Fumanjian, a Classic Chinese Herbal Formula, Can Ameliorate the Impairment of Spatial Learning and Memory through Apoptotic Signaling Pathway in the Hippocampus of Rats withAβ1–40-Induced Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia and lacks disease-altering treatments. Fumanjian (FMJ), a famous classic Chinese herbal prescription for dementia, was first recorded in theComplete Works of Jingyueduring the Ming Dynasty. This study aimed to investigate whether FMJ could prevent cognitive deficit and take neuroprotective effects inAβ1–40-induced rat model through apoptotic signaling pathway. AD model was established by bilateral injection ofAβ1–40into hippocampus in rat. All rats were tested for their capabilities of spatial navigation and memorization by Morris water maze. Apoptosis was tested using TUNEL staining in hippocampus neuronal cells; RT-PCR tested expression of Bcl-2 and Bax mRNA; western blotting tested protein level of cleaved caspase-3. After 14 days of treatment, FMJ significantly improved the escape latency and enhanced platform-cross number compared with theAβ1–40-injected group (P<0.05orP<0.01). FMJ also significantly decreased number of TUNEL-positive neuronal apoptosis and the expressions of Bax and cleaved Caspase-3 and increased the expression of Bcl-2 (P<0.01) compared with AD model group. In conclusion, FMJ exerts a protective effect againstAβ1–40-induced learning and memory deficits and neuronal apoptosis, suggesting that FMJ could be used as a potential therapeutic formula for AD.

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Ganoderma lucidum Triterpenoids (GLTs) Reduce Neuronal Apoptosis via Inhibition of ROCK Signal Pathway in APP/PS1 Transgenic Alzheimer’s Disease Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/9894037 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Nanhui Yu ◽

Yongpan Huang ◽

Yu Jiang ◽

Lianhong Zou ◽

Xiehong Liu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Signaling Pathway ◽

Ganoderma Lucidum ◽

Hippocampal Neurons ◽

Caspase 3 ◽

Neuronal Damage ◽

Tunel Staining ◽

Ganoderma Lucidum Triterpenoids

Alzheimer’s disease (AD) is the most common cause of dementia among senior citizen. Ganoderma lucidum triterpenoids (GLTs) have nutritional health benefits and has been shown to promote health and longevity, but a protective effect of GLTs on AD damage has not yet been reported. The objective of this research was to elucidate the phylactic effect of GLTs on AD model mice and cells and to explore its underlying mechanisms. Morris water maze (MWM) test was conducted to detect changes in the cognitive function of mice. Hematoxylin-eosin (HE) staining was applied to observe pathological changes in the hippocampus. Silver nitrate staining was applied to observe the hippocampal neuronal tangles (NFTs). Apoptosis of the hippocampal neurons in mouse brain tissue was determined by TUNEL staining. The expression levels of apoptosis-related protein Bcl2, Bax, and caspase 3/cleaved caspase 3; antioxidative protein Nrf2, NQO1, and HO1; and ROCK signaling pathway-associated proteins ROCK2 and ROCK1 were measured by western blot. In vivo experiments show that 5-month-old APP/PS1 mice appeared to have impaired acquisition of spatial learning and GLTs could reduce cognitive impairment in AD mice. Compared to normal mice, the hippocampus of APP/PS1 mouse’s brains was severely damaged, while GLTs could alleviate this symptom by inhibiting apoptosis, relieving oxidative damage, and inactivating the ROCK signaling pathway. In in vitro cell experiments, Aβ25-35 was applied to induce hippocampal neurons into AD model cells. GLTs promoted cell proliferation, facilitated superoxide dismutase (SOD) expression, and inhibited malondialdehyde (MDA) and lactic dehydrogenase (LDH) expression of neurons. Our study highlights that GLTs improve cognitive impairment, alleviate neuronal damage, and inhibit apoptosis in the hippocampus tissues and cells in AD through inhibiting the ROCK signaling pathway.

