The apolipoprotein E ε4 (APOE4) allele is a major genetic risk factor for Alzheimer's disease (AD), and its protein product, ApoE4, exerts its deleterious effects mainly by influencing amyloid-β (Aβ) ...and Tau (neurofibrillary tangles, NFTs) deposition in the brain. However, the molecular mechanism dictating its expression during ageing and in AD remains incompletely clear. Here we show that C/EBPβ acts as a pivotal transcription factor for APOE and mediates its mRNA levels in an age-dependent manner. C/EBPβ binds the promoter of APOE and escalates its expression in the brain. Knockout of C/EBPβ in AD mouse models diminishes ApoE expression and Aβ pathologies, whereas overexpression of C/EBPβ accelerates AD pathologies, which can be attenuated by anti-ApoE monoclonal antibody or deletion of ApoE via its specific shRNA. Remarkably, C/EBPβ selectively promotes more ApoE4 expression versus ApoE3 in human neurons, correlating with higher activation of C/EBPβ in human AD brains with ApoE4/4 compared to ApoE3/3. Therefore, our data support that C/EBPβ is a crucial transcription factor for temporally regulating APOE gene expression, modulating ApoE4's role in AD pathogenesis.
Intraneuronal accumulation of wild‐type tau plays a key role in Alzheimer's disease, while the mechanisms underlying tauopathy and memory impairment remain unclear. Here, we report that ...overexpressing full‐length wild‐type human tau (hTau) in mouse hippocampus induces learning and memory deficits with remarkably reduced levels of multiple synapse‐ and memory‐associated proteins. Overexpressing hTau inhibits the activity of protein kinase A (PKA) and decreases the phosphorylation level of cAMP‐response element binding protein (CREB), GluA1, and TrkB with reduced BDNF mRNA and protein levels both in vitro and in vivo. Simultaneously, overexpressing hTau increased PKAR2α (an inhibitory subunit of PKA) in nuclear fraction and inactivated proteasome activity. With an increased association of PKAR2α with PA28γ (a nuclear proteasome activator), the formation of PA28γ‐20S proteasome complex remarkably decreased in the nuclear fraction, followed by a reduced interaction of PKAR2α with 20S proteasome. Both downregulating PKAR2α by shRNA and upregulating proteasome by expressing PA28γ rescued hTau‐induced PKA inhibition and CREB dephosphorylation, and upregulating PKA improved hTau‐induced cognitive deficits in mice. Together, these data reveal that intracellular tau accumulation induces synapse and memory impairments by inhibiting PKA/CREB/BDNF/TrkB and PKA/GluA1 signaling, and deficit of PA28γ‐20S proteasome complex formation contributes to PKAR2α elevation and PKA inhibition.
Tau overexpressed decreases the formation of PA28γ‐20S proteasome complex by increasing the association of PKAR2α (an inhibitory subunit of PKA) with PA28γ (a nuclear proteasome activator), which leads to reduced PKAR2α degradation in ubiquitin‐independent proteasome degradation pathway mediated by PA28γ‐20S proteasome complex. PKA inhibition by elevated PKAR2α in nuclear fraction finally induces synapse impairments and memory deficits by inhibiting PKA/CREB/BDNF/TrkB and PKA/GluA1 signaling.
Delta-secretase cleaves both APP and Tau to mediate the formation of amyloid plaques and neurofibrillary tangle in Alzheimer's disease (AD). However, how aging contributes to an increase in ...delta-secretase expression and AD pathologies remains unclear. Here we show that a CCAAT-enhancer-binding protein (C/EBPβ), an inflammation-regulated transcription factor, acts as a key age-dependent effector elevating both delta-secretase (AEP) and inflammatory cytokines expression in mediating pathogenesis in AD mouse models. We find that C/EBPβ regulates delta-secretase transcription and protein levels in an age-dependent manner. Overexpression of C/EBPβ in young 3xTg mice increases delta-secretase and accelerates the pathological features including cognitive dysfunctions, which is abolished by inactive AEP C189S. Conversely, depletion of C/EBPβ from old 3xTg or 5XFAD mice diminishes delta-secretase and reduces AD pathologies, leading to amelioration of cognitive impairment in these AD mouse models. Thus, our findings support that C/EBPβ plays a pivotal role in AD pathogenesis via increasing delta-secretase expression.
