Will Smoking Stop Alzheimer's Disease?
Source: Salomon AR, et al.. Biochemistry 1996;35:13568-13578.
Nicotine is well known to most of us as a major component of cigarette smoke and is generally vilified as the pharmacological basis of smokers' addiction. In research partially funded by a purveyor of tobacco products (the Philip Morris company), nicotine has been cast in a more positive light as a potent inhibitor of the aggregation of synthetic amyloid peptides, preventing the formation in a test-tube of the b-pleated sheets of amyloid that are characteristic of Alzheimer's disease pathology in the brain.
Salomon and colleagues used a precipitation assay, a common approach to studying amyloid aggregation, and applied circular dichroism (CD) measurements and nuclear magnetic resonance (NMR) techniques to further characterize nicotine-amyloid b-peptide interactions. They used the synthetic b-(1-42) peptides in their aggregation studies because several lines of evidence have suggested that this form is the most "amyloidogenic." The addition of nicotine (at concentrations roughly 100 times greater than the peak level in the blood of an average smoker) to solutions containing b-(1-42) peptide (at concentrations roughly 1000-fold greater than are found in Alzheimer cerebrospinal fluid) led to a reduction in the rate of amyloid b-sheet formation sufficient to inhibit the precipitation of amyloid peptide completely. Various nicotine analogues were less efficacious in inhibiting precipitation and, in some cases, promoted the reaction. The NMR studies suggested that nicotine binds to a histidine residue within the a-helical structure of the b-peptide. It may, therefore, exert an inhibitory effect on amyloid precipitation by slowing the conversion of the a-helical structure to a b-sheet formation.
Comment by Norman R. Relkin, MD, PhD
A major shortcoming of this study was its failure to investigate nicotine's interactions at physiologic concentration ranges, limiting the interpretation of the results in terms of their relevance to AD pathophysiology and treatment. Although the peptide concentrations were high relative to those found in biological fluids, it is at least conceivable that local concentrations in the brain could reach these levels under some circumstances, such as following brain injury. The investigators are presently undertaking further studies at more physiologic concentrations to help resolve this issue.
These results are particularly intriguing because past studies have suggested that the risk of developing AD is reduced in smokers (see Friedland RP. Neurobiol Aging 1994;15:239-241). Therapeutic trials of subcutaneous and transdermal nicotine to treat mild-to-moderate AD symptoms were previously carried out after studies revealed decreased nicotinic receptors in AD brains. Modest improvements in some areas of cognitive function were attributed to nicotine treatment. Inquiring patients should be reminded that the risks inherent in cigarette smoking far outweigh any hypothetical protective effects that the associated nicotine may have against AD. The more likely effect of cigarette smoking will be to foster the development of lung cancer or emphysema, reducing the likelihood that the smoker will live to the age of risk of AD. There is insufficient evidence to support the therapeutic use of nicotine patches in AD patients; and, while the patches are often well-tolerated in younger normal individuals, they can cause cardiac and central nervous system side effects in elderly AD patients. Therefore, this study does not have direct implications for clinical practice but adds to the growing body of evidence that various elements of the underlying pathophysiology of AD can be targeted for therapeutic interventions and may ultimately prove amenable to treatment.
Dr. Relkin is Assistant Professor of Neurology, New York Hospital-Cornell Medical Center.
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