RESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disease with the hallmark of aggregation of beta-amyloid (Aß) into extracellular fibrillar deposition. Accumulating evidence suggests that soluble toxic Aß oligomers exert diverse roles in neuronal cell death, oxidative stress, neuroinflammation, and the eventual pathogenesis of AD. Aß is derived from the sequential cleavage of amyloid-ß precursor protein (APP) by ß-secretase (BACE1) and γ-secretase. The current effect of single targeting is not ideal for the treatment of AD. Therefore, developing multipotent agents with multiple properties, including anti-Aß generation and anti-Aß aggregation, is attracting more attention for AD treatment. Previous studies indicated that Quercetin was able to attenuate the effects of several pathogenetic factors in AD. Here, we showed that naturally synthesized Quercetin-3-O-glc-1-3-rham-1-6-glucoside (YCC31) could inhibit Aß production by reducing ß-secretase activity. Further investigations indicated that YCC31 could suppress toxic Aß oligomer formation by directly binding to Aß. Moreover, YCC31 could attenuate Aß-mediated neuronal death, ROS and NO production, and pro-inflammatory cytokines release. Taken together, YCC31 targeting multiple pathogenetic factors deserves further investigation for drug development of AD.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Humanos , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Quercetina/farmacología , Quercetina/uso terapéutico , Citocinas , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Glucósidos/uso terapéuticoRESUMEN
AIMS: Alzheimer's disease (AD) is a significant global health concern, and it is crucial that we find effective methods to prevent or slow down AD progression. Recent studies have highlighted the essential role of blood vessels in clearing Aß, a protein that contributes to AD. Scientists are exploring blood biomarkers as a potential tool for future AD diagnosis. One promising method that may help prevent AD is remote ischemic conditioning (RIC). RIC involves using sub-lethal ischemic-reperfusion cycles on limbs. However, a comprehensive understanding of how RIC can prevent AD and its long-term effectiveness is still lacking. Further research is essential to fully comprehend the potential benefits of RIC in preventing AD. METHODS: Female wild-type (WT) and APP/PS1 transgenic rats, aged 12 months, underwent ovariectomy and were subsequently assigned to WT, APP/PS1, and APP/PS1 + RIC groups. RIC was conducted five times a week for 4 weeks. The rats' depressive and cognitive behaviors were evaluated using force swimming, open-field tests, novel objective recognition, elevated plus maze, and Barnes maze tests. Evaluation of the neurovascular unit (NVU), synapses, vasculature, astrocytes, and microglia was conducted using immunofluorescence staining (IF), Western blot (WB), and transmission electron microscopy (TEM). Additionally, the cerebro-vasculature was examined using micro-CT, and cerebral blood flow (CBF) was measured using Speckle Doppler. Blood-brain barrier (BBB) permeability was determined by measuring the Evans blue leakage. Finally, Aß levels in the rat frontal cortex were measured using WB, ELISA, or IF staining. RESULTS: RIC enhanced memory-related protein expression and rescued depressive-like behavior and cognitive decline in APP/PS1 transgenic rats. Additionally, the intervention protected NVU in the rat frontal cortex, as evidenced by (1) increased expression of TJ (tight junction) proteins, pericyte marker PDGFRß, and glucose transporter 1 (GLUT1), as well as decreased VCAM1; (2) mitigation of ultrastructure impairment in neuron, cerebral vascular, and astrocyte; (3) upregulation of A2 astrocyte phenotype markers and downregulation of A1 phenotype markers, indicating a shift toward a healthier phenotype. Correspondingly, RIC intervention alleviated neuroinflammation, as evidenced by the decreased Iba1 level, a microglia marker. Meanwhile, RIC intervention elevated CBF in frontal cortex of the rats. Notably, RIC intervention effectively suppressed Aß toxicity, as demonstrated by the enhancement of α-secretase and attenuation of ß-secretase (BACE1) and γ- secretase and Aß1-42 and Aß1-40 levels as well. CONCLUSION: Chronic RIC intervention exerts vascular and neuroprotective roles, suggesting that RIC could be a promising therapeutic strategy targeting the BBB and NVU during AD development.