Regulation of BACE1 expression after injury is linked to the p75 neurotrophin receptor

Saadipour, Khalil; Tiberi, Alexia; Lombardo, Sylvia; Grajales, Elena; Montroull, Laura Ester; Mañucat-Tan, Noralyn B.; LaFrancois, John; Cammer, Michael; Mathews, Paul M.; Scharfman, Helen E.; Liao, Francesca‐Fang; Friedman, Wilma J.; Zhou, Xin‐Fu; Tesco, Giueseppina; Chao, Moses V.

doi:10.1016/j.mcn.2019.103395

Cited by 7 publications

(5 citation statements)

References 104 publications

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“…Furthermore, we noticed that the JNK inhibitor (SP600125) dose-dependently upregulated ADAM10 expression and downregulated BACE1 and PS-1 expression in N2a-APPswe (Fig. S4), which is consistent with previous research demonstrating that the JNK pathway is directly involved in the regulation of APP secretase expression [34][35][36][37][38]. VPA and WT161 inhibited JNK phosphorylation and downregulated JNK3 and c-Jun expression levels (Fig.…”

Section: Regulation Of App Secretase Expression By Hdac1 and Hdac6 Is...supporting

confidence: 90%

“…Previous studies have demonstrated that HDAC6 overexpression activated JNK and enhanced c-Jun phosphorylation [72], while HDAC6 inhibition resulted in a striking reduction in JNK and c-Jun phosphorylation [73,74]. On the other hand, the expression of BACE1 (β-secretase) and PSEN1 (γsecretase) can be regulated by the JNK/c-Jun pathway [34][35][36][37][38]. In the current study, we showed that JNK phosphorylation was markedly increased in the cerebral cortex of AD mice (Fig.…”

Section: Vpa and Wt161 Reduce Aβ42 Deposition In The Brains Of Ad Mic...mentioning

confidence: 99%

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Histone deacetylase inhibitors VPA and WT161 ameliorate the pathological features and cognitive impairments of the Alzheimer's disease mouse model by regulating the expression of App secretases

Zhang

Wang

et al. 2023

Preprint

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Background Alzheimer's disease (AD) is a degenerative neurological disorder. Recent studies have indicated that histone deacetylases (HDACs) are among the most prominent epigenetic therapy targets and that HDAC inhibitors have therapeutic effects on AD. Here, we identified sodium valproate (VPA), a pan-HDAC inhibitor, and WT161, a novel HDAC6 selective inhibitor, as potential therapeutic agents for AD. Underlying molecular mechanisms were investigated. Methods A cellular model, N2a-APPswe, was established via lentiviral infection, and the APPswe/PSEN1dE9 transgenic mouse model was employed in the study. Western blotting, immunohistochemical staining, thioflavin-S staining, and ELISA were applied to detect protein expression in cells, tissues, or serum. RNA interference was utilized to knockdown the expression of specific genes in cells. The cognitive function of mice was assessed via the nest-building test, novel object recognition test, and Morris water maze test. Results Previous studies have focused mainly on the impact of HDAC inhibitors on histone deacetylase activity. Our study discovered that VPA and WT161 can downregulate the expression of multiple HDACs, such as HDAC1 and HDAC6, in both AD cell and mouse models. Moreover, they also affect the expression of APP and APP secretases (BACE1, PSEN1, ADAM10). RNA interference and subsequent vitamin C induction further confirmed that the expression of APP and APP secretases is indeed regulated by HDAC1 and HDAC6, with the JNK pathway being the intermediate link in this regulatory process. Through the above pathways, VPA and WT161 effectively reduced Aβ deposition in both AD cell and mouse models and significantly improved cognitive function in AD mice. Conclusions In general, we have discovered that the HDAC6-JNK-APP secretases cascade is an important pathway for VPA and WT161 to exert their therapeutic effects on AD. Investigations into the safety and efficacy of VPA and WT161 were also conducted, providing essential preclinical evidence for assessing these two epigenetic drugs for the treatment of AD.

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Section: Regulation Of App Secretase Expression By Hdac1 and Hdac6 Is...supporting

confidence: 90%

Section: Vpa and Wt161 Reduce Aβ42 Deposition In The Brains Of Ad Mic...mentioning

confidence: 99%

Histone deacetylase inhibitors VPA and WT161 ameliorate the pathological features and cognitive impairments of the Alzheimer's disease mouse model by regulating the expression of App secretases

Zhang

Wang

et al. 2023

Preprint

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“…This phenomenon likely helps to explain the well-known association between cerebrovascular disease and stroke and AD risk [ 110 ]. The MAP kinase JNK, which as we have seen, is also activated by oxidative stress, also up-regulates BACE1 expression at the transcriptional level; the basis for this effect remains unknown [ 111 , 112 ]. On the other hand, enhanced levels of cGMP suppress BACE1 expression [ 113 , 114 ].…”

