov. 20, 2001, reports that depletion of cellular cholesterol markedly and specifically reduces production of HIV-1, the AIDS virus. The article is titled: ¿Plasma membrane rafts play a critical role in HIV-1 assembly and release.¿ Its authors are molecular biologists at NIAID ¿ the National Institute of Allergy and Infectious Diseases.
They demonstrate that interaction between those rafts and key viral protein particles, notably the Gag protein, is a critical step in HIV-1 proliferation. Conversely, the paper reported, ¿Treatment of virus-producing cells or virus particles with raft-disrupting agents significantly impairs viral infectivity.¿ Viral output dropped when cellular cholesterol went down. The paper concludes: ¿Considering that simvastatin [Zocor] and related compounds are widely used clinically to treat high cholesterol, further analysis of Gag-raft interaction may provide insights into new strategies for controlling HIV-1 replication in vivo.¿