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Ratones , Ratas , Femenino , Animales , Barrera Hematoencefálica/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Ratones Transgénicos , Ratas Transgénicas , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/terapia , Modelos Animales de Enfermedad , Presenilina-1/genética , Presenilina-1/metabolismoRESUMEN
Ageing increases susceptibility to neurodegenerative disorders, such as Alzheimer's disease (AD). Serum levels of sclerostin, an osteocyte-derived Wnt-ß-catenin signalling antagonist, increase with age and inhibit osteoblastogenesis. As Wnt-ß-catenin signalling acts as a protective mechanism for memory, we hypothesize that osteocyte-derived sclerostin can impact cognitive function under pathological conditions. Here we show that osteocyte-derived sclerostin can cross the blood-brain barrier of old mice, where it can dysregulate Wnt-ß-catenin signalling. Gain-of-function and loss-of-function experiments show that abnormally elevated osteocyte-derived sclerostin impairs synaptic plasticity and memory in old mice of both sexes. Mechanistically, sclerostin increases amyloid ß (Aß) production through ß-catenin-ß-secretase 1 (BACE1) signalling, indicating a functional role for sclerostin in AD. Accordingly, high sclerostin levels in patients with AD of both sexes are associated with severe cognitive impairment, which is in line with the acceleration of Αß production in an AD mouse model with bone-specific overexpression of sclerostin. Thus, we demonstrate osteocyte-derived sclerostin-mediated bone-brain crosstalk, which could serve as a target for developing therapeutic interventions against AD.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Masculino , Femenino , Ratones , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Osteocitos/metabolismo , Osteocitos/patología , beta Catenina/metabolismo , beta Catenina/uso terapéutico , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/uso terapéutico , Vía de Señalización Wnt , Cognición , EnvejecimientoRESUMEN
RATIONALE: The ß-secretase BACE1 initiates amyloid-ß (Aß) generation and represents a long-standing prime therapeutic target for the treatment of Alzheimer's disease (AD). However, BACE1 inhibitors tested to date in clinical trials have yielded no beneficial outcomes. In fact, prior BACE1 inhibitor trials targeted at ~ 50-90% Aß reductions in symptomatic or prodromal AD stages have ended in the discontinuation due to futility and/or side effects, including cognitive worsening rather than expected improvement at the highest dose. OBJECTIVES: We tested whether a combination strategy with the selective BACE1 inhibitor GRL-8234 and the FDA-approved symptomatic drug memantine may provide synergistic cognitive benefits within their safe dose range. METHODS: The drug effects were evaluated in the advanced symptomatic stage of 5XFAD mice that developed extensive cerebral Aß deposition. RESULTS: Chronic combination treatment with 33.4-mg/kg GRL-8234 and 10-mg/kg memantine, but not either drug alone, rescued cognitive deficits in 5XFAD mice at 12 months of age (the endpoint after 60-day drug treatment), as assessed by the contextual fear conditioning, spontaneous alternation Y-maze and nest building tasks. Intact baseline performances of wild-type control mice on three cognitive paradigms demonstrated that combination treatment did not augment potential cognitive side effects of individual drugs. Biochemical and immunohistochemical examination showed that combination treatment did not synergistically reduce the ß-amyloidogenic processing of amyloid precursor protein or Aß levels in 5XFAD mouse brains. CONCLUSIONS: A combination strategy with BACE1 inhibitors and memantine may be able to increase the effectiveness of individual drugs within their safe dose range in AD therapy.
