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

Abstract

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 (Abeta) 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 Abeta deposition in hippocampus (decrease 40%) and entorhinal cortex (decrease 46%), as well as correlated decreases in brain soluble Abeta levels. Mechanistically, evidence is provided that caffeine suppression of BACE1 involves the cRaf-1/NFkappaB 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 Abeta burden, aged APPsw mice exhibited memory restoration and reversal of AD pathology, suggesting a treatment potential of caffeine in cases of established AD.

Coffee, but not caffeine, has positive effects on cognition and psychomotor behavior in aging

“…When measuring cognitive performance, caffeine equivalent to that in seven or ten cups of coffee impaired reference memory (which contributed to the improvement seen in working memory), but no impairment was seen at the highest dose of coffee (0.825 %, equivalent to 15 cups a day). These results are in contrast to those of other studies that found that caffeine improves measures of learning and memory in AD transgenic mice (Arendash et al 2006;Arendash et al 2009). However, when normal wildtype mice were treated long-term with caffeine from adulthood through old age, no cognitive benefit was found ).…”

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

“…In this context, caffeine administration has been reported to reverse cognitive impairment and amyloid b (Ab) levels in transgenic Alzheimer's disease model mice (Arendash et al 2009). To examine the protective effects of coffee in a genetically tractable model, we investigated the effects of aqueous coffee extracts in a C. elegans model of Ab toxicity (Link et al 2003).…”

Caffeine blocks cholesterol-enriched diet induced AD-like pathology in rabbits

“…Substantial evidence from human epidemiological studies and from experimental studies conducted in animals and cultured cell models indicate that caffeine, when ingested chronically, can decrease Aβ levels, protect against the onset and severity of AD, and in some cases it can reverse behavioral and pathological features of AD [19,21,24,29]. Less clear, however, are the mechanisms by which caffeine exhibits these protective features.…”

“…Additionally, it has been shown that it can reverse behavioral and pathological features of AD [19,21,22,24,25,[29][30][31][32][33]. Importantly, these protective effects of caffeine are observed using pharmacologically relevant doses [28,34].…”

“…Human epidemiological and animal experimentation studies as well as studies conducted in cultured cell models have shown that caffeine protects against the onset and severity of AD [19][20][21][22][23][24][25][26][27][28]. Additionally, it has been shown that it can reverse behavioral and pathological features of AD [19,21,22,24,25,[29][30][31][32][33].…”