Authors: Arendash, Gary W. | Cao, Chuanhai
Article Type: Research Article
Abstract: Epidemiologic studies have increasingly suggested that caffeine/coffee could be an effective therapeutic against Alzheimer's disease (AD). We have utilized a transgenic mouse model for AD in well-controlled studies to determine if caffeine and/or coffee have beneficial actions to protect against or reverse AD-like cognitive impairment and AD pathology. AD mice given caffeine in their drinking water from young adulthood into older age showed protection against memory impairment and lower brain levels of the abnormal protein (amyloid-β; Aβ) thought to be central to AD pathogenesis. Moreover, “aged” cognitively-impaired AD mice exhibited memory restoration and lower brain Aβ levels following only 1–2 …months of caffeine treatment. We believe that the cognitive benefits of chronic caffeine administration in AD mice are due to caffeine itself, and not metabolites of caffeine; this, because our long-term administration of theophylline to AD mice provided no cognitive benefits. In acute studies involving AD mice, one oral caffeine treatment quickly reduced both brain and plasma Aβ levels – similarly rapid alterations in plasma Aβ levels were seen in humans following acute caffeine administration. “Caffeinated” coffee provided to AD mice also quickly decreased plasma Aβ levels, but not “decaffeinated” coffee, suggesting that caffeine is critical to decreasing blood Aβ levels. Caffeine appears to provide its disease-modifying effects through multiple mechanisms, including a direct reduction of Aβ production through suppression of both β- and γ-secretase levels. These results indicate a surprising ability of moderate caffeine intake (the human equivalent of 500 mg caffeine or 5 cups of coffee per day) to protect against or treat AD in a mouse model for the disease and a therapeutic potential for caffeine against AD in humans. Show more
Keywords: Alzheimer's disease, amyloid-β, caffeine, coffee, memory
DOI: 10.3233/JAD-2010-091249
Citation: Journal of Alzheimer's Disease, vol. 20, no. s1, pp. S117-S126, 2010
Authors: Aljassabi, Ali | Zieneldien, Tarek | Kim, Janice | Regmi, Deepika | Cao, Chuanhai
Article Type: Review Article
Abstract: Alzheimer’s disease (AD) is an extremely complex and heterogeneous pathology influenced by many factors contributing to its onset and progression, including aging, amyloid-beta (Aβ) plaques, tau fibril accumulation, inflammation, etc. Despite promising advances in drug development, there is no cure for AD. Although there have been substantial advancements in understanding the pathogenesis of AD, there have been over 200 unsuccessful clinical trials in the past decade. In recent years, immunotherapies have been at the forefront of these efforts. Immunotherapy alludes to the immunological field that strives to identify disease treatments via the enhancement, suppression, or induction of immune responses. Interestingly, …immunotherapy in AD is a relatively new approach for non-infectious disease. At present, antibody therapy (passive immunotherapy) that targets anti-Aβ aimed to prevent the fibrillization of Aβ peptides and disrupt pre-existing fibrils is a predominant AD immunotherapy due to the continuous failure of active immunotherapy for AD. The most rational and safe strategies will be those targeting the toxic molecule without triggering an abnormal immune response, offering therapeutic advantages, thus making clinical trial design more efficient. This review offers a concise overview of immunotherapeutic strategies, including active and passive immunotherapy for AD. Our review encompasses approved methods and those presently under investigation in clinical trials, while elucidating the recent challenges, complications, successes, and potential treatments. Thus, immunotherapies targeting Aβ throughout the disease progression using a mutant oligomer-Aβ stimulated dendritic cell vaccine may offer a promising therapy in AD. Show more
Keywords: Alzheimer’s disease, amyloid-β, dendritic cell, immunotherapies, vaccine
DOI: 10.3233/JAD-231163
Citation: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 755-772, 2024
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: Sanchez-Ramos, Juan | Cimino, Cynthia | Avila, Ross | Rowe, Amanda | Chen, Ren | Whelan, Glenn | Lin, Xiaoyang | Cao, Chuanhai | Ashok, Raj
Article Type: Research Article
