NEWS OF THE WEEK
ALZHEIMER'S DISEASE Free-radical reactions may play key role loid peptide causes the brain cell dam- py and high-performance liquid chroage associated with Alzheimer's. But ex- matography-mass spectrometry to deperiments to identify a molecular mech- termine that (3-amyloid peptide breaks anism to explain this process have yielded down in aqueous solution, generating free-radical peptides. They hypothesize inconsistent results. The Kentucky researchers have now that these radicals may combine with each determined that (3-amyloid peptide other into high-mass aggregates that form spontaneously fragments into free radi- senile plaque and may also attack nerve cals in solution, and that these free radi- cell membranes, causing dysfunctional cals take part in reactions that damage modifications. "We have direct experimental EPR nerve cell membranes and inactivate enzymes inside the cells. This suggests, and biochemical evidence that (J-amythey say, that free radicals may cause the loid free-radical peptides can cause brain membrane oxidation/' notes Butterfield. neurodegeneration in Alzheimer's. The research was done by Butter- "Among the key proteins affected are field, graduate student Kenneth Hens- those [that] regulate the amount of calciley, pharmacology professor John M. um ions in the cell. Consequently, large Carney, neurobiology professor Mark amounts of this ion can enter the neuron Mattson, and coworkers. Their work is or other brain cells," causing cell death. described in the April 12 Proceedings of The team also finds that the free radicals the National Academy of Sciences USA [91,can inactivate enzymes inside cultured neurons. 3270 (1994)]. According to the researchers, this The researchers used electron paramagnetic resonance (EPR) spectrosco- free-radical model unifies known facts about the disease into a coherent theoretical framework. For example, they say, the model "is consistent with the Alzheimer's model proposes that free slow onset of Alzheimer's disease— radicals disrupt cell membranes younger persons may have greater antioxidant capacity and can withstand free-radical stress, [whereas] aging ... could exacerbate consequences of pamyloid peptide radicalization." Their Senile plaque forms findings suggest free-radical scavenger Fragmentation Peptide P-Amyloid compounds could act as anti-Alzheimer's peptide and free radical drugs. radical formation Brad Dickerson, manager of the information program for medical and scientific affairs at the Alzheimer's Disease & Related Disorders Association, notes the model must be considered speculative at Nerve present, but that "this is a well done cell piece of research that needs to be purmembrane sued further." He says the free-radical model is one Membrane lipids of several proposed explanations for Peptide undergo radicalradicals the action of (J-amyloid peptide. For exinduced damage _ ,. ' , Excess Ca 2+ enters ample, a paper by National Institutes membrane Radicals form peroxidation cell through calcium of Health researchers in the April 8 isadducts with channels modified by membrane sue of Science [264, 276 (1994)] proposradical reactions proteins es that p-amyloid peptide may impair
A team of researchers at the Univer/ % sity of Kentucky has proposed a JL J L new mechanism for Alzheimer's disease—that the nerve cell damage associated with the illness is caused by free radicals generated from the breakdown of (3-amyloid peptide. The team's findings put "all of the pathological, biochemical, and age-related aspects of Alzheimer's disease under one theoretical framework/' says the group's leader, chemistry professor D. Allan Butterfield. But the mechanism is speculative and will require considerable verification. Alzheimer's is primarily a disease of old age, characterized by progressive neural degeneration and loss of cognitive function. The two major pathological hallmarks are brain lesions called neurofibrillary tangles and senile plaques. The senile plaque cores consist primarily of p-amyloid peptide aggregates. One hypothesis proposes that (3-amy-
