Reducing Aβ load and tau phosphorylation: Emerging perspective for treating Alzheimer's disease

Kalra, Jaspreet; Khan, Aamir Ghafoor

doi:10.1016/j.ejphar.2015.07.043

Cited by 44 publications

(25 citation statements)

References 146 publications

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“…Novel drugs have been developed for the treatment of Alzheimer's disease that act on multiple targets, including cholinesterase activity, monoamine oxidase activity, Aβ aggregation, γ-secretase activity, serotonin transporter activity, production of reactive oxygen species, calcium channels, mitochondrial permeability transition pores, and interactions of amyloid-β with mitochondrial enzymes (Xie et al 2006, Lim et al 2011, Bolea et al 2013). Statins also have been discussed as an alternative treatment approach in Alzheimer's disease (Kalra and Khan 2015). However, there is some controversy regarding the effect of statins on dementia: some studies have found beneficial effects, while other studies have not (Feldman et al 2010, Padala et al 2012, Valenti et al 2014, Chatterjee et al 2015.…”

Section: Introductionmentioning

confidence: 99%

Statin-Induced Changes in Mitochondrial Respiration in Blood Platelets in Rats and Human With Dyslipidemia

Vevera

Fišar

Nekovarova³

et al. 2016

Physiol Res

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3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used drugs for lowering blood lipid levels and preventing cardiovascular diseases. However, statins can have serious adverse effects, which may be related to development of mitochondrial dysfunctions. The aim of study was to demonstrate the in vivo effect of high and therapeutic doses of statins on mitochondrial respiration in blood platelets. Model approach was used in the study. Simvastatin was administered to rats at a high dose for 4 weeks. Humans were treated with therapeutic doses of rosuvastatin or atorvastatin for 6 weeks.Platelet mitochondrial respiration was measured using highresolution respirometry. In rats, a significantly lower physiological respiratory rate was found in intact platelets of simvastatintreated rats compared to controls. In humans, no significant changes in mitochondrial respiration were detected in intact platelets; however, decreased complex I-linked respiration was observed after statin treatment in permeabilized platelets. We propose that the small in vivo effect of statins on platelet energy metabolism can be attributed to drug effects on complex I of the electron transport system. Both intact and permeabilized platelets can be used as a readily available biological model to study changes in cellular energy metabolism in patients treated with statins.

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Section: Introductionmentioning

confidence: 99%

Statin-Induced Changes in Mitochondrial Respiration in Blood Platelets in Rats and Human With Dyslipidemia

Vevera

Fišar

Nekovarova³

et al. 2016

Physiol Res

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“…Therefore, it is expected that agents that are capable of inhibiting both Aβ levels and Tau hyperphosphorylation should be more potent anti-AD agents 19 . Accordingly, considering that natural products are major sources of bioactive agents based on their large-scale structural and acting target diversities, we have recently constructed a “one stone, two birds” platform against our laboratory's in-house natural product library to identify agents that are able to inhibit both Aβ levels and Tau hyperphosphorylation.…”

Section: Introductionmentioning

confidence: 99%

Thamnolia vermicularis extract improves learning ability in APP/PS1 transgenic mice by ameliorating both Aβ and Tau pathologies

Guo

Lei

et al. 2016

Acta Pharmacol Sin

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Considering the complicated pathogenesis of Alzheimer's disease (AD), multi-targets have become a focus in the discovery of drugs for treatment of this disease. In the current work, we established a multi-target strategy for discovering active reagents capable of suppressing both Aβ level and Tau hyperphosphorylation from natural products, and found that the ethanol extract of Thamnolia vermicularis (THA) was able to improve learning ability in APP/PS1 transgenic mice by inhibiting both Aβ levels and Tau hyperphosphorylation. SH-SY5Y and CHO-APP/BACE1 cells and primary astrocytes were used in cell-based assays. APP/PS1 transgenic mice [B6C3-Tg(APPswe, PS1dE9)] were administered THA (300 mg·kg−1·d−1, ig) for 100 d. After the administration was completed, the learning ability of the mice was detected using a Morris water maze (MWM) assay; immunofluorescence staining, Congo red staining and Thioflavine S staining were used to detect the senile plaques in the brains of the mice. ELISA was used to evaluate Aβ and sAPPβ contents, and Western blotting and RT-PCR were used to investigate the relevant signaling pathway regulation in response to THA treatment. In SH-SY5Y cells, THΑ (1, 10, 20 μg/mL) significantly stimulated PI3K/AKT/mTOR and AMPK/raptor/mTOR signaling-mediated autophagy in the promotion of Aβ clearance as both a PI3K inhibitor and an AMPK indirect activator, and restrained Aβ production as a suppressor against PERK/eIF2α-mediated BACE1 expression. Additionally, THA functioned as a GSK3β inhibitor with an IC50 of 1.32±0.85 μg/mL, repressing Tau hyperphosphorylation. Similar effects on Aβ accumulation and Tau hyperphosphorylation were observed in APP/PS1 transgenic mice treated with THA. Furthermore, administration of THA effectively improved the learning ability of APP/PS1 transgenic mice, and markedly reduced the number of senile plaques in their hippocampus and cortex. The results highlight the potential of the natural product THA for the treatment of AD.

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“…Alzheimer's disease (AD) is by far the greatest cause of dementia and is characterised by the onset of a gradual cognitive decline. Current treatments include cholinesterase inhibitors such as Donepezil, Rivastigmine and Galantamine; and Memantine which prevents glutamate-mediated neurotoxicity (Kalra and Khan, 2015). However, these drugs offer no long-term cure for the disease and often provide only short-term slow-down of disease progression.…”

Section: Introductionmentioning

confidence: 99%

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer’s disease

Ryan

Kelly

2016

Ageing Research Reviews

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a b s t r a c tIt is now well established, at least in animal models, that exercise elicits potent pro-cognitive and proneurogenic effects. Alzheimer's disease (AD) is one of the leading causes of dementia and represents one of the greatest burdens on healthcare systems worldwide, with no effective treatment for the disease to date. Exercise presents a promising non-pharmacological option to potentially delay the onset of or slow down the progression of AD. Exercise interventions in mouse models of AD have been explored and have been found to reduce amyloid pathology and improve cognitive function. More recent studies have expanded the research question by investigating potential pro-neurogenic and anti-inflammatory effects of exercise. In this review we summarise studies that have examined exercise-mediated effects on AD pathology, cognitive function, hippocampal neurogenesis and neuroinflammation in transgenic mouse models of AD. Furthermore, we attempt to identify the optimum exercise conditions required to elicit the greatest benefits, taking into account age and pathology of the model, as well as type and duration of exercise.© 2016 Elsevier B.V. All rights reserved. Please cite this article in press as: Ryan, S.M., Kelly, Á.M., Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer's disease. Ageing Res. Rev. (2016), http://dx

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Reducing Aβ load and tau phosphorylation: Emerging perspective for treating Alzheimer's disease

Cited by 44 publications

References 146 publications

Statin-Induced Changes in Mitochondrial Respiration in Blood Platelets in Rats and Human With Dyslipidemia

Statin-Induced Changes in Mitochondrial Respiration in Blood Platelets in Rats and Human With Dyslipidemia

Thamnolia vermicularis extract improves learning ability in APP/PS1 transgenic mice by ameliorating both Aβ and Tau pathologies

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer’s disease

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