Abstract: Human granulocyte colony-stimulating-factor (G-CSF) is widely used for treatment of neutropenia and to mobilize stem/progenitor cells for bone marrow transplantation. In studies of thousands of healthy donor subjects treated with G-CSF to mobilize stem/progenitor cells, the side-effect profile has been reported to be mild and reversible. In pre-clinical studies, G-CSF was reported to improve spatial learning performance and to markedly reduce amyloid deposition in hippocampus and entorhinal cortex in a murine model of Alzheimer's disease (AD). The present study investigated the effects of a five day schedule of G-CSF administration on tolerability, safety, and cognition in eight patients with mild …to moderate stage AD. A double-blind placebo control, cross-over design was implemented. Treatment with G-CSF did not result in serious adverse events. The most common and expected side effects were transient increases in white blood cell count, myalgias and diffuse aching that improved with non-steroidal anti-inflammatory medications. Of a battery of cognitive tests administered using the CANTAB computerized system, only the mean paired associate learning (PAL total trials adjusted) was significantly improved at the final visit of the study compared to baseline values (p < 0.05). There were no significant differences in amyloid-β1-42 levels in cerebrospinal fluid measured two weeks after G-CSF and two weeks after placebo treatments. In conclusion, administration of G-CSF in a dosage regimen commonly used for bone marrow donors was well tolerated and safe, and provided a signal of positive change in a hippocampal-dependent task of cognitive performance. Show more
Keywords: Alzheimer's disease, amyloid-β, computer assisted neuropsychological battery, cytokines, filgrastim, granulocyte-colony stimulating factor, NEUPOGEN®, paired-associate learning
DOI: 10.3233/JAD-2012-120196
Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 843-855, 2012
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: Arendash, Gary | Cao, Chuanhai | Abulaban, Haitham | Baranowski, Rob | Wisniewski, Gary | Becerra, Lino | Andel, Ross | Lin, Xiaoyang | Zhang, Xiaolin | Wittwer, David | Moulton, Jay | Arrington, John | Smith, Amanda
Article Type: Research Article
Abstract: Background: Small aggregates (oligomers) of the toxic proteins amyloid-β (Aβ) and phospho-tau (p-tau) are essential contributors to Alzheimer’s disease (AD). In mouse models for AD or human AD brain extracts, Transcranial Electromagnetic Treatment (TEMT) disaggregates both Aβ and p-tau oligomers, and induces brain mitochondrial enhancement. These apparent “disease-modifying” actions of TEMT both prevent and reverse memory impairment in AD transgenic mice. Objective: To evaluate the safety and initial clinical efficacy of TEMT against AD, a comprehensive open-label clinical trial was performed. Methods: Eight mild/moderate AD patients were treated with TEMT in-home by their caregivers for 2 months utilizing a unique …head device. TEMT was given for two 1-hour periods each day, with subjects primarily evaluated at baseline, end-of-treatment, and 2 weeks following treatment completion. Results: No deleterious behavioral effects, discomfort, or physiologic changes resulted from 2 months of TEMT, as well as no evidence of tumor or microhemorrhage induction. TEMT induced clinically important and statistically significant improvements in ADAS-cog, as well as in the Rey AVLT. TEMT also produced increases in cerebrospinal fluid (CSF) levels of soluble Aβ1-40 and Aβ1-42 , cognition-related changes in CSF oligomeric Aβ, a decreased CSF p-tau/Aβ1-42 ratio, and reduced levels of oligomeric Aβ in plasma. Pre- versus post-treatment FDG-PET brain scans revealed stable cerebral glucose utilization, with several subjects exhibiting enhanced glucose utilization. Evaluation of diffusion tensor imaging (fractional anisotropy) scans in individual subjects provided support for TEMT-induced increases in functional connectivity within the cognitively-important cingulate cortex/cingulum. Conclusion: TEMT administration to AD subjects appears to be safe, while providing cognitive enhancement, changes to CSF/blood AD markers, and evidence of stable/enhanced brain connectivity. Show more
Keywords: Amyloid-β, brain electromagnetic waves, cognitive enhancement, FDG-PET, functional MRI
DOI: 10.3233/JAD-190367
Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 57-82, 2019
Authors: Dragicevic, Natasa | Smith, Adam | Lin, Xiaoyang | Yuan, Fang | Copes, Neil | Delic, Vedad | Tan, Jun | Cao, Chuanhai | Shytle, R. Douglas | Bradshaw, Patrick C.