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neuronal function by altering potassium channels. He says verification of the free-radical model and other proposed mechanisms will depend to a large extent on whether those models can be used to mimic the pathology of Alzheimer's in animals. "Clearly, [Butterfield and coworkers] propose an interesting idea that ties a lot of pieces together/' but further confirmation is needed, adds Zaven S. Khachaturian, director of the Office of Alzheimer's Disease Research at the National Institute on Aging. For example, he says, 'The work is done in culture, and one needs to find out if it really works that way in the brain." He further points out that the study does not address the issue of specificity—why certain classes of neurons are damaged and not others. Using a tree as a metaphor for the brain, he explains that in Alzheimer's "you're not losing leaves all over the place. You're losing them only on certain branches and twigs. So a generalized notion of defoli-
The Monsanto process, Sen explains, requires steam reforming of methane to produce synthesis gas (mixtures of hydrogen and carbon monoxide). This is followed by high-temperature conversion of syngas to methanol, then carbonylation of methanol to acetic acid. Sen notes that the Monsanto process uses no oxidant and has no net oxidation. Also, that process employs a higher reduction temperature (about 180 °C) and a substantially lower carbon monoxide pressure than his system. Sen's process requires a higher carbon monoxide pressure to prevent catalyst degradation. Preliminary mechanistic studies indicate that a Rh-CH3 species is formed in both systems. In Sen's process, this species is then hydrolyzed to acetic acid. In the Monsanto system, the Rh-CH3 speButterfield: all under one framework cies formed from methanol is carbonyation is not appropriate." In addition, he lated, then hydrolyzed to acetic acid. To establish that the two systems are says, the contention that susceptibility to Alzheimer's is related to lower antioxi- indeed different mechanistically, Sen examined the products formed when dant levels must be demonstrated. Stu Borman methane and methanol were added together to his system as substrates. Using isotopic methods, he determined that only methane is converted to acetic acid, while methanol is simply oxidized to such as acetic acid has potential for use formic acid. Sen says these results clearly demonin large-scale production. The new scheme, developed by strate that Rh-CH3 species are formed chemistry professor Ayusman Sen and from methane at a faster rate than they research assistant Minren Lin, is based are from methanol. The methanol formed on the reaction CH 4 + CO + Vi02 -> in his system, he believes, arises from hyCH3COOH, which takes place at about drolysis of a fraction of the Rh-CH3 spe100 °C [Nature, 368, 613 (1994)]. Rhodi- cies formed from methane. Joseph Haggin um chloride, RhCl3, dissolved in water, is the catalyst. The only significant byproducts are methanol and formic acid. No reaction occurs in the absence of carbon monoxide or oxygen. Yields of acetic acid increase with the addition of iodide ions as a promoter or addition of 5% metallic palladium on 3M, Union Carbide, and three small macarbon. There is no significant decrease terials and implant manufacturers have in catalytic activity, even after 400 hours agreed to join the global silicone breast implant settlement proposed in Februof reaction time. Sen says his observations appear to be ary. Collectively, the firms will add nearconsistent with the behavior of soluble ly $500 million to a fund to compensate rhodium catalysts, rather than with metal- women who claim the implants have lic rhodium catalyzing acetic acid forma- compromised their health. The infusion of cash from the five tion. He is not yet certain, but believes the active species in this catalytic system may companies would bring assets available for compensation to $4.2 billion. Three be Rh(D-carbonyl compounds. There are some similarities between major implant makers—Dow Corning, Sen's system and a Monsanto process Bristol-Myers Squibb, and Baxter Health used commercially for carbonylation of Care—previously agreed to provide a methanol to acetic acid using a rhodi- total of $3.7 billion (C&EN, April 11, um-based catalyst. But there are also page 9). The fund could ultimately reach a proposed $4.75 billion if the setsignificant differences.
Direct process converts methane to acetic acid A new catalytic route to directly convert methane to acetic acid has been developed by researchers at Pennsylvania State University, University Park. Selective conversion of methane would be of great value, but has been difficult to accomplish. Methane is the most abundant alkane, but is also the least reactive. Thus, a direct route for converting methane to other products
3M, Union Carbide join breast implant fund
Sen: soluble rhodium catalysts
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