Authors: Gray, Nora E. | Sampath, Harini | Zweig, Jonathan A. | Quinn, Joseph F. | Soumyanath, Amala
Article Type: Research Article
Abstract: Background: We previously showed that a water extract of the medicinal plant Centella asiatica (CAW) attenuates amyloid-β (Aβ)-induced cognitive deficits in vivo, and prevents Aβ-induced cytotoxicity in vitro. Yet the neuroprotective mechanism of CAW is unknown. Objective: The goal of this study was to identify biochemical pathways altered by CAW using in vitro models of Aβ toxicity. Methods: The effects of CAW on aberrations in antioxidant response, calcium homeostasis, and mitochondrial function induced by Aβ were evaluated in MC65 and SH-SY5Y neuroblastoma cells. Results: CAW decreased intracellular reactive oxygen species and calcium levels elevated in response to Aβ, and induced …the expression of antioxidant response genes in both cell lines. In SH-SY5Y cells, CAW increased basal and maximal oxygen consumption without altering spare capacity, and attenuated Aβ-induced decreases in mitochondrial respiration. CAW also prevented Aβ-induced decreases in ATP and induced the expression of mitochondrial genes and proteins in both cell types. Caffeoylquinic acids from CAW were shown to have a similar effect on antioxidant and mitochondrial gene expression in neuroblastoma cells. Primary rat hippocampal neurons treated with CAW also showed an increase in mitochondrial and antioxidant gene expression. Conclusions: These data suggest an effect of CAW on mitochondrial biogenesis, which in conjunction with activation of antioxidant response genes and normalizing calcium homeostasis, likely contributes to its neuroprotective action against Aβ toxicity. Show more
Keywords: Amyloid-β toxicity, calcium homeostasis, Centella asiatica, mitochondrial dysfunction, neuroprotection, reactive oxygen species
DOI: 10.3233/JAD-142217
Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 933-946, 2015
Authors: Harris, Christopher J. | Gray, Nora E. | Caruso, Maya | Hunter, Marguex | Ralle, Martina | Quinn, Joseph F.
Article Type: Research Article
Abstract: Background: Environmental copper has been implicated in the pathogenesis of Alzheimer’s disease based on evidence that: 1) brain copper levels increase with age, 2) copper promotes misfolding and toxicity of amyloid-β in vitro , 3) copper-modulating interventions reduce amyloid pathology in animal models. However, the effect of copper upon non-amyloid Alzheimer’s pathology is relatively under-explored. Objective: To determine if modulation of brain copper level affects brain tau pathology and/or associated cognitive impairment. Methods: We tested the hypothesis that brain copper modulates tau pathology by manipulating brain levels of copper in the PS19 transgenic mouse model of tau pathology. We treated …PS19 and wild-type mice with oral zinc acetate, an established therapy for long term control of excess brain copper, and examined treatment effects upon brain copper, brain tau, NFT-like pathology, and spatial memory. We treated a second cohort of mice with exogenous dietary copper in order to evaluate whether excess environmental copper promotes brain tau pathology. Results: Copper-lowering with oral zinc attenuated spatial memory impairment in female but not male PS19 mice, without a significant effect upon tau pathology. Copper loading increased brain copper, but did not have an effect on brain tau pathology or spatial memory function. Conclusion: These findings suggest that a strategy to lower brain copper may be viable for symptomatic benefit in the setting of tau neuropathology, but unlikely to have robust effects on the underlying pathology. These findings are consistent with dietary or other exogenous copper being unlikely to promote tau pathology. Show more
Keywords: Copper, neurofibrillary tangles, tau, zinc
DOI: 10.3233/JAD-200002
Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 49-60, 2020
Authors: Gray, Nora E. | Zweig, Jonathan A. | Kawamoto, Colleen | Quinn, Joseph F. | Copenhaver, Philip F.
Article Type: Research Article
Abstract: Because STX is a selective ligand for membrane estrogen receptors, it may be able to confer the beneficial effects of estrogen without eliciting the deleterious side effects associated with activation of the nuclear estrogen receptors. This study evaluates the neuroprotective properties of STX in the context of amyloid-β (Aβ) exposure. MC65 and SH-SY5Y neuroblastoma cell lines, as well as primary hippocampal neurons from wild type (WT) and Tg2576 mice, were used to investigate the ability of STX to attenuate cell death, mitochondrial dysfunction, dendritic simplification, and synaptic loss induced by Aβ. STX prevented Aβ-induced cell death in both neuroblastoma cell …lines; it also normalized the decrease in ATP and mitochondrial gene expression caused by Aβ in these cells. Notably, STX also increased ATP content and mitochondrial gene expression in control neuroblastoma cells (in the absence of Aβ). Likewise in primary neurons, STX increased ATP levels and mitochondrial gene expression in both genotypes. In addition, STX treatment enhanced dendritic arborization and spine densities in WT neurons and prevented the diminished outgrowth of dendrites caused by Aβ exposure in Tg2576 neurons. These data suggest that STX can act as an effective neuroprotective agent in the context of Aβ toxicity, improving mitochondrial function as well as dendritic growth and synaptic differentiation. In addition, since STX also improved these endpoints in the absence of Aβ, this compound may have broader therapeutic value beyond Alzheimer’s disease. Show more
Keywords: Amyloid-β toxicity, mitochondrial dysfunction, neuroprotection, selective estrogen receptor modulator
DOI: 10.3233/JAD-150756
Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 391-403, 2016
Authors: Gray, Nora E. | Morré, Jeff | Kelley, Jeremiah | Maier, Claudia S. | Stevens, Jan F. | Quinn, Joseph F. | Soumyanath, Amala
Article Type: Research Article
Abstract: The accumulation of amyloid-β (Aβ) is a hallmark of Alzheimer's disease and is known to result in neurotoxicity both in vivo and in vitro. We previously demonstrated that treatment with the water extract of Centella asiatica (CAW) improves learning and memory deficits in Tg2576 mice, an animal model of Aβ accumulation. However the active compounds in CAW remain unknown. Here we used two in vitro models of Aβ toxicity to confirm this neuroprotective effect and identify several active constituents of the CAW extract. CAW reduced Aβ-induced cell death and attenuated Aβ-induced changes in tau expression and phosphorylation in both the …MC65 and SH-SY5Y neuroblastoma cell lines. We confirmed and quantified the presence of several mono- and dicaffeoylquinic acids (CQAs) in CAW using chromatographic separation coupled to mass spectrometry and ultraviolet spectroscopy. Multiple dicaffeoylquinic acids showed efficacy in protecting MC65 cells against Aβ-induced cytotoxicity. Isochlorogenic acid A and 1,5-dicaffeoylquinic acid were found to be the most abundant CQAs in CAW, and the most active in protecting MC65 cells from Aβ-induced cell death. Both compounds showed neuroprotective activity in MC65 and SH-SY5Y cells at concentrations comparable to their levels in CAW. Each compound not only mitigated Aβ-induced cell death, but was able to attenuate Aβ-induced alterations in tau expression and phosphorylation in both cell lines, as seen with CAW. These data suggest that CQAs are active neuroprotective components in CAW, and therefore are important markers for future studies on CAW standardization, bioavailability, and dosing. Show more
Keywords: Amyloid-β toxicity, caffeoylquinic acids, Centella asiatica, neuroprotection, tau
DOI: 10.3233/JAD-131913
Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 359-373, 2014
Authors: Zweig, Jonathan A. | Brandes, Mikah S. | Brumbach, Barbara H. | Caruso, Maya | Wright, Kirsten M. | Quinn, Joseph F. | Soumyanath, Amala | Gray, Nora E.
Article Type: Research Article
Abstract: Background: The medicinal herb Centella asiatica has been long been used for its neuroprotective and cognitive enhancing effects. We have previously shown that two weeks of treatment with a water extract of Centella asiatica (CAW) improves cognition and activates the endogenous antioxidant response pathway without altering amyloid-β (Aβ) plaque burden. Objective: Here, we assess the effect of long-term treatment of CAW in the 5xFAD mouse model of Aβ accumulation. Methods: Four-month-old 5xFAD mice were treated with CAW in their drinking water (2 g/L) for three months at which point they underwent cognitive testing as well as analysis of Aβ plaque levels …and antioxidant and synaptic gene expression. In order to confirm the involvement of the antioxidant regulatory transcription factor NRF2 on the effects of CAW on synaptic plasticity, neurons isolated from 5xFAD mice were also treated with CAW and the targeted inhibitor ML385. Results: Three months of treatment with CAW improved spatial and contextual memory as well as executive function in 5xFAD mice. This improvement was accompanied by increased antioxidant gene expression and a decrease in Aβ plaque burden relative to untreated 5xFAD animals. In isolated neurons, treatment with ML385 blocked the effects of CAW on dendritic arborization and synaptic gene expression. Conclusion: These results suggest that prolonged CAW exposure could be beneficial in Alzheimer’s disease and that these effects likely involve NRF2 activation. Moreover, these findings suggest that targeting NRF2 itself may be a relevant therapeutic strategy for improving synaptic plasticity and cognitive function in Alzheimer’s disease. Show more
Keywords: Alzheimer’s disease, amyloid-β, centella asiatica, cognition, NRF2
DOI: 10.3233/JAD-210271
Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1453-1468, 2021
Authors: Khorani, Mona | Bobe, Gerd | Matthews, Donald G. | Magana, Armando Alcazar | Caruso, Maya | Gray, Nora E. | Quinn, Joseph F. | Stevens, Jan F. | Soumyanath, Amala | Maier, Claudia S.
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) peptide in the brain. Objective: To gain a better insight into alterations in major biochemical pathways underlying AD. Methods: We compared metabolomic profiles of hippocampal tissue of 20-month-old female Tg2576 mice expressing the familial AD-associated hAPP695SW transgene with their 20-month-old wild type female littermates. Results: The hAPP695SW transgene causes overproduction and accumulation of Aβ in the brain. Out of 180 annotated metabolites, 54 metabolites differed (30 higher and 24 lower in Tg2576 versus wild-type hippocampal tissue) and were linked to the amino acid, nucleic acid, …glycerophospholipid, ceramide, and fatty acid metabolism. Our results point to 1) heightened metabolic activity as indicated by higher levels of urea, enhanced fatty acid β-oxidation, and lower fatty acid levels; 2) enhanced redox regulation; and 3) an imbalance of neuro-excitatory and neuro-inhibitory metabolites in hippocampal tissue of aged hAPP695SW transgenic mice. Conclusion: Taken together, our results suggest that dysregulation of multiple metabolic pathways associated with a concomitant shift to an excitatory-inhibitory imbalance are contributing mechanisms of AD-related pathology in the Tg2576 mouse. Show more
Keywords: Alzheimer’s disease, excitatory and inhibitory imbalance, fatty acids, hAPP695SW, hippocampus, metabolomics, Tg2576
DOI: 10.3233/JAD-215084
Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1601-1619, 2022
