title: Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production.
abstract: A recent epidemiological study suggested that higher caffeine intake over decades reduces the risk of Alzheimer's disease (AD). The present study sought to determine any long-term protective effects of dietary caffeine intake in a controlled longitudinal study involving AD transgenic mice. Caffeine (an adenosine receptor antagonist) was added to the drinking water of amyloid precursor protein, Swedish mutation (APPsw) transgenic (Tg) mice between 4 and 9 months of age, with behavioral testing done during the final 6 weeks of treatment. The average daily intake of caffeine per mouse (1.5 mg) was the human equivalent of 500 mg caffeine, the amount typically found in five cups of coffee per day. Across multiple cognitive tasks of spatial learning/reference memory, working memory, and recognition/identification, Tg mice given caffeine performed significantly better than Tg control mice and similar to non-transgenic controls. In both behaviorally-tested and aged Tg mice, long-term caffeine administration resulted in lower hippocampal beta-amyloid (Abeta) levels. Expression of both Presenilin 1 (PS1) and beta-secretase (BACE) was reduced in caffeine-treated Tg mice, indicating decreased Abeta production as a likely mechanism of caffeine's cognitive protection. The ability of caffeine to reduce Abeta production was confirmed in SweAPP N2a neuronal cultures, wherein concentration-dependent decreases in both Abeta1-40 and Abeta1-42 were observed. Although adenosine A(1) or A(2A) receptor densities in cortex or hippocampus were not affected by caffeine treatment, brain adenosine levels in Tg mice were restored back to normal by dietary caffeine and could be involved in the cognitive protection provided by caffeine. Our data demonstrate that moderate daily intake of caffeine may delay or reduce the risk of AD.
authors.affiliation: The Byrd Alzheimer's Center and Research Institute, Tampa, FL 33647, USA. arendash@cas.usf.edu
authors.forename: G W
authors.initials: GW
authors.lastname: Arendash
authors.forename: W
authors.initials: W
authors.lastname: Schleif
authors.forename: K
authors.initials: K
authors.lastname: Rezai-Zadeh
authors.forename: E K
authors.initials: EK
authors.lastname: Jackson
authors.forename: L C
authors.initials: LC
authors.lastname: Zacharia
authors.forename: J R
authors.initials: JR
authors.lastname: Cracchiolo
authors.forename: D
authors.initials: D
authors.lastname: Shippy
authors.forename: J
authors.initials: J
authors.lastname: Tan
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002110:Caffeine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003072:Cognition Disorders / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism; D053764:Presenilin-1 / Q000187:drug effects / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D053764:Presenilin-1; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D002110:Caffeine; D053829:Amyloid Precursor Protein Secretases; D000241:Adenosine