Activation of PKA/SIRT1 signaling pathway by photobiomodulation therapy reduces Aβ levels in Alzheimer's disease models

Zhang, Zhan; Shen, Qi; Wu, Xiaolei; Zhang, Di; Xing, Da

doi:10.1111/acel.13054

Cited by 107 publications

(139 citation statements)

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“…Aβ, the main component of amyloid plaques, was shown to play a crucial role in the development of AD pathologies [51]. Recent study reported that excessive Aβ generation and deposition could change cell metabolism and trigger Tau hyperphosphorylation, synaptic dysfunction, oxidative stress and neuroin ammation, further leading to progressive recognition dysfunction [1]. Aβ is produced by sequential cleavage of β-and γ-secretases at the C terminus of amyloid precursor protein (APP) [51].…”

Section: Discussionmentioning

confidence: 99%

“…Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive decline. Clinically, the main pathological features of AD are the extracellular accumulation of senile plaques comprised of amyloid-beta (Aβ) peptides, intracellular neuro brillary tangle composed of highly phosphorylated Tau (p-Tau) and neurodegenerative changes accompanied by synaptic dysfunction and neuronal damage [1]. Currently, the pathogenesis of AD is still not completely understood.…”

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confidence: 99%

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Ginsenoside Rg1 alleviates Aβ deposition and neuronal damage by inhibiting NLRP1 inflammasome activation in APP/PS1 mice

Zhang¹,

Su²,

Sun³

et al. 2020

Preprint

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Background: Oxidative stress and neuroinflammation play important roles in the whole pathogenesis of Alzheimer's disease (AD). NADPH oxidase 2 (NOX2) is an important enzyme that is responsible for ROS generation in many neurodegenerative diseases. The nucleotide-binding oligomerization domain (NOD)-like receptor protein 1 (NLRP1) inflammasome is responsible for the formation of pro-inflammatory molecules in neurons. However, it is still unclear whether inhibition of NOX2 and NLRP1 inflammasome decreases amyloid-beta (Aβ) generation and deposition in APP/PS1 mice. Ginsenoside Rg1 (Rg1) is an active component in ginseng, and maybe a potential agent for neurodegenerative diseases. In this study, we investigated the effects and mechanisms of Rg1 treatment on cognitive performance, neuronal damage, Aβ deposition and NOX2-NLRP1 inflammasome activation in APP/PS1 mice.Methods: WT and APP/PS1 mice were used in the experiment from 6 months (M) old to 9M old, and 6M APP/PS1 mice were used as pre-treatment controls. The open field test (OFT) and Morris water maze (MWM) were used to detect behavioral change and cognitive function. The H&E and Nissl staining were used to assess neuronal damage. We further examined PSD95 expression, Aβ generation and deposition, Tau and p-Tau expression, NOX2-mediated ROS generation and NLRP1 inflammasome activation by using immunofluorescence, western blot analysis, and real time q-PCR.Results: Rg1 treatment for 12 weeks alleviated learning and memory impairments and neuronal damage, decreased p-Tau level, APP expression and Aβ deposition in APP/PS1 mice. Meanwhile, Rg1 treatment significantly decreased the levels of ROS and IL-1β, and reduced the expressions of NOX2 and NLRP1 inflammasome in the brain cortex and hippocampus in APP/PS1 mice. Furthermore, apocynin (a NOX inhibitor) and NLRP1-siRNA treatment also alleviated cognitive impairments, neuronal damage and Aβ deposition, and reduced the expression of NLRP1 inflammasome in brain cortex and hippocampus in APP/PS1 mice.Conclusions: Rg1 treatment could alleviate learning and memory impairment, neuronal damage, and reduce Aβ generation and deposition by inhibiting NLRP1 inflammasome activation in APP/PS1 mice.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Ginsenoside Rg1 alleviates Aβ deposition and neuronal damage by inhibiting NLRP1 inflammasome activation in APP/PS1 mice

Zhang¹,

Su²,

Sun³

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…In addition to activating CREB [74][75][76][77][78][79], which induces PGC1␣ transcription [83,91], both cAMP/PKA and cGMP/PKG signaling activate SIRT1 [94-96, 98, 104-110]. SIRT1 exerts multiple beneficial effects in AD, including downregulating pro-amyloidogenic ␤-secretase (BACE1) and upregulating anti-amyloidogenic A Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) [106], as well as deacetylating and thereby post-translationally activating PGC1␣ [97,[111][112][113][114][115][116][117][118].…”

Section: Camp Cgmp Sirt1 and Pgc1αmentioning

confidence: 99%

Phosphodiesterase Inhibitors for Alzheimer’s Disease: A Systematic Review of Clinical Trials and Epidemiology with a Mechanistic Rationale