Asunto(s)
Enfermedad de Alzheimer , Ácidos Ftálicos , Sulfonamidas , Ratones , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Memantina/farmacología , Memantina/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Ratones Transgénicos , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Cognición , Modelos Animales de EnfermedadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Oxalis corniculata (O. corniculata) is a member of Oxalidaceae family, widely distributed in Asia, Europe, America, and Africa, used extensively as food and its traditional folkloric uses include management of epilepsy, gastric disorders, and neurodegenerative diseases, together with its use in enhancing health. Numerous pharmacological benefits of O. corniculata are linked to its anti-inflammatory and antioxidant abilities. One of the most prevalent neurodegenerative disorders is Alzheimer's disease (AD) in which neuroinflammation and oxidative stress are its main pathogenic processes. AIM OF THE STUDY: Our research aimed to study the neuroprotective effect of the methanolic extract of Oxalis corniculata Linn. (O. corniculata ME), compared to selenium (Se) against AlCl3-induced AD. MATERIALS AND METHODS: Forty male albino rats were allocated into four groups (Gps). Gp I a control group, the rest of the animals received AlCl3 (Gp II-Gp IV). Rats in Gp III and IV were treated with Se and O. corniculata ME, respectively. RESULTS: The chemical profile of O. corniculata ME was studied using ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry, allowing the tentative identification of sixty-six compounds, including organic acids, phenolics and others, cinnamic acid and its derivatives, fatty acids, and flavonoids. AlCl3 showed deterioration in short-term memory and brain histological pictures. Our findings showed that O. corniculata ME and selenium helped to combat oxidative stress produced by accumulation of AlCl3 in the brain and in prophylaxis against AD. Thus, Selenium (Se) and O. corniculata ME restored antioxidant defense, via enhancing Nrf2/HO-1 hub, hampered neuroinflammation, via TLR4/NF-κß/NLRP3, along with dampening apoptosis, Aß generation, tau hyperphosphorylation, BACE1, ApoE4 and LRP1 levels. Treatments also promoted autophagy and modulated Wnt 3/ß-catenin/GSK3ß cue. CONCLUSIONS: It was noted that O. corniculata ME showed a notable ameliorative effect compared to Se on Nrf2/HO-1, TLR4/NF-κß/NLRP3, APOE4/LRP1, Wnt 3/ß-catenin/GSK-3ß and PERK axes.
Asunto(s)
Enfermedad de Alzheimer , Oxalidaceae , Selenio , Ratas , Masculino , Animales , Glucógeno Sintasa Quinasa 3 beta , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Oxalidaceae/química , Señales (Psicología) , Apolipoproteína E4 , Secretasas de la Proteína Precursora del Amiloide , Receptor Toll-Like 4 , Selenio/uso terapéutico , beta Catenina , Enfermedades Neuroinflamatorias , Factor 2 Relacionado con NF-E2 , Proteína con Dominio Pirina 3 de la Familia NLR , Ácido Aspártico Endopeptidasas/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
Alzheimer's disease (AD) is the most common neurodegenerative disease. The morbidity of Alzheimer's disease is currently on the rise worldwide, but no effective treatment is available. Cornus officinalis is an herb and edible plant used in traditional Chinese medicine, whose extract has neuroprotective properties. In this investigation, we endeavored to refine a systems pharmacology strategy combining bioinformatics analysis, drug prediction, network pharmacology, and molecular docking to screen tetrahydroalstonine (THA) from Cornus officinalis as a therapeutic component for AD. Subsequent in vitro experiments were validated using MTT assay, Annexin V-PI flow cytometry, Western blotting, and immunofluorescence analysis. In Palmitate acid-induced SK-N-MC cells, THA restored the impaired PI3K/AKT signaling pathway, regulated insulin resistance, and attenuated BACE1 and GSK3ß activity. In addition, THA significantly reduced cell apoptosis rate, down-regulated relative levels of p-JNK/JNK, Bax/Bcl-2, cytochrome C, active caspase-3 and caspase-3, and attenuated Palmitate acid-induced Aß1-42 and Tau generation. THA may regulate the phenotype of AD and reduce cell apoptosis by modulating the PI3K/AKT signaling pathway. This systematic analysis provides new ramifications concerning the therapeutic utility of tetrahydroalstonine for AD.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Ácido Palmítico/toxicidad , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Caspasa 3/metabolismo , Péptidos beta-Amiloides/metabolismo , Simulación del Acoplamiento Molecular , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/farmacología , Ácido Aspártico Endopeptidasas/uso terapéutico , Transducción de Señal , Palmitatos/farmacologíaRESUMEN
Clinical studies have shown that asthma is a risk factor for dementia or Alzheimer's disease (AD). To investigate whether asthma aggravates AD in APP/PS1 mice and explore the potential mechanisms, an asthma model was established using six-month-old APP/PS1 mice, and montelukast was used as a therapeutic agent in APP/PS1 mice with asthma. The Morris water maze test showed that asthma aggravates spatial learning and memory abilities. Asthma also upregulates the NF-κB inflammatory pathway in APP/PS1 mice and promotes the expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), amyloid-ß (Aß) deposition, neuronal damage, synaptic plasticity deficiency, activation of microglia and astrocytes. The level of LTD4 and its receptor CysLT1R in the hippocampus of APP/PS1 mice after the asthma modeling was established was higher than that in APP/PS1 mice, suggesting that asthma may affect the pathology of AD through LTD4 and its receptor Cys-LT1R. Montelukast ameliorates these pathological changes and cognitive impairment. These results suggest that asthma aggravates AD pathology and cognitive impairment of APP/PS1 mice via upregulation of the NF-κB inflammatory pathway, and montelukast ameliorates these pathological changes.