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Qiangji Decoction Alleviates Neurodegenerative Changes and Hippocampal Neuron Apoptosis Induced by D-Galactose via Regulating AMPK/SIRT1/NF-κB Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.735812 ◽

2021 ◽

Vol 12 ◽

Author(s):

Li-Ling He ◽

Yun-Cui Wang ◽

Ya-Ting Ai ◽

Ling Wang ◽

Si-Meng Gu ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Signaling Pathway ◽

Learning And Memory ◽

Hippocampal Neuron ◽

Caspase 3 ◽

Brain Aging ◽

Tunel Staining ◽

Nissl Staining ◽

Memory Impairments ◽

Neuron Apoptosis

Qiangji Decoction (QJD), a classic formula, has been widely used to treat brain aging–related neurodegenerative diseases. However, the mechanisms underlying QJD’s improvement in cognitive impairment of neurodegenerative diseases remain unclear. In this study, we employed D-galactose to establish the model of brain aging by long-term D-galactose subcutaneous injection. Next, we investigated QJD’s effect on cognitive function of the model of brain aging and the mechanisms that QJD suppressing neuroinflammation as well as improving neurodegenerative changes and hippocampal neuron apoptosis. The mice of brain aging were treated with three different dosages of QJD (12.48, 24.96, and 49.92 g/kg/d, respectively) for 4 weeks. Morris water maze was used to determine the learning and memory ability of the mice. HE staining and FJB staining were used to detect the neurodegenerative changes. Nissl staining and TUNEL staining were employed to detect the hippocampal neuron apoptosis. The contents of TNF-α, IL-1β, and IL-6 in the hippocampus were detected by using ELISA. Meanwhile, we employed immunofluorescence staining to examine the levels of GFAP and IBA1 in the hippocampus. Besides, the protein expression levels of Bcl-2, Bax, caspase-3, cleaved caspase-3, AMPKα, p-AMPKα-Thr172, SIRT1, IκBα, NF-κB p65, p-IκBα-Ser32, and p-NF-κB p65-Ser536 in the hippocampus of different groups were detected by Western blot (WB). Our findings showed that the QJD-treated groups, especially the M-QJD group, mitigated learning and memory impairments of the model of brain aging as well as the improvement of neurodegenerative changes and hippocampal neuron apoptosis. Moreover, the M-QJD markedly attenuated the neuroinflammation by regulating the AMPK/SIRT1/NF-κB signaling pathway. Taken together, QJD alleviated neurodegenerative changes and hippocampal neuron apoptosis in the model of brain aging via regulating the AMPK/SIRT1/NF-κB signaling pathway.

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Yishen Huazhuo Decoction Induces Autophagy to Promote the Clearance of Aβ1-42 in SAMP8 Mice: Mechanism Research of a Traditional Chinese Formula Against Alzheimer’s Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200604174223 ◽

2020 ◽

Vol 19 (4) ◽

pp. 276-289

Author(s):

Kai Wang ◽

Weiming Sun ◽

Jiachun Xu ◽

Qijing Qin ◽

Zhen Yu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Learning And Memory ◽

Neuronal Loss ◽

Tunel Staining ◽

Initiation Increase ◽

Apoptosis Index ◽

Significant Difference ◽

Related Proteins ◽

Samp8 Mice

Background: Studies have found that autophagy could promote the clearance of Aβ. To promote and maintain the occurrence of autophagy in Alzheimer's disease (AD) might be a potential way to reduce neuronal loss and improve the learning and memory of AD. Objective: To investigate the possible mechanisms of Yishen Huazhuo Decoction (YHD) against AD model. Methods: Forty 7-month-old male SAMP8 mice were randomly divided into model (P8) group and YHD group, 20 in each group, with 20 SAMR1 mice as control (R1) group. All mice were intragastrically administered for 4 weeks, YHD at the dosage of 6.24g/kg for YHD group, and distilled water for P8 group and R1 group. Morris water maze (MWM) test, Nissl’s staining, TEM, TUNEL staining, immunofluorescence double staining, and western blot analysis were applied to learning and memory, structure and ultrastructure of neurons, autophagosome, apoptosis index, Aβ, LAMP1, and autophagy related proteins. Results: The escape latency time of YHD group was significantly shorter on the 4th and 5th day during MWM test than those in P8 group (P=0.011, 0.008<0.05), and the number of crossing platform in YHD group increased significantly (P=0.02<0.05). Nissl’s staining showed that the number of neurons in YHD group increased significantly (P<0.0001). TEM showed in YHD group, the nucleus of neurons was slightly irregular, with slightly reduced organelles, partially fused and blurred cristae and membrane of mitochondria. The apoptosis index of YHD group showed a decreasing trend, without statistically significant difference (P=0.093>0.05), while Caspase3 expression in YHD group was significantly lower (P=0.044<0.05). YHD could promote the clearance of Aβ1-42 protein, improve the expression of Beclin-1 and p-Bcl2 proteins, reduce mTOR and p62 proteins. Conclusions: YHD could induce autophagy initiation, increase the formation of autophagosomes and autolysosome, promote the degradation of autophagy substrates, thereby to regulate autophagy, thereby to promote the clearance of Aβ1-42 to improve memory impairment in SAMP8 mice.