Intracellular accumulating of the hyperphosphorylated tau plays a pivotal role in neurodegeneration of Alzheimer disease (AD), but the mechanisms underlying the gradually aggravated tau ...hyperphosphorylation remain elusive. Here, we show that increasing intracellular tau could upregulate mRNA and protein levels of TRPC1 (transient receptor potential channel 1) with an activated store‐operated calcium entry (SOCE), an increased intraneuronal steady‐state Ca2+i, an enhanced endoplasmic reticulum (ER) stress, an imbalanced protein kinases and phosphatase, and an aggravated tauopathy. Furthermore, overexpressing TRPC1 induced ER stress, kinases‐phosphatase imbalance, tau hyperphosphorylation and cognitive deficits in cultured neurons and mice, while pharmacological inhibiting or knockout TRPC1 attenuated the hTau‐induced deregulations in SOCE, ER homeostasis, kinases‐phosphatase balance, and tau phosphorylation level with improved synaptic and cognitive functions. Finally, an increased CCAAT‐enhancer‐binding protein (C/EBPβ) activity was observed in hTau‐overexpressing cells and the hippocampus of the AD patients, while downregulating C/EBPβ by siRNA abolished the hTau‐induced TRPC1 upregulation. These data reveal that increasing intracellular tau can upregulate C/EBPβ‐TRPC1‐SOCE signaling and thus disrupt phosphorylating system, which together aggravates tau pathologies leading to a chronic neurodegeneration.
Increasing tau accumulation leads to hyperactivated SOCE, ER stress, and kinases‐phosphatase imbalance through C/EBPβ‐mediated upregulation of TRPC1, which thereby induces persistent and aggravated tau hyperphosphorylation and cognitive deficits in cultured neurons or mice, while pharmacological inhibiting or knockout TRPC1 attenuated the hTau‐induced dysregulations in SOCE, ER homeostasis, kinases‐phosphatase balance, and tau phosphorylation level with improved synaptic and cognitive functions.
Histone lysine specific demethylase 1 (LSD1) was reported to be overexpressed in several human cancers and recognized as a promising anticancer drug target. In the current study, we designed and ...synthesized a novel series of pyrimidine–thiourea hybrids and evaluated their potential LSD1 inhibitory effect. One of the compounds, 6b, containing a terminal alkyne appendage, was shown to be the most potent and selective LSD1 inhibitor in vitro and exhibited strong cytotoxicity against LSD1 overexpressed gastric cancer cells. Compound 6b also showed marked inhibition of cell migration and invasion as well as significant in vivo tumor suppressing and antimetastasis role, without significant side effects by oral administration. Our findings indicate that the pyrimidine–thiourea-based LSD1 inactivator may serve as a leading compound targeting LSD1 overexpressed cancers.
This research investigated the impacts of model prediction on the optimization of hybrid energy systems using a system consisting of solar panels, batteries, a proton exchange membrane fuel cell ...(PEMFC), and a chemical hydrogen generation system. A PEMFC has several advantages, such as low operating temperatures, fast response times, high power density, and environmental friendliness, and it can convert hydrogen into electricity. However, because hydrogen costs are an important consideration, the PEMFC is usually integrated with hybrid energy systems to guarantee system sustainability. Therefore, in this study, a whole-year household load and solar radiation data were applied to optimize the system components and power management, thereby reducing the system cost by 42.43% and improving system sustainability by 7.05%. The system responses showed that some hydrogen consumption might be saved if the solar and load profiles could be foreseen. Two prediction models were developed that could accurately forecast the radiation and load profiles. Next, a second-year dataset was employed to verify the effectiveness of the model prediction. The results showed that the system cost was reduced by 40.20% without model prediction and by 44.06% with model prediction compared to the original system settings. Finally, experiments to illustrate the feasibility of the hybrid energy system were conducted using prediction models. Based on the results, the model prediction was deemed effective in improving the performance of hybrid energy systems.
Melatonin in Alzheimer's disease Lin, Li; Huang, Qiong-Xia; Yang, Shu-Sheng ...
International Journal of Molecular Sciences,
07/2013, Letnik:
14, Številka:
7
Journal Article, Book Review
Recenzirano
Odprti dostop
Alzheimer's disease (AD), an age-related neurodegenerative disorder with progressive cognition deficit, is characterized by extracellular senile plaques (SP) of aggregated β-amyloid (Aβ) and ...intracellular neurofibrillary tangles, mainly containing the hyperphosphorylated microtubule-associated protein tau. Multiple factors contribute to the etiology of AD in terms of initiation and progression. Melatonin is an endogenously produced hormone in the brain and decreases during aging and in patients with AD. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning and slows down the progression of cognitive impairment in AD patients. Melatonin efficiently protects neuronal cells from Aβ-mediated toxicity via antioxidant and anti-amyloid properties. It not only inhibits Aβ generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Aβ. Our studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting the cholinergic system and in anti-inflammation. The aim of this review is to stimulate interest in melatonin as a potentially useful agent in the prevention and treatment of AD.
