Death-associated protein kinase 1 as a therapeutic target for Alzheimer's disease

Zhang, Tao; Kim, Byeong Mo; Lee, Tae Ho

doi:10.1186/s40035-023-00395-5

Cited by 3 publications

(1 citation statement)

References 237 publications

(371 reference statements)

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“…Apoptosis, a well-known form of programmed cell death, acts as an essential physiological mechanism restricting uncontrolled cell population growth to maintain tissue stability or eliminate potentially harmful cells, such as those with DNA damage [170]. However, inappropriate positioning of this balancing function may contribute to normal cell growth/proliferation or autoimmune disorders and promote [171][172][173][174].…”

Section: Bm Oxidative Stress Mithocondrial Dysfunction and Apoptosismentioning

confidence: 99%

Investigating the Neuroprotective and Cognitive-Enhancing Effects of Bacopa monnieri: A Systematic Review Focused on Inflammation, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis

Valotto Neto,

Reverete de Araujo,

Moretti Junior

et al. 2024

Antioxidants

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The aging of the global population has increased the prevalence of neurodegenerative conditions. Bacopa monnieri (BM), an herb with active compounds, such as bacosides A and B, betulinic acid, loliolide, asiatic acid, and quercetin, demonstrates the potential for brain health. Limited research has been conducted on the therapeutic applications of BM in neurodegenerative conditions. This systematic review aims to project BM’s beneficial role in brain disorders. BM has anti-apoptotic and antioxidant actions and can repair damaged neurons, stimulate kinase activity, restore synaptic function, improve nerve transmission, and increase neuroprotection. The included twenty-two clinical trials demonstrated that BM can reduce Nuclear Factor-κB phosphorylation, improve emotional function, cognitive functions, anhedonia, hyperactivity, sleep routine, depression, attention deficit, learning problems, memory retention, impulsivity, and psychiatric problems. Moreover, BM can reduce the levels of pro-inflammatory biomarkers and oxidative stress. Here, we highlight that BM provides notable therapeutic benefits and can serve as a complementary approach for the care of patients with neurodegenerative conditions associated with brain disorders. This review adds to the growing interest in natural products and their potential therapeutic applications by improving our understanding of the mechanisms underlying cognitive function and neurodegeneration and informing the development of new therapeutic strategies for neurodegenerative diseases.

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Section: Bm Oxidative Stress Mithocondrial Dysfunction and Apoptosismentioning

confidence: 99%

Investigating the Neuroprotective and Cognitive-Enhancing Effects of Bacopa monnieri: A Systematic Review Focused on Inflammation, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis

Valotto Neto,

Reverete de Araujo,

Moretti Junior

et al. 2024

Antioxidants

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Identifying Proteomic Prognostic Markers for Alzheimer’s Disease with Survival Machine Learning: the Framingham Heart Study

Leng,

Ding,

Ang

et al. 2024

Preprint

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Background: Protein abundance levels, sensitive to both physiological changes and external interventions, are useful for assessing the Alzheimer's disease (AD) risk and treatment efficacy. However, identifying proteomic prognostic markers for AD is challenging by their high dimensionality and inherent correlations. Methods: Our study analyzed 1128 plasma proteins, measured by the SOMAscan platform, from 858 participants 55 years and older (mean age 63 years, 52.9% women) of the Framingham Heart Study (FHS) Offspring cohort. We conducted regression analysis and machine learning models, including LASSO-based Cox proportional hazard regression model (LASSO) and generalized boosted regression model (GBM), to identify protein prognostic markers. These markers were used to construct a weighted proteomic composite score, the AD prediction performance of which was assessed using time-dependent area under the curve (AUC). The association between the composite score and memory domain was examined in 339 (of the 858) participants with available memory scores, and in an independent group of 430 participants younger than 55 years (mean age 46, 56.7% women). Results: Over a mean follow-up of 20 years, 132 (15.4%) participants developed AD. After adjusting for baseline age, sex, education, and APOE ε4+ status, regression models identified 309 proteins (P ≤ 0.2). After applying machine learning methods, nine of these proteins were selected to develop a composite score. This score improved AD prediction beyond the factors of age, sex, education, and APOE ε4+ status across 15 to 25 years of follow-up, achieving its peak AUC of 0.84 in the LASSO model at the 22-year follow-up. It also showed a consistent negative association with memory scores in 339 participants (beta = -0.061, P = 0.046), 430 independent participants (beta = -0.060, P = 0.018), and the pooled 769 samples (beta = -0.058, P = 0.003). Conclusion: These findings highlight the utility of proteomic markers in improving AD prediction and emphasize the complex pathology of AD. The composite score may aid early AD detection and efficacy monitoring, warranting further validation in diverse populations.