Asunto(s)
Acetatos , Enfermedad de Alzheimer , Disfunción Cognitiva , Ciclopropanos , Quinolinas , Sulfuros , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , FN-kappa B/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Leucotrieno D4/uso terapéutico , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Ratones Transgénicos , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/metabolismo , Transducción de Señal , Modelos Animales de Enfermedad , Presenilina-1/metabolismoRESUMEN
BACKGROUND: Increasing evidence highlights the importance of novel players in Alzheimer's disease (AD) pathophysiology, including alterations of lipid metabolism and neuroinflammation. Indeed, a potential involvement of Proprotein convertase subtilisin/kexin type 9 (PCSK9) in AD has been recently postulated. Here, we first investigated the effects of PCSK9 on neuroinflammation in vitro. Then, we examined the impact of a genetic ablation of PCSK9 on cognitive performance in a severe mouse model of AD. Finally, in the same animals we evaluated the effect of PCSK9 loss on Aß pathology, neuroinflammation, and brain lipids. METHODS: For in vitro studies, U373 human astrocytoma cells were treated with Aß fibrils and human recombinant PCSK9. mRNA expression of the proinflammatory cytokines and inflammasome-related genes were evaluated by q-PCR, while MCP-1 secretion was measured by ELISA. For in vivo studies, the cognitive performance of a newly generated mouse line - obtained by crossing 5XFADHet with PCSK9KO mice - was tested by the Morris water maze test. After sacrifice, immunohistochemical analyses were performed to evaluate Aß plaque deposition, distribution and composition, BACE1 immunoreactivity, as well as microglia and astrocyte reactivity. Cholesterol and hydroxysterols levels in mouse brains were quantified by fluorometric and LC-MS/MS analyses, respectively. Statistical comparisons were performed according to one- or two-way ANOVA, two-way repeated measure ANOVA or Chi-square test. RESULTS: In vitro, PCSK9 significantly increased IL6, IL1B and TNFΑ mRNA levels in Aß fibrils-treated U373 cells, without influencing inflammasome gene expression, except for an increase in NLRC4 mRNA levels. In vivo, PCSK9 ablation in 5XFAD mice significantly improved the performance at the Morris water maze test; these changes were accompanied by a reduced corticohippocampal Aß burden without affecting plaque spatial/regional distribution and composition or global BACE1 expression. Furthermore, PCSK9 loss in 5XFAD mice induced decreased microgliosis and astrocyte reactivity in several brain regions. Conversely, knocking out PCSK9 had minimal impact on brain cholesterol and hydroxysterol levels. CONCLUSIONS: In vitro studies showed a pro-inflammatory effect of PCSK9. Consistently, in vivo data indicated a protective role of PCSK9 ablation against cognitive impairments, associated with improved Aß pathology and attenuated neuroinflammation in a severe mouse model of AD. PCSK9 may thus be considered a novel pharmacological target for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Ratones , Humanos , Animales , Ratones Transgénicos , Proproteína Convertasa 9/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Enfermedades Neuroinflamatorias , Cromatografía Liquida , Inflamasomas , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/uso terapéutico , Espectrometría de Masas en Tándem , Enfermedad de Alzheimer/metabolismo , ARN Mensajero , Colesterol , Péptidos beta-Amiloides/metabolismo , Modelos Animales de EnfermedadRESUMEN
Gene therapy has great potential in treating neurodegenerative diseases with complex pathologies. The combination of small interfering RNAs (siRNAs) targeting ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) and caspase-3 will provide an effective treatment option for Alzheimer's disease (AD). To overcome the multiple physiological barriers and improve the therapeutic efficacy of siRNAs, lesion-recognizing nanoparticles (NPs) are constructed in this study for the synergistic treatment of AD. The lesion-recognizing NPs contain rabies virus glycoprotein peptide-modified mesenchymal stem cell-derived exosomes as the shell and a reactive oxygen species (ROS)-responsive polymer loaded with siRNAs as the core. After intranasal administration, the lesion-recognizing NPs cross the nasal mucosa and migrate to the affected brain areas. Furthermore, the NPs recognize the target cells and fuse with the cell membranes of neurons. The cores of NPs directly enter into the cytoplasm and achieve the controlled release of siRNAs in a high-ROS environment to downregulate the level of BACE1 and caspase-3 to ameliorate neurologic injury. In addition, lesion-recognizing NPs can significantly reduce the number of reactive astrocytes. Lesion-recognizing NPs have a positive effect on regulating the phase of neurons and astrocytes, which results in better restoration of memory deficits in 3 × Tg-AD mice. Therefore, this work provides a promising platform for neurodegenerative disease treatment.
