Authors: Cao, Chuanhai | Wang, Li | Lin, Xiaoyang | Mamcarz, Malgorzata | Zhang, Chi | Bai, Ge | Nong, Jasson | Sussman, Sam | Arendash, Gary
Article Type: Research Article
Abstract: Retrospective and prospective epidemiologic studies suggest that enhanced coffee/caffeine intake during aging reduces risk of Alzheimer's disease (AD). Underscoring this premise, our studies in AD transgenic mice show that long-term caffeine administration protects against cognitive impairment and reduces brain amyloid-β levels/deposition through suppression of both β- and γ-secretase. Because coffee contains many constituents in addition to caffeine that may provide cognitive benefits against AD, we examined effects of caffeinated and decaffeinated coffee on plasma cytokines, comparing their effects to caffeine alone. In both AβPPsw+PS1 transgenic mice and non-transgenic littermates, acute i.p. treatment with caffeinated coffee greatly and specifically increased plasma …levels of granulocyte-colony stimulating factor (GCSF), IL-10, and IL-6. Neither caffeine solution alone (which provided high plasma caffeine levels) or decaffeinated coffee provided this effect, indicating that caffeine synergized with some as yet unidentified component of coffee to selectively elevate these three plasma cytokines. The increase in GCSF is particularly important because long-term treatment with coffee (but not decaffeinated coffee) enhanced working memory in a fashion that was associated only with increased plasma GCSF levels among all cytokines. Since we have previously reported that long-term GCSF treatment enhances cognitive performance in AD mice through three possible mechanisms (e.g., recruitment of microglia from bone marrow, synaptogenesis, and neurogenesis), the same mechanisms could be complimentary to caffeine's established ability to suppress Aβ production. We conclude that coffee may be the best source of caffeine to protect against AD because of a component in coffee that synergizes with caffeine to enhance plasma GCSF levels, resulting in multiple therapeutic actions against AD. Show more
Keywords: AD mice, Alzheimer's disease, caffeine, coffee, cognitive benefits, cytokines, GCSF
DOI: 10.3233/JAD-2011-110110
Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 323-335, 2011
Authors: Cao, Chuanhai | Li, Yaqiong | Liu, Hui | Bai, Ge | Mayl, Jonathan | Lin, Xiaoyang | Sutherland, Kyle | Nabar, Neel | Cai, Jianfeng
Article Type: Research Article
Abstract: The purpose of this study was to investigate the potential therapeutic qualities of Δ9 -tetrahydrocannabinol (THC) with respect to slowing or halting the hallmark characteristics of Alzheimer's disease. N2a-variant amyloid-β protein precursor (AβPP) cells were incubated with THC and assayed for amyloid-β (Aβ) levels at the 6-, 24-, and 48-hour time marks. THC was also tested for synergy with caffeine, in respect to the reduction of the Aβ level in N2a/AβPPswe cells. THC was also tested to determine if multiple treatments were beneficial. The MTT assay was performed to test the toxicity of THC. Thioflavin T assays and western blots …were performed to test the direct anti-Aβ aggregation significance of THC. Lastly, THC was tested to determine its effects on glycogen synthase kinase-3β (GSK-3β) and related signaling pathways. From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin's enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer's disease through multiple functions and pathways. Show more
Keywords: Alzheimer's disease, amyloid-β peptide, cannabinoid, CB1 receptor, CB2 receptor, delta(9)-tetrahydrocannabinol, neurodegeneration
DOI: 10.3233/JAD-140093
Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 973-984, 2014
Authors: Cao, Chuanhai | Loewenstein, David A. | Lin, Xiaoyang | Zhang, Chi | Wang, Li | Duara, Ranjan | Wu, Yougui | Giannini, Alessandra | Bai, Ge | Cai, Jianfeng | Greig, Maria | Schofield, Elizabeth | Ashok, Raj | Small, Brent | Potter, Huntington | Arendash, Gary W.
Article Type: Research Article
Abstract: Although both human epidemiologic and animal model studies have suggested that caffeine/coffee protects against Alzheimer's disease, direct human evidence for this premise has been lacking. In the present case-control study, two separate cohorts consisting of 124 total individuals (65–88 years old) were cognitively assessed and a blood sample taken for caffeine/biomarker analysis. Subjects were then monitored for cognitive status over the ensuing 2–4 year period to determine the extent to which initial plasma caffeine/biomarkers levels would be predictive of changes in cognitive status. Plasma caffeine levels at study onset were substantially lower (−51%) in mild cognitive impairment (MCI) subjects who …later progressed to dementia (MCI→DEM) compared to levels in stable MCI subjects (MCI→MCI). Moreover, none of the MCI→DEM subjects had initial blood caffeine levels that were above a critical level of 1200 ng/ml, while half of stable MCI→MCI subjects had blood caffeine levels higher than that critical level. Thus, plasma caffeine levels greater than 1200 ng/ml (≈6 μM) in MCI subjects were associated with no conversion to dementia during the ensuing 2–4 year follow-up period. Among the 11 cytokines measured in plasma, three of them (GCSF, IL-10, and IL-6) were decreased in MCI→DEM subjects, but not in stable MCI→MCI subjects with high plasma caffeine levels. Coffee would appear to be the major or perhaps only source of caffeine for such stable MCI patients. This case-control study provides the first direct evidence that caffeine/coffee intake is associated with a reduced risk of dementia or delayed onset, particularly for those who already have MCI. Show more
Keywords: Alzheimer's disease, caffeine, coffee, dementia, immune response, mild cognitive impairment, plasma cytokines
DOI: 10.3233/JAD-2012-111781
Citation: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 559-572, 2012