Alzforum News Highlights: Caffeine, Anesthesia, and Twin Epigenetics

Abstract

16 July 2009. Could the morning coffee that provided a lift for the day also help you stay mentally sharp for the long haul? This prospect, which has simmered on the backburner of neurodegenerative disease research, has bubbled to the fore with the publication of two mouse studies in this month’s Journal of Alzheimer’s Disease [1,2]. Led by Gary Arendash, researchers at the University of South Florida, Tampa, with collaborators elsewhere, report that caffeine restores normal cognition and decreases brain and blood amyloid-β (Aβ) levels in old, memory-impaired Alzheimer’s disease (AD) mice. The work also sheds light mechanistically on how caffeine suppresses βand γ-secretases, enzymes that help churn out the peptides in the pathological plaques peppering AD brains. At the end of the year, the Journal of Alzheimer’s Disease will publish a focus issue featuring these and other studies presented at a small,closed meeting, “Caffeine and the Brain,” held in Lisbon last month. The idea that caffeine could protect against AD has percolated for some time, through both epidemiological studies [3] and research in animal models. In 2002, a case-control study by Portuguese researchers found that daily caffeine consumption by AD patients in the 20 years preceding disease onset was much lower than that of same-aged participants who did not develop AD [4]. Earlier this year, scientists reported that people who drank three to five cups of coffee per day during midlife had a 65 percent reduced risk for AD in a longitudinal study of more than 1,400 Finnish seniors [5]. On the basic science front, Gary Arendash and colleagues at the University of South Florida have tackled the issue with a controlled longitudinal study in AD transgenic mice (AβPPsw). They provided caffeine-spiked drinking water (1.5 mg per day, equivalent to five cups of coffee in humans) to four-month-old young adult mice and continued the treatment through nine months of age, when the mice typically have AD-like behavioral symptoms. When tested at this older age, the caffeinated AD mice performed virtually as well as non-transgenic controls in a host of cognitive tasks, and had reduced brain amyloid load compared with untreated AD mice. In that study [6], caffeine’s benefits seemed to stem from its suppression of βand γ-secretases. “That was our initial indication that it was having a direct effect on the disease process and not simply acting as an antiinflammatory or something that just affects attention or reaction time,” Arendash said in an interview with the Alzheimer Research Forum (ARF). His team designed the current study to further unpack caffeine’s mechanism of action and to determine whether its benefits could extend to older AD mice that already show AD-like pathology and cognitive problems. To address the latter question, Arendash and colleagues withheld caffeine administration in the same AD transgenic mice (AβPPsw) until 19 months of age, when the mice had memory impairment. After five weeks of treatment at the same daily dose used previously (1.5 mg), the impaired AD mice greatly improved their performance on the radial arm water maze, a common rodent test of working memory, compared to transgenic counterparts chugging regular water. Like the prior study that tested caffeine as a preventive treatment, caffeine consumption in older, impaired mice restored their cognitive performance to levels indistin-