Sanders

Rajagopal²

2020

Journal of Alzheimer's Disease Reports

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Background: Preclinical studies, clinical trials, and reviews suggest increasing 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) with phosphodiesterase inhibitors is disease-modifying in Alzheimer's disease (AD). cAMP/protein kinase A (PKA) and cGMP/protein kinase G (PKG) signaling are disrupted in AD. cAMP/PKA and cGMP/PKG activate cAMP response element binding protein (CREB). CREB binds mitochondrial and nuclear DNA, inducing synaptogenesis, memory, and neuronal survival gene (e.g., brain-derived neurotrophic factor) and peroxisome proliferator-activated receptor-␥ coactivator-1␣ (PGC1␣). cAMP/PKA and cGMP/PKG activate Sirtuin-1, which activates PGC1␣. PGC1␣ induces mitochondrial biogenesis and antioxidant genes (e.g.,Nrf2) and represses BACE1. cAMP and cGMP inhibit BACE1-inducing NFκB and tau-phosphorylating GSK3␤. Objective and Methods: We review efficacy-testing clinical trials, epidemiology, and meta-analyses to critically investigate whether phosphodiesteraseinhibitors prevent or treat AD. Results: Caffeine and cilostazol may lower AD risk. Denbufylline and sildenafil clinical trials are promising but preliminary and inconclusive. PF-04447943 and BI 409,306 are ineffective. Vinpocetine, cilostazol, and nicergoline trials are mixed. Deprenyl/selegiline trials show only short-term benefits. Broad-spectrum phosphodiesterase inhibitor propentofylline has been shown in five phase III trials to improve cognition, dementia severity, activities of daily living, and global assessment in mild-to-moderate AD patients on multiple scales, including the ADAS-Cogand the CIBIC-Plus in an 18-month phase III clinical trial. However, two books claimed based on a MedScape article an 18-month phase III trial failed, so propentofylline was discontinued. Now, propentofylline is used to treat canine cognitive dysfunction, which, like AD, involves age-associated wild-type A␤ deposition. Conclusion: Phosphodiesterase inhibitors may prevent and treat AD.

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“…PBM is known to activate multiple pathways such as ERK/ CREB (Meng et al 2013;Gu et al 2017;Heo et al 2019), cAMP/PKA/SIRT1 (Zhang et al 2020), PKC (Zhang et al 2008), Src/Syk/PI3K/Akt (Song et al 2012), and Akt/ GSK3β/β-catenin (Liang et al 2012), involved in various molecular networks in the cellular system. From the data, three significant paths through which the above-mentioned signaling cascades might be activated after PBM by CCO stimulation could be identified as follows:…”

Section: Mitochondrial Stimulation Triggers Several Signaling Pathwaysmentioning

confidence: 99%

“…Drp1-S616 (serine 616) phosphorylation (fission promoting) was repressed, and Drp1-S637 (serine 637) phosphorylation (fusion promoting) was supported, Drp1-Fis1/Mff interactions were prevented, and expression and localization of the other fission proteins OPA1 and MFN1 were attenuated by irradiation, allowing the preservation of mitochondrial integrity (Wong-Riley et al 2005;De Taboada et al 2011;Purushothuman et al 2014;Huang et al 2014;Lu et al 2017;Zhang et al 2020). SIRT1, activated by PBM (Zhang et al 2020), is also previously known to support mitochondrial biogenesis (Xu et al 2018;Zhou et al 2018). Hence, improvement in mitochondrial health through PBM therapy could also be through this mechanism.…”

Section: Antioxidant Capacity and Mitochondrial Preservationmentioning

confidence: 99%

The Molecular Mechanisms of Action of Photobiomodulation Against Neurodegenerative Diseases: A Systematic Review

2020

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Neurodegenerative diseases might be slow but relentless, as we continue to fail in treating or delaying their progression. Given the complexity in the pathogenesis of these diseases, a broad-acting approach like photobiomodulation can prove promising. Photobiomodulation (PBM) uses red and infrared light for therapeutic benefits, working by stimulating growth and proliferation. The implications of photobiomodulation have been studied in several neurodegenerative disease models. It has been shown to improve cell survival, decrease apoptosis, alleviate oxidative stress, suppress inflammation, and rescue mitochondrial function. In in vivo models, it has reportedly preserved motor and cognitive skills. Beyond mitochondrial stimulation, the molecular mechanisms by which photobiomodulation protects against neurodegeneration have not been very well studied. This review has systematically been undertaken to study the effects of photobiomodulation at a molecular level and identify the different biochemical pathways and molecular changes in the process. The data showed the involvement of pathways like extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK), and protein kinase B (Akt). In addition, the expression of several genes and proteins playing different roles in the disease mechanisms was found to be influenced by PBM, such as neurotrophic factors and secretases. Studying the literature indicated that PBM can be translated to a potential therapeutic tool, acting through a spectrum of mechanisms that work together to decelerate disease progression in the organism, which is difficult to achieve through pharmacological interventions.

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Activation of PKA/SIRT1 signaling pathway by photobiomodulation therapy reduces Aβ levels in Alzheimer's disease models

Cited by 107 publications

References 41 publications

Ginsenoside Rg1 alleviates Aβ deposition and neuronal damage by inhibiting NLRP1 inflammasome activation in APP/PS1 mice

Ginsenoside Rg1 alleviates Aβ deposition and neuronal damage by inhibiting NLRP1 inflammasome activation in APP/PS1 mice

Phosphodiesterase Inhibitors for Alzheimer’s Disease: A Systematic Review of Clinical Trials and Epidemiology with a Mechanistic Rationale

The Molecular Mechanisms of Action of Photobiomodulation Against Neurodegenerative Diseases: A Systematic Review

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