Asunto(s)
Enfermedad de Alzheimer , Nanopartículas , Enfermedades Neurodegenerativas , Ratones , Animales , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Caspasa 3/genética , Caspasa 3/metabolismo , ARN Interferente Pequeño/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/uso terapéutico , Encéfalo/metabolismo , Péptidos beta-Amiloides/metabolismoRESUMEN
The prominence of autophagy in the modulation of neurodegenerative disorders has sparked interest to investigate its stimulation in Alzheimer's disease (AD). Nobiletin possesses several bioactivities such as anti-inflammation, antioxidation, and neuroprotection. Consequently, the study's aim was to inspect the possible neurotherapeutic impact of Nobiletin in damping AD through autophagy regulation. Mice were randomly assigned into: Group I which received DMSO, Groups II, III, and IV obtained STZ (3 mg/kg) intracerebroventricularly once with Nobiletin (50 mg/kg/day; i.p.) in Group III and Nobiletin with EX-527 (2 mg/kg, i.p.) in Group IV. Interestingly, Nobiletin ameliorated STZ-induced AD through enhancing the motor performance and repressing memory defects. Moreover, Nobiletin de-escalated hippocampal acetylcholinesterase (AChE) activity and enhanced acetylcholine level while halting BACE1 and amyloid-ß levels. Meanwhile, Nobiletin stimulated the autophagy process through activating the SIRT1/FoxO3a, LC3B-II, and ATG7 pathway. Additionally, Nobiletin inhibited Akt pathway and controlled the level of NF-κB and TNF-α. Nobiletin amended the oxidative stress through enhancing GSH and cutting down MDA levels. However, EX527, SIRT1 inhibitor, counteracted the neurotherapeutic effects of Nobiletin. Therefore, the present study provides a strong verification for the therapeutic influence of Nobiletin in AD. This outcome may be assigned to autophagy stimulation through SIRT1/FoxO3a, inhibiting AChE activity, reducing neuroinflammation and oxidative stress.
Asunto(s)
Enfermedad de Alzheimer , Citrus , Ratones , Animales , Flavonoides/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Citrus/metabolismo , Sirtuina 1/metabolismo , Acetilcolinesterasa , Ácido Aspártico Endopeptidasas/uso terapéutico , Autofagia , Modelos Animales de EnfermedadRESUMEN
Alzheimer's disease (AD) is globally recognized as a prominent cause of dementia for which efficient treatment is still lacking. New candidate compounds that are biologically potent are regularly tested. We, therefore, hypothesized to study the neuroprotective potential of Zinc Ortho Methyl Carbonodithioate (thereafter called ZOMEC) against Scopolamine (SCOP) induced Alzheimer's disease (AD) model using adult albino mice. We post-administered ZOMEC (30 mg/Kg) into two group of mice for three weeks on daily basis that received either 0.9% saline or SCOP (1 mg/Kg) for initial two weeks. The other two groups of mice received 0.9% saline and SCOP (1 mg/Kg) respectively. After memory related behavioral analysis the brain homogenates were evaluated for the antioxidant potential of ZOMEC and multiple protein markers were examined through western blotting. Our results provide enough evidences that ZOMEC decrease oxidative stress by increasing catalase (CAT) and glutathione S transferase (GST) and decreasing the lipid peroxidation (LPO). The SIRT1 and pre and post synaptic marker proteins, synaptophysin (SYP) as well as post synaptic density protein (PSD-95) expression were also enhanced upon ZOMEC treatment. Furthermore, memory impairment was rescued and ZOMEC appreciably abrogated the Aß accumulation, BACE1 expression C and the p-JNK pathway. The inflammatory protein markers, NF-kß and IL-1ß in ZOMEC treated mice were also comparable with control group. The predicted interaction of ZOMEC with SIRT1 was further confirmed by molecular docking. These findings thus provide initial reports on efficacy of ZOMEC in SCOP