16 Jul 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. 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 Aβ levels in old, memory-impaired AD mice. The work also sheds light mechanistically on how caffeine suppresses β- and 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 (see Rosso et al., 2008, review) 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 (Maia and de Mendonça, 2002). 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 (Eskelinen et al., 2009). 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 (APPsw). 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 (Arendash et al., 2006), caffeine’s benefits seemed to stem from its suppression of β- and γ-secretases. “That was our initial indication that it was having a direct effect on the disease process and not simply acting as an anti-inflammatory or something that just affects attention or reaction time,” Arendash said in an interview with 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 (APPsw) 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 indistinguishable from same-aged wild-type animals. Furthermore, the caffeine treatment strikingly reduced Aβ deposition and soluble Aβ levels in the entorhinal cortex and hippocampus of treated relative to untreated AD mice.

Delving further into the mechanisms underlying these effects, the scientists found that caffeine’s suppression of β-secretase involves toning down the Raf-1/NF-κB inflammatory pathway. Their results also suggest that caffeine suppresses γ-secretase by inhibiting its primary stimulator, glycogen synthase kinase (GSK)-3α. There could be a tie-in with tau, too, since GSK-3β, a key stimulator of neurofibrillary tangle (NFT) formation, was also suppressed by caffeine in the recent study. “I would be very surprised if caffeine did not suppress NFT formation or tau phosphorylation, but we haven't looked at that specifically yet,” Arendash told ARF.

In the meantime, the scientists are excited about caffeine’s effects on Aβ load, which are not only behaviorally meaningful but also fast. In the same issue of the Journal of Alzheimer’s Disease, a study led by Chuanhai Cao, also at the University of South Florida, and collaborator David Holtzman at Washington University School of Medicine in St. Louis, Missouri, shows that acute caffeine administration reduces both brain and blood Aβ levels in AD transgenic mice within a few hours (Cao et al., 2009). Arendash said his group has found similar effects in unpublished human studies involving acute caffeine administration. “The fact that we can get a caffeine response within hours in AD mice and in humans, to me, is encouraging,” he said.

To address the possibility that caffeine might have had some effects on mice through non-AD-specific mechanisms, Arendash and colleagues gave wild-type mice caffeinated drinking water throughout adulthood and examined their cognition in older age. The caffeinated mice fared no better than untreated counterparts on the radial arm water maze and four other cognitive tasks. “We believe caffeine only affects memory when it is impaired or is going to be impaired,” Arendash said. “It's not going to be a memory-enhancing drug over and above normal.”

Still, Arendash thinks caffeine holds promise as an inexpensive, brain-penetrating agent that warrants long-term clinical trials in AD patients. It meets all three criteria he deems critical for a successful AD therapeutic: 1) strong epidemiological evidence for effectiveness, 2) compelling behavioral results in AD mice, and 3) demonstrated effects on disease process. “If you have all three of those lined up, at least in 2009, you've maximized your chances of seeing a therapeutic effect against the disease in humans,” Arendash said. “Our whole concept of how to pursue an effective therapeutic against AD in the shortest amount of time is to focus on therapeutics that are inherently safe or that are already in use clinically for other sorts of medical issues. When you focus on therapeutics like that, you're cutting years off drug development.”

In the spirit of disclosure, Arendash noted that both caffeine studies were financed by the NIH-designated Florida Alzheimer’s Disease Research Center, directed by Huntington Potter, and not by any coffee industries. And on a lighter note, he practices what he preaches. “I've been drinking coffee, at least three to four cups a day, ever since I can remember. I think perhaps I've increased it a little bit after our studies showing that five cups seems optimal. But yeah, I've had four cups today. I'm right on schedule,” he quipped during a recent phone conversation with this reporter.—Esther Landhuis

Comments

1. • susan boydston
     
   • Posted: 29 Jul 2009

   It is good to know that coffee has a good benefit for AD. However, I feel too much coffee can also cause too much stimulation in the brain, which can cause agitation, confusion, delusions, etc. I am not sure about coffee. That's why I end up researching about how coffee may benefit AD. It was just my observation before. But I need to back it up.

   View all comments by susan boydston

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References

Paper Citations

1. Rosso A, Lippa CF, Mossey J. Caffeine: Neuroprotective Functions in Cognition and Alzheimer""s Disease. Am J Alzheimers Dis Other Demen. 2008 Jul 3; PubMed.
2. Maia L, de Mendonça A. Does caffeine intake protect from Alzheimer's disease?. Eur J Neurol. 2002 Jul;9(4):377-82. PubMed.
3. Eskelinen MH, Ngandu T, Tuomilehto J, Soininen H, Kivipelto M. Midlife coffee and tea drinking and the risk of late-life dementia: a population-based CAIDE study. J Alzheimers Dis. 2009;16(1):85-91. PubMed.
4. Arendash GW, Schleif W, Rezai-Zadeh K, Jackson EK, Zacharia LC, Cracchiolo JR, Shippy D, Tan J. Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production. Neuroscience. 2006 Nov 3;142(4):941-52. PubMed.
5. Cao C, Cirrito JR, Lin X, Wang L, Verges DK, Dickson A, Mamcarz M, Zhang C, Mori T, Arendash GW, Holtzman DM, Potter H. Caffeine suppresses amyloid-beta levels in plasma and brain of Alzheimer's disease transgenic mice. J Alzheimers Dis. 2009;17(3):681-97. PubMed.

Further Reading

Papers

1. Arendash GW, Schleif W, Rezai-Zadeh K, Jackson EK, Zacharia LC, Cracchiolo JR, Shippy D, Tan J. Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production. Neuroscience. 2006 Nov 3;142(4):941-52. PubMed.
2. Eskelinen MH, Ngandu T, Tuomilehto J, Soininen H, Kivipelto M. Midlife coffee and tea drinking and the risk of late-life dementia: a population-based CAIDE study. J Alzheimers Dis. 2009;16(1):85-91. PubMed.
3. Maia L, de Mendonça A. Does caffeine intake protect from Alzheimer's disease?. Eur J Neurol. 2002 Jul;9(4):377-82. PubMed.
4. Rosso A, Lippa CF, Mossey J. Caffeine: Neuroprotective Functions in Cognition and Alzheimer""s Disease. Am J Alzheimers Dis Other Demen. 2008 Jul 3; PubMed.