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Neuroprotective Effect of Danggui Shaoyao San via the Mitophagy-Apoptosis Pathway in a Rat Model of Alzheimer’s Disease

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/3995958 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Zhenyan Song ◽

Deyong Luo ◽

Yuke Wang ◽

Yushan Zheng ◽

Peiying Chen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Learning And Memory ◽

Neuronal Apoptosis ◽

Terminal Deoxynucleotidyl Transferase ◽

Morris Water Maze Test ◽

High Dose ◽

Sham Operation ◽

Apoptosis Pathway ◽

Model Of Alzheimer’S Disease

Alzheimer’s disease (AD) is a serious neurodegenerative disease. While the main pathological characteristic of AD is widely believed to be the accumulation of amyloid-beta (Aβ) in neurons around neurofibrillary plaques, the molecular mechanism of pathological changes is not clear. Traditional Chinese medicine offers many treatments for AD. Among these, Danggui Shaoyao San (DSS) is a classic prescription. In this study, an AD model was established by injecting Aβ 1–42 into the brains of rats, which were then treated with different concentrations of Danggui Shaoyao San (sham operation; model; and Danggui Shaoyao San high-dose, medium-dose, and low-dose intervention groups). The Morris water maze test was used to assess the learning and memory abilities of the animals in each group. Nissl staining was used to detect neurons. Mitophagy was evaluated by transmission electron microscopy and immunofluorescence colocalization. Apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The expression levels of autophagy- and apoptosis-related proteins were measured by western blot. Compared to the model group, the groups of AD rats administered medium and high doses of Danggui Shaoyao San showed significantly increased learning and memory abilities ( P < 0.05 ), as well as significantly increased autophagosomes in the hippocampus. Moreover, the expression of PTEN-induced kinase 1 (PINK1), Parkin, and microtubule-associated protein light chain 3 (LC3-I/LC3-II) was increased, while that of p62 was significantly decreased ( P < 0.05 ). The neuronal apoptosis rate was also significantly decreased, the Bcl-2/Bax ratio was significantly increased, and the cleaved caspase-3 protein expression was significantly decreased ( P < 0.05 ). Therefore, Danggui Shaoyao San inhibited neuronal apoptosis in AD rats via a mechanism that may be related to the activation of the PINK1-Parkin-mediated mitophagy signaling pathway.

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miR-590-3 and SP1 Promote Neuronal Apoptosis in Patients with Alzheimer’s Disease via AMPK Signaling Pathway

Contrast Media & Molecular Imaging ◽

10.1155/2021/6010362 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Yanqun Cao ◽

Xiangxiang Tan ◽

Quzhe Lu ◽

Kai Huang ◽

Xiaoer Tang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Signaling Pathway ◽

Neuronal Apoptosis ◽

Differential Expression Analysis ◽

Enrichment Analysis ◽

Hub Gene ◽

Pathogenic Mechanisms ◽

Ampk Signaling ◽

Regulatory Effects

Alzheimer’s disease (AD) is a progressive neurological degenerative illness with a hidden onset. Its pathogenesis is complicated, although with molecular biology research on cancer and targeted research on pathogenic mechanisms, good progress has not yet been made. Therefore, this work built a multifactor-driven neuronal apoptosis dysfunction module for the purpose of probing its underlying pathogenic mechanisms. We performed differential expression analysis, coexpression analysis, enrichment analysis, and hypergeometric tests to calculate the underlying regulatory effects of multifactors on the modules by the way of the whole gene expression profile of AD and identify a series of ncRNA (miR-320a) and TF (NFKB1). Additionally, we screened 10 modules corresponding to the Hub gene, which tend to regulate the physiological progress of inflammation, regulation of autophagy, cerebral cortex neuron differentiation, glial cell apoptotic, and so on. Meanwhile, Alzheimer’s disease is triggered by signaling pathways such as the MPK signaling pathway. In this study, a dysfunction module is utilized to verify that miR-590-3 and SP1 motility factors can regulate neurons in Alzheimer’s disease through the MPK signaling pathway, not only providing new insights into the pathogenesis of Alzheimer’s disease but also laying a solid theoretical foundation for the biologists to further cure Alzheimer’s disease.

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