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6-Shogaol Alleviates Neuronal Cell Excessive Autophagy and Calcium Overload in Cerebral Ischemia-Reperfusion Injury via Modulating miRNA-26a-5p/DAPK1 Signaling Axis

Rao,

Li,

Zhu

et al. 2024

Preprint

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Objectives：Clarifying the Potential of 6-shogaol (6-SH) in Reducing Excessive Autophagy and Calcium Overload in Neuronal Cells during Cerebral Ischemia-Reperfusion Injury via Regulation of the miRNA-26a-5p/DAPK1 Signaling Axis. Methods：In this study, oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 cells was used to create an in vitro model of cerebral ischemia-reperfusion Injury (CIRI). The following groups of cells were created：normal control (NC), model (OGD/R), model+6-shogaol treatment (6-SH+OGD/R), model+6-shogaol treatment+miRNA-26a-5p inhibitor negative control (inhibitorNC+6-SH+OGD/R) and model+6-shogaol treatment+miRNA-26a-5p inhibitor (inhibitor+6-SH+OGD/R).Cell morphology was observed under an inverted microscope, cell viability was assessed using the CCK8 assay, neuronal ultrastructure was examined via transmission electron microscopy, intracellular calcium ion concentration was measured using flow cytometry, and the fluorescence intensity of LC3 and Beclin1 was detected by immunofluorescence. Western blotting was performed to evaluate the expression levels of proteins related to autophagy and calcium ion channels, and Quantitative real-time PCR（RT-qPCR）was conducted to measure the gene expression levels of miRNA-26a-5p and DAPK1. The Sprague Dawley rat CIRI model was established in vivo utilizing the suture-occluded approach. Three groups were used: sham, model (I/R), and model+6-shogaol therapy (6-SH+I/R).TTC staining was used to observe cerebral infarction, HE staining to assess brain tissue pathology, immunofluorescence to detect the fluorescence intensity of LC3 and Beclin1, Western blotting to measure protein expression levels related to autophagy and calcium ion channels, and RT-qPCR to determine gene expression levels of miRNA-26a-5p and DAPK1. Additionally, molecular docking techniques were employed to validate the spontaneous binding of 6-SH to miRNA-26a-5p, and dual luciferase reporter gene assays were conducted to confirm the targeting relationship between miRNA-26a-5p and DAPK1. Results：The molecular docking study showed that 6-SH spontaneously bound to miRNA-26a-5p, and the dual luciferase reporter gene assay confirmed that miRNA-26a-5p can target and regulate DAPK1. According to the outcomes of in vitro experiments, 6-SH dramatically improved HT22 cell viability during OGD/R, reduced pathological damage, elevated miRNA-26a-5p, downregulated DAPK1, and reduced excessive autophagy and calcium overload. The ability of 6-SH to downregulate DAPK1-mediated neuronal excessive autophagy and calcium overload was greatly diminished when miRNA-26a-5p expression was blocked. Results of in vivo experiments showed that 6-SH markedly decreased the size of the cerebral infarct area in SD rats following MCAO/R, mitigated excessive autophagy and calcium overload, relieved pathological damage, and partially recovered neuronal function. It also elevated miRNA-26a-5p and downregulated DAPK1. Conclusion：6-SH modulates miRNA-26a-5p to target and inhibit DAPK1, thereby attenuating the neurons excessive autophagy and calcium overload caused by cerebral ischemia-reperfusion Injury.

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Death-associated protein kinase 1 as a therapeutic target for Alzheimer's disease

Cited by 3 publications

References 237 publications

Investigating the Neuroprotective and Cognitive-Enhancing Effects of Bacopa monnieri: A Systematic Review Focused on Inflammation, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis

Investigating the Neuroprotective and Cognitive-Enhancing Effects of Bacopa monnieri: A Systematic Review Focused on Inflammation, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis

Identifying Proteomic Prognostic Markers for Alzheimer’s Disease with Survival Machine Learning: the Framingham Heart Study

6-Shogaol Alleviates Neuronal Cell Excessive Autophagy and Calcium Overload in Cerebral Ischemia-Reperfusion Injury via Modulating miRNA-26a-5p/DAPK1 Signaling Axis

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