Article Type: Research Article
Abstract: Amyloid-β (Aβ)-induced mitochondrial dysfunction may play a role in the onset and progression of Alzheimer's disease (AD). Therefore, therapeutics targeted to improve mitochondrial function could be beneficial. Plant-derived flavonoids have shown promise in improving certain AD phenotypes, but the overall mechanism of action(s) through which flavonoids protect from AD is still unknown. To identify flavonoids and other natural products that may correct amyloid-induced mitochondrial dysfunction, 25 natural products were screened for their ability to restore altered mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, or ATP levels in neuroblastoma cells expressing mutant amyloid-β protein precursor (AβPP). Epigallocatechin-3-gallate (EGCG) and …luteolin were identified as the top two mitochondrial restorative compounds from the in vitro screen. EGCG was further tested in vivo to determine its effects on brain mitochondrial function in an AβPP/PS-1 (presenilin 1) double mutant transgenic mouse model of AD. EGCG treatment restored mitochondrial respiratory rates, MMP, ROS production, and ATP levels by 50 to 85% in mitochondria isolated from the hippocampus, cortex, and striatum. The results of this study lend further credence to the notion that EGCG and other flavonoids, such as luteolin, are ‘multipotent therapeutic agents’ that not only reduce toxic levels of brain Aβ, but also hold the potential to protect neuronal mitochondrial function in AD. Show more
Keywords: Adenosine triphosphate, Alzheimer's disease, EGCG, flavonoids, membrane potential, mitochondrial, polyphenols, reactive oxygen species, respiration
DOI: 10.3233/JAD-2011-101629
Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 507-521, 2011
Authors: Arendash, Gary W. | Sanchez-Ramos, Juan | Mori, Takashi | Mamcarz, Malgorzata | Lin, Xiaoyang | Runfeldt, Melissa | Wang, Li | Zhang, Guixin | Sava, Vasyl | Tan, Jun | Cao, Chuanhai
Article Type: Research Article
Abstract: Despite numerous studies, there is no definitive evidence that high-frequency electromagnetic field (EMF) exposure is a risk to human health. To the contrary, this report presents the first evidence that long-term EMF exposure directly associated with cell phone use (918 MHz; 0.25 w/kg) provides cognitive benefits. Both cognitive-protective and cognitive-enhancing effects of EMF exposure were discovered for both normal mice and transgenic mice destined to develop Alzheimer's-like cognitive impairment. The cognitive interference task utilized in this study was designed from, and measure-for-measure analogous to, a human cognitive interference task. In Alzheimer's disease mice, long-term EMF exposure reduced brain amyloid-β (Aβ) …deposition through Aβ anti-aggregation actions and increased brain temperature during exposure periods. Several inter-related mechanisms of EMF action are proposed, including increased Aβ clearance from the brains of Alzheimer's disease mice, increased neuronal activity, and increased cerebral blood flow. Although caution should be taken in extrapolating these mouse studies to humans, we conclude that EMF exposure may represent a non-invasive, non-pharmacologic therapeutic against Alzheimer's disease and an effective memory-enhancing approach in general. Show more
Keywords: Alzheimer's disease, amyloid-β, electromagnetic fields, memory, transgenic mice
DOI: 10.3233/JAD-2010-1228
Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 191-210, 2010
Authors: Cao, Chuanhai | Cirrito, John R. | Lin, Xiaoyang | Wang, Lilly | Verges, Deborah K. | Dickson, Alexander | Mamcarz, Malgorzata | Zhang, Chi | Mori, Takashi | Arendash, Gary W. | Holtzman, David M. | Potter, Huntington
Article Type: Research Article
Abstract: 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 amyloid-β (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; and second, that plasma Aβ levels are not an accurate index of brain Aβ levels/deposition or cognitive performance in aged AD mice. Show more
Keywords: Alzheimer's disease, amyloid-β, brain interstitial fluid, caffeine, plasma, transgenic mice
DOI: 10.3233/JAD-2009-1071
Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 681-697, 2009
Authors: Arendash, Gary W. | Mori, Takashi | Cao, Chuanhai | Mamcarz, Malgorzata | Runfeldt, Melissa | Dickson, Alexander | Rezai-Zadeh, Kavon | Tan, Jun | Citron, Bruce A. | Lin, Xiaoyang | Echeverria, Valentina | Potter, Huntington
Article Type: Research Article
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-β (Aβ) levels due to suppression of both β-secretase (BACE1) and presenilin 1 (PS1)/γ-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 Aβ deposition in hippocampus (↓ 40% and entorhinal cortex (↓46%), as well as correlated decreases in brain soluble Aβ levels. Mechanistically, evidence is provided that caffeine suppression of BACE1 involves the cRaf-1/NFκB 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 Aβ burden, aged APPsw mice exhibited memory restoration and reversal of AD pathology, suggesting a treatment potential of caffeine in cases of established AD. Show more
Keywords: Alzheimer's disease, Alzheimer's transgenic mice, amyloid-β, caffeine, cognitive impairment, memory, treatment
DOI: 10.3233/JAD-2009-1087
Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 661-680, 2009