Caffeine Reverses Cognitive Impairment and Decreases Brain Amyloid-β Levels in Aged Alzheimer's Disease Mice

We have 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-beta (A beta) levels due to suppression of both beta-secretase ( BACE1) and presenilin 1 ( PS1)/gamma-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 A beta deposition in hippocampus (down arrow 40%) and entorhinal cortex (down arrow 46%), as well as correlated decreases in brain soluble A beta levels. Mechanistically, evidence is provided that caffeine suppression of BACE1 involves the cRaf-1/NF kappa B 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 A beta burden, aged APPsw mice exhibited memory restoration and reversal of AD pathology, suggesting a treatment potential of caffeine in cases of established AD.