Caffeine Suppresses Amyloid-β Levels in Plasma and Brain of Alzheimer's Disease Transgenic Mice

Article type: Research Article

Authors: Cao, Chuanhai^{a; b} | Cirrito, John R.^c | Lin, Xiaoyang^{a; b} | Wang, Lilly^{b; d} | Verges, Deborah K.^c | Dickson, Alexander^{b; d} | Mamcarz, Malgorzata^{b; d} | Zhang, Chi^{a; b} | Mori, Takashi^e | Arendash, Gary W.^{b; d; *} | Holtzman, David M.^{c; f; g} | Potter, Huntington^{a; b; h}

Affiliations: [a] The Byrd Alzheimer's Center & Research Institute, Tampa, FL, USA | [b] Florida Alzheimer's Disease Research Center, University of South Florida, Tampa, FL, USA | [c] Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA | [d] Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, USA | [e] Departments of Medical Science and Pathology, Saitama Medical Center and Saitama Medical University, Kawagoe, Saitama, Japan | [f] Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA | [g] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA | [h] Suncoast Gerontology and Alzheimer's Center, University of South Florida College of Medicine, Tampa, FL, USA

Correspondence: [*] Corresponding author: Gary W. Arendash, Ph.D., Department of Cell Biology, Microbiology, & Molecular Biology, University of South Florida, Tampa, FL 33620, USA. Tel.: +1 813 974 1584; Fax: +1 813 974 1614; E-mail: [email protected].

Abstract: Recent epidemiologic studies suggest that caffeine may be protective against Alzheimer's disease (AD). Supportive of this premise, our previous studies have shown that moderate caffeine administration protects/restores cognitive function and suppresses brain amyloid-β (Aβ) production in AD transgenic mice. In the present study, we report that acute caffeine administration to both young adult and aged AD transgenic mice rapidly reduces Aβ levels in both brain interstitial fluid and plasma without affecting Aβ elimination. Long-term oral caffeine treatment to aged AD mice provided not only sustained reductions in plasma Aβ, but also decreases in both soluble and deposited Aβ in hippocampus and cortex. Irrespective of caffeine treatment, plasma Aβ levels did not correlate with brain Aβ levels or with cognitive performance in individual aged AD mice. Although higher plasma caffeine levels were strongly associated with lower plasma Aβ1-40 levels in aged AD mice, plasma caffeine levels were also not linked to cognitive performance. Plasma caffeine and theophylline levels were tightly correlated, both being associated with reduced inflammatory cytokine levels in hippocampus. Our conclusion is two-fold: first, that both plasma and brain Aβ levels are reduced by acute or chronic caffeine administration in several AD transgenic lines and ages, indicating a therapeutic value of caffeine against AD; and second, that plasma Aβ levels are not an accurate index of brain Aβ levels/deposition or cognitive performance in aged AD mice.

Keywords: Alzheimer's disease, amyloid-β, brain interstitial fluid, caffeine, plasma, transgenic mice

DOI: 10.3233/JAD-2009-1071

Journal: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 681-697, 2009