Donepezil attenuates Aβ-associated mitochondrial dysfunction and reduces mitochondrial Aβ accumulation in vivo and in vitro

Ye, Chun Yan; Lei, Yun; Tang, Xi; Zhang, Hai Yan

doi:10.1016/j.neuropharm.2015.02.020

Cited by 63 publications

(33 citation statements)

References 54 publications

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“…Noh et al [27] showed that donepezil improved Aβ1-42-induced neurotoxicity through activation of PP2A, which could decrease hyperphosphorylation of tau. Furthermore, donepezil could attenuate Aβ-associated mitochondrial dysfunction and reduce mitochondrial Aβ accumulation in vivo and in vitro, which might differ from its previously reported effect on AChE [28] . Our previous study [5] indicated that donepezil could ameliorate OKA-induced hyperphosphorylation of tau and Aβ accumulation.…”

Section: Discussioncontrasting

confidence: 98%

A new coumarin derivative, IMM-H004, attenuates okadaic acid-induced spatial memory impairment in rats

et al. 2016

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Aim: A novel coumarin derivative 7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-coumarin (IMM-H004) has shown antiapoptotic, anti-inflammatory and neuroprotective activities. In this study we investigated the effects of IMM-H004 on spatial memory in rats treated with okadaic acid (OKA), which was used to imitate Alzheimer's disease (AD)-like symptoms. Methods: SD rats were administered IMM-H004 (8 mg·kg -1 ·d -1 , ig) or donepezil (positive control, 1 mg·kg -1 ·d -1 , ig) for 25 d. On d 8 and 9, OKA (200 ng) was microinjected into the right ventricle. Morris water maze test was used to evaluate the spatial memory impairments. Tau and β-amyloid (Aβ) pathology in the hippocampus was detected using Western blot and immunohistochemistry. TUNEL staining was used to detect cell apoptosis. Results: OKA-treated rats showed significant impairments of spatial memory in Morris water maze test, which were largely reversed by administration of IMM-H004 or donepezil. Furthermore, OKA-treated rats exhibited significantly increased phosphorylation of tau, deposits of Aβ protein and cell apoptosis in the hippocampus, which were also reversed by administration of IMM-H004 or donepezil. Conclusion: Administration of IMM-H004 or donepezil protects rats against OKA-induced spatial memory impairments via attenuating tau or Aβ pathology. Thus, IMM-H004 may be developed as a therapeutic agent for the treatment of AD.

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Section: Discussioncontrasting

confidence: 98%

A new coumarin derivative, IMM-H004, attenuates okadaic acid-induced spatial memory impairment in rats

et al. 2016

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“…In cultured cells, when the concentration of cholesterol ester is increased, there is a proportional elevation in APP [126]. It has been shown that Aβ deposition can be seen in mitochondria and, correspondingly, that Aβ deposition can lead to dysfunctional mitochondria such as mitochondrial swelling, mPTPs, and excessive ROS production [127][128][129][130][131][132][133][134]. Therefore, Aβ has a destructive influence on mitochondrial structure and function.…”

Section: Metabolism and Aβ Depositionmentioning

confidence: 99%

Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer’s Disease

Sun

et al. 2020

Journal of Diabetes Research

121

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As a chronic metabolic disease, diabetes mellitus (DM) is broadly characterized by elevated levels of blood glucose. Novel epidemiological studies demonstrate that some diabetic patients have an increased risk of developing dementia compared with healthy individuals. Alzheimer’s disease (AD) is the most frequent cause of dementia and leads to major progressive deficits in memory and cognitive function. Multiple studies have identified an increased risk for AD in some diabetic populations, but it is still unclear which diabetic patients will develop dementia and which biological characteristics can predict cognitive decline. Although few mechanistic metabolic studies have shown clear pathophysiological links between DM and AD, there are several plausible ways this may occur. Since AD has many characteristics in common with impaired insulin signaling pathways, AD can be regarded as a metabolic disease. We conclude from the published literature that the body’s diabetic status under certain circumstances such as metabolic abnormalities can increase the incidence of AD by affecting glucose transport to the brain and reducing glucose metabolism. Furthermore, due to its plentiful lipid content and high energy requirement, the brain’s metabolism places great demands on mitochondria. Thus, the brain may be more susceptible to oxidative damage than the rest of the body. Emerging evidence suggests that both oxidative stress and mitochondrial dysfunction are related to amyloid-β (Aβ) pathology. Protein changes in the unfolded protein response or endoplasmic reticulum stress can regulate Aβ production and are closely associated with tau protein pathology. Altogether, metabolic disorders including glucose/lipid metabolism, oxidative stress, mitochondrial dysfunction, and protein changes caused by DM are associated with an impaired insulin signal pathway. These metabolic factors could increase the prevalence of AD in diabetic patients via the promotion of Aβ pathology.

