IC‐P3‐174: Plasma Aβ level can be used as marker for AD treatment in PS1/APP Alzheimer's mouse model

Retrospective studies have suggested that caffeine intake reduces the risk of Alzheimer's Disease (AD) Consistent with this premise, we have previously reported (Neuroscience 142:941, 2006) that long-term caffeine treatment can prevent memory impairment in a transgenic mouse model of Alzheimer's disease (AD). To find an early marker for the effect of caffeine on AD, we have conducted a series of caffeine studies involving both young adult and aged APPsw or APPsw/PS1 transgenic mice. Both gavage and i.p. delivery of 1.5 mg and 3.0 mg caffeine was given acutely. For example, a single dose of 3.0 mg caffeine was administered to 19 months old APPsw/PS1 mice. This single dose decreased blood Aβ40 and Aβ42 levels within 4 hours by more than 30%. In such acute administration studies, reductions in plasma Aβ levels are strongly correlated with plasma caffeine concentration . Long term treatment of APPsw mice with 1.5 mg caffeine per day in drinking water over a period of 3 months resulted in substantial reductions in plasma and brain soluble Aβ, as well as marked reductions in brain Aβ deposition. Moreover, decreased plasma levels of multiple plasma cytokines (including TNF–α) were evident in caffeine-treated APPsw mice months into oral caffeine treatment. Interestingly, even if 1.5 mg of caffeine were administered only once every fourth day, a significant and continuous reduction of plasma Aβ40 and Aβ42 was evident through a two month treatment period. Specifically, Aβ40 decreased from 6500pg/ml to 2500 pg/ml and Aβ42 from 1000pg to 500pg/ml. These results imply that the effect of caffeine exceeds its own half life and that caffeine ability to reduce Aβ reduction may be independent of its receptor. The ability of caffeine to quickly and chronically reduce plasma and brain Aβ appears due to caffeine's ability to reduce both β- and γ-secretase activity in brain. Since long term administration of caffeine does not result in any adverse effects, we conclude that caffeine may be an excellent natural compound for protection against and treatment of Alzheimer's disease. As such, results of our Phase II clinical trials with caffeine will also be reported.