Caffeine protects Alzheimer’s mice against cognitive impairment and reduces brain β-amyloid production

• Published in: Neuroscience Vol. 142; no. 4; pp. 941 - 952
• Main Authors: Arendash, G.W., Schleif, W., Rezai-Zadeh, K., Jackson, E.K., Zacharia, L.C., Cracchiolo, J.R., Shippy, D., Tan, J.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 03.11.2006; Elsevier
• Subjects: adenosine; Adenosine - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - physiopathology; Alzheimer Disease - prevention & control; Amyloid beta-Peptides - biosynthesis; Amyloid beta-Peptides - drug effects; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - drug effects; Amyloid Precursor Protein Secretases - metabolism; Animals; BACE; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Brain - physiopathology; Caffeine - pharmacology; Cell Line, Tumor; Cognition Disorders - drug therapy; Cognition Disorders - physiopathology; Cognition Disorders - prevention & control; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; learning; Medical sciences; memory; Memory Disorders - drug therapy; Memory Disorders - physiopathology; Memory Disorders - prevention & control; Memory, Short-Term - drug effects; Memory, Short-Term - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurology; Neuroprotective Agents - pharmacology; Neuropsychological Tests; Peptide Fragments - drug effects; Peptide Fragments - metabolism; Presenilin-1 - drug effects; Presenilin-1 - metabolism; PS1; Purinergic P1 Receptor Antagonists; Receptors, Purinergic P1 - metabolism; transgenic mice; Treatment Outcome; Vertebrates: nervous system and sense organs; memory; AD; RAWM; TBS; MR; NT; FOR; learning; PS1; adenosine; Aβ; Tg; transgenic mice; PD; ANOVA; OD; ESI; Tg+Caff; FA; APPsw; LSD; DFA; BACE; Nervous system diseases; Adenosine; CNS stimulant; Psychotropic; Alzheimer disease; Memory; Rodentia; Transgenic animal; Cognition; Cerebral disorder; Learning; Vertebrata; Mammalia; Acquisition process; Mouse; β Amyloid protein; Central nervous system disease; Degenerative disease; Caffeine
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2006.07.021

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 β-amyloid (Aβ) levels. Expression of both Presenilin 1 (PS1) and β-secretase (BACE) was reduced in caffeine-treated Tg mice, indicating decreased Aβ production as a likely mechanism of caffeine’s cognitive protection. The ability of caffeine to reduce Aβ production was confirmed in SweAPP N2a neuronal cultures, wherein concentration-dependent decreases in both Aβ1–40 and Aβ1–42 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.