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“…For example, Ye et al reported that donepezil reduced the Aβ accumulation in mitochondria. 44) Guo et al found that donepezil improved the cognitive deficits in APP/PS1 mice by inhibiting microglial activation and the release of pro-inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

The Anti-dementia Effects of Donepezil Involve miR-206-3p in the Hippocampus and Cortex

Wang

et al. 2017

Biological & Pharmaceutical Bulletin

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Alzheimer's disease (AD) is a most serious age-related neurodegenerative disorder accompanied with significant memory impairments in this world. Recently, microRNAs (miRNAs) have been reported to be invlolved in the pathophysiology of AD. Previous studies have shown that miRNA-206 (miR-206) is implicated in the pathogenesis of AD via suppressing the expression of brain-derived neurotrophic factor (BDNF) in the brain. Here, we examined the miR-206-3p and miR-206-5p expression in the hippocampus and cortex of Abeta precursor protein (APP)/presenilin-1 (PS1) transgenic mice treated with donepezil, a drug approved for treating AD in clinic. We found that the expression of miR-206-3p was significantly up-regulated in the hippocampus and cortex of APP/PS1 mice, while donepezil administration significantly reversed this dysfunction. In addition, enhancing the miR-206-3p level by the usage of AgomiR-206-3p significantly attenuated the anti-dementia effects of donepezil in APP/PS1 mice. Together, these results suggested that miR-206-3p is involved in the anti-dementia effects of donepezil, and could be a novel pharmacological target for treating AD.Key words Alzheimer's disease; brain-derived neurotrophic factor; donepezil; microRNA (miRNA)-206-3pAlzheimer's disease (AD) is a serious neurodegenerative disorder in old people, and always accompanied with significant memory impairments, affecting mainly the hippocampus and frontal cortex. 1,2) AD patients display relatively slow, chronic but progressive neurodegeneration and memory impairments, ultimately leading to full dementia.3,4) Recent survey found that AD is responsible for about 50-60% of all cases of dementia in people over age 65. 3,4) The etiology of AD remains unclear, though many pathophysiologic hallmarks of this disease have been disclosed and are currently well established. They involve a complex network of interconnected factors such as cholinergic dysfunction, aggregation and accumulation of β-amyloid (Aβ), intracellular formation of neurofibrillary tangles composed by tau, oxidative stress, neuronal loss, and so on.5-8) A lot of reports have shown that brain-derived neurotrophic factor (BDNF) is critical for the establishment and maintenance of memory, while the dysfunction of BDNF system leads to memory impairments.9,10) It is known that BDNF combines to tyrosine kinase receptor B (TrkB) in the cell membrane, and then inducing the activation of several intracellular signaling pathways.11-13) Accumulating evidences have indicated that BDNF is implicated in the pathophysiology of AD. Previous studies have already found the reduced expression of BDNF in several brain regions (especially the hippocampus) of postmortem AD samples.14,15) By using the immunohistochemical method, Connor et al. found a significant reduction in not only intensity, but also the number of BDNF-immunoreactive cell in the hippocampus and cortex of AD samples.16) In addition, it was also thought that the Aβ-induced neurotoxicity and dendrite atrophy may due to a consequence of BDNF def...

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Donepezil attenuates Aβ-associated mitochondrial dysfunction and reduces mitochondrial Aβ accumulation in vivo and in vitro

Cited by 63 publications

References 54 publications

A new coumarin derivative, IMM-H004, attenuates okadaic acid-induced spatial memory impairment in rats

A new coumarin derivative, IMM-H004, attenuates okadaic acid-induced spatial memory impairment in rats

Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer’s Disease

The Anti-dementia Effects of Donepezil Involve miR-206-3p in the Hippocampus and Cortex

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