Aqueous rechargeable zinc-ion battery (ZIB) is considered to be a potential energy storage system for large-scale applications due to its environmental friendliness, high safety, and low cost. ...However, it remains challenging to develop suitable cathode materials with high specific capacity and long-term cyclic stability. Herein, we have fabricated freestanding Sr
0.19
V
2
O
5
·1.3H
2
O/carbon nanotubes (SrVO/CNTs) composite films with different mass ratios by incorporating SrVO into CNTs network. The synthesized SrVO possesses a large interlayer spacing of 1.31 nm, which facilitates Zn
2+
diffusion. Furthermore, the SrVO/CNTs composite film with conductive network structure promotes electron transfer and ensures good contact between SrVO and CNTs during the long-term cycling process. As a result, the battery based on the SrVO/CNTs composite cathode with a mass ratio of 7:3 delivers a specific capacity of 326 mAh·g
−1
at 0.1 A·g
−1
and 145 mAh·g
−1
at 5 A·g
−1
, demonstrating a high capacity and excellent rate capability. Remarkably, the assembled ZIB shows good capacity retention of 91% even after ultra-long cycling for 7500 cycles at a high current rate of 5 A·g
−1
. More importantly, the battery also delivers a high energy density and power density, as 290 Wh·kg
−1
at 125 W·kg
−1
(0.1 A·g
−1
), or 115 Wh·kg
−1
at 6078 W·kg
−1
(5 A·g
−1
). The results demonstrate that the SrVO/CNTs composite is a promising cathode toward large-scale energy storage applications.
Graphic abstract
δ-secretase, also known as asparagine endopeptidase (AEP) or legumain, is a lysosomal cysteine protease that cleaves both amyloid precursor protein (APP) and tau, mediating the amyloid-β and tau ...pathology in Alzheimer's disease (AD). Here we report the therapeutic effect of an orally bioactive and brain permeable δ-secretase inhibitor in mouse models of AD. We performed a high-throughput screen and identified a non-toxic and selective δ-secretase inhibitor, termed compound 11, that specifically blocks δ-secretase but not other related cysteine proteases. Co-crystal structure analysis revealed a dual active site-directed and allosteric inhibition mode of this compound class. Chronic treatment of tau P301S and 5XFAD transgenic mice with this inhibitor reduces tau and APP cleavage, ameliorates synapse loss and augments long-term potentiation, resulting in protection of memory. Therefore, these findings demonstrate that this δ-secretase inhibitor may be an effective clinical therapeutic agent towards AD.
Significance Intracellular accumulation of the abnormally modified tau is hallmark pathology of AD, but the mechanism leading to tau aggregation is not fully characterized. In the present study, we ...studied the effects of tau SUMOylation on its phosphorylation, ubiquitination, degradation, and aggregation. We discovered that sumoylation competes with ubiquitination in modifying tau, correlating with tau hyperphosphorylation. Identification of the posttranslational modification on tau provides the new insight into the molecular mechanism in tau aggregation.
Intracellular accumulation of the abnormally modified tau is hallmark pathology of Alzheimer’s disease (AD), but the mechanism leading to tau aggregation is not fully characterized. Here, we studied the effects of tau SUMOylation on its phosphorylation, ubiquitination, and degradation. We show that tau SUMOylation induces tau hyperphosphorylation at multiple AD-associated sites, whereas site-specific mutagenesis of tau at K340R (the SUMOylation site) or simultaneous inhibition of tau SUMOylation by ginkgolic acid abolishes the effect of small ubiquitin-like modifier protein 1 (SUMO-1). Conversely, tau hyperphosphorylation promotes its SUMOylation; the latter in turn inhibits tau degradation with reduction of solubility and ubiquitination of tau proteins. Furthermore, the enhanced SUMO-immunoreactivity, costained with the hyperphosphorylated tau, is detected in cerebral cortex of the AD brains, and β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of the hyperphosphorylated tau. Our findings suggest that tau SUMOylation reciprocally stimulates its phosphorylation and inhibits the ubiquitination-mediated tau degradation, which provides a new insight into the AD-like tau accumulation.
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