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.

Recent epidemiologic studies suggest that caffeine may be protective against Alzheimer’s Disease (AD). Supportive of this premise, our previous studies have shown that moderate caffeine administration protects/restores cognitive function and suppresses brain β-amyloid (Aβ) production in AD transgenic mice. In the present study, we report that acute caffeine administration to both young adult and aged AD transgenic mice rapidly reduces Aβ levels in both brain interstitial fluid and plasma without affecting Aβ elimination. Long-term oral caffeine treatment to aged AD mice provided not only sustained reductions in plasma Aβ, but also decreases in both soluble and deposited Aβ in hippocampus and cortex. Irrespective of caffeine treatment, plasma Aβ levels did not correlate with brain Aβ levels or with cognitive performance in individual aged AD mice. Although higher plasma caffeine levels were strongly associated with lower plasma Aβ1-40 levels in aged AD mice, plasma caffeine levels were also not linked to cognitive performance. Plasma caffeine and theophylline levels were tightly correlated — both being associated with reduced inflammatory cytokine levels in hippocampus. Our conclusion is two-fold. First, that both plasma and brain Aβ levels are reduced by acute or chronic caffeine administration in several AD transgenic lines and ages, indicating a therapeutic value of caffeine against AD. Second, that plasma Aβ levels are not an accurate index of brain Aβ levels/deposition or cognitive performance in aged AD mice.

We have found that a small number of purified Th2-biased Aβ-specific T cells are sufficient to provide profound cognitive and pathological benefits in an APP+PS1 mouse model for Alzheimer’s disease. Six weeks after receiving T cell infusions, cognitively-impaired mice performed significantly better in working memory tasks, which correlated with higher plasma levels of soluble Aβ. Pathological analysis of the hippocampus revealed a 30% decrease of plaque- associated microglia and less vascular amyloidosis in T cell treated mice. The infusion of Aβ-specific Th2 cells also reduced plasma levels of IFN-γ, TNF-α, GM-CSF, IL-2 and IL-4, which are elevated in untreated APP+PS1 mice. No significant immune cell infiltration and no anti-Abeta antibody titers occurred in the T cell treated mice. These results demonstrate that Aβ-specific Th2 cells are sufficient to reverse cognitive impairment and provide multiple pathological benefits in an Alzheimer’s mouse model.

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