Section: A Comprehensive Antioxidant Strategy May Aid Prevention Omentioning

confidence: 99%

A Fundamental Role for Oxidants and Intracellular Calcium Signals in Alzheimer’s Pathogenesis—And How a Comprehensive Antioxidant Strategy May Aid Prevention of This Disorder

McCarty

DiNicolantonio

Lerner

2021

IJMS

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Oxidative stress and increased cytoplasmic calcium are key mediators of the detrimental effects on neuronal function and survival in Alzheimer’s disease (AD). Pathways whereby these perturbations arise, and then prevent dendritic spine formation, promote tau hyperphosphorylation, further amplify amyloid β generation, and induce neuronal apoptosis, are described. A comprehensive program of nutraceutical supplementation, comprised of the NADPH oxidase inhibitor phycocyanobilin, phase two inducers, the mitochondrial antioxidant astaxanthin, and the glutathione precursor N-acetylcysteine, may have important potential for antagonizing the toxic effects of amyloid β on neurons and thereby aiding prevention of AD. Moreover, nutraceutical antioxidant strategies may oppose the adverse impact of amyloid β oligomers on astrocyte clearance of glutamate, and on the ability of brain capillaries to export amyloid β monomers/oligomers from the brain. Antioxidants, docosahexaenoic acid (DHA), and vitamin D, have potential for suppressing microglial production of interleukin-1β, which potentiates the neurotoxicity of amyloid β. Epidemiology suggests that a health-promoting lifestyle, incorporating a prudent diet, regular vigorous exercise, and other feasible measures, can cut the high risk for AD among the elderly by up to 60%. Conceivably, complementing such lifestyle measures with long-term adherence to the sort of nutraceutical regimen outlined here may drive down risk for AD even further.

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“…In the adult CNS, the expression of p75NTR in vivo can be modulated by injury, stimuli, and in various CNS pathologies. For instance, increased p75NTR expression is observed in injured cerebral cortex (Saadipour et al., 2019) or spinal cord (Beattie et al., 2002), or in the hippocampus after seizure (Volosin et al., 2008; VonDran et al., 2014). Anatomically specific up‐regulation of p75NTR has also been described in neurodegenerative diseases such as Alzheimer's (Hu, Zhang, et al., 2002) and Huntington's diseases (Suelves et al., 2018), or during alcohol withdrawal (Darcq et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Neuronal apoptosis induced by morphine withdrawal is mediated by the p75 neurotrophin receptor

Asuni

Speidell

Mocchetti

2021

Journal of Neurochemistry

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Morphine withdrawal evokes neuronal apoptosis through mechanisms that are still under investigation. We have previously shown that morphine withdrawal increases the levels of pro-brain-derived neurotrophic factor (BDNF), a proneurotrophin that promotes neuronal apoptosis through the binding and activation of the panneurotrophin receptor p75 (p75NTR). In this work, we sought to examine whether morphine withdrawal increases p75NTR-driven signaling events. We employed a repeated morphine treatment-withdrawal paradigm in order to investigate biochemical and histological indicators of p75NTR-mediated neuronal apoptosis in mice. We found that repeated cycles of spontaneous morphine withdrawal promote an accumulation of p75NTR in hippocampal synapses. At the same time, TrkB, the receptor that is crucial for BDNF-mediated synaptic plasticity in the hippocampus, was decreased, suggesting that withdrawal alters the neurotrophin receptor environment to favor synaptic remodeling and apoptosis. Indeed, we observed evidence of neuronal apoptosis in the hippocampus, including activation of c-Jun N-terminal kinase (JNK) and increased active caspase-3. These effects were not seen in saline or morphinetreated mice which had not undergone withdrawal. To determine whether p75NTR was necessary in promoting these outcomes, we repeated these experiments in p75NTR heterozygous mice. The lack of one p75NTR allele was sufficient to prevent the increases in phosphorylated JNK and active caspase-3. Our results suggest that p75NTR participates in the neurotoxic and proinflammatory state evoked by morphine withdrawal. Because p75NTR activation negatively influences synaptic repair and promotes cell death, preventing opioid withdrawal is crucial for reducing neurotoxic mechanisms accompanying opioid use disorders.

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Regulation of BACE1 expression after injury is linked to the p75 neurotrophin receptor

Cited by 7 publications

References 104 publications

Histone deacetylase inhibitors VPA and WT161 ameliorate the pathological features and cognitive impairments of the Alzheimer's disease mouse model by regulating the expression of App secretases

Histone deacetylase inhibitors VPA and WT161 ameliorate the pathological features and cognitive impairments of the Alzheimer's disease mouse model by regulating the expression of App secretases

A Fundamental Role for Oxidants and Intracellular Calcium Signals in Alzheimer’s Pathogenesis—And How a Comprehensive Antioxidant Strategy May Aid Prevention of This Disorder

Neuronal apoptosis induced by morphine withdrawal is mediated by the p75 neurotrophin receptor

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