Journal of Alzheimer’s Disease 17 (2009) 661–680 661 DOI 10.3233/JAD-2009-1087 IOS Press Caffeine Reverses Cognitive Impairment and Decreases Brain Amyloid-β Levels in Aged Alzheimer’s Disease Mice Gary W. Arendash a,b,* , Takashi Mori c , Chuanhai Cao a,b,d , Malgorzata Mamcarz a,b , Melissa Runfeldt a,b , Alexander Dickson a,b , Kavon Rezai-Zadeh e , Jun Tan e , Bruce A. Citron f ,g , Xiaoyang Lin a,d , Valentina Echeverria f ,g and Huntington Potter a,b,d,h a Florida Alzheimer’s Disease Research Center, University of South Florida, Tampa, FL, USA b Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, USA c Departments of Medical Science and Pathology, Saitama Medical Center and Saitama Medical University, Kawagoe, Saitama, Japan d The Byrd Alzheimer’s Center and Research Institute, Tampa, FL, USA e Department of Psychiatry and Behavioral Medicine, University of South Florida, Tampa, FL, USA f Department of Molecular Medicine, University of South Florida, Tampa, FL, USA g Bay Pines VA Healthcare System, Bay Pines, FL, USA h Suncoast Gerontology and Alzheimer’s Center, University of South Florida College of Medicine, Tampa, FL, USA Accepted 20 January 2009 Abstract. Wehave recently shown that Alzheimer’s disease (AD) transgenic mice given a moderate level of caffeine intake (the human equivalent of 5 cups of coffee per day) are protected from development of otherwise certain cognitive impairment and have decreased hippocampal amyloid-β (Aβ) levels due to suppression of both β-secretase (BACE1) and presenilin 1 (PS1)/γ-secretase expression. To determine if caffeine intake can have beneficial effects in “aged” APPsw mice already demonstrating cognitive impairment, we administered caffeine in the drinking water of 18–19 month old APPsw mice that were impaired in working memory. At 4–5 weeks into caffeine treatment, those impaired transgenic mice given caffeine (Tg/Caff) exhibited vastly superior working memory compared to the continuing impairment of control transgenic mice. In addition, Tg/Caff mice had substantially reduced Aβ deposition in hippocampus (↓40%) and entorhinal cortex (↓46%), as well as correlated decreases in brain soluble Aβ levels. Mechanistically, evidence is provided thatcaffeine suppression of BACE1 involves the cRaf-1/NFκB pathway. We also determined that caffeine concentrations within human physiological range effectively reduce active and total glycogen synthase kinase 3 levels in SweAPP N2a cells. Even with pre-existing and substantial Aβ burden, aged APPsw mice exhibited memory restoration and reversal of AD pathology, suggesting a treatment potential of caffeine in cases of established AD. Keywords: Alzheimer’s disease, Alzheimer’s transgenic mice, amyloid-β, caffeine, cognitive impairment, memory, treatment ∗ Address for correspondence: Gary W. Arendash, Ph.D., Depart- ment of Cell Biology, Microbiology, & Molecular Biology, BSF218, University of South Florida, Tampa, Florida 33620, USA. Tel.: +1 813 974 1584; Fax: +1 813 974 1614; E-mail: arendash@ cas.usf.edu. INTRODUCTION Caffeine is the most widely consumed psychoactive substance known to man, being primarily consumed in coffee, tea, and soft drinks. As a brain stimu- lant, its primary actions are to increase cerebral energy metabolism, cortical activity, and extracellular levels of acetylcholine, collectively resulting in enhanced alert- ISSN 1387-2877/09/$17.00  2009 – IOS Press and the authors. All rights reserved UNDER EMBARGO UNTIL JULY 6, 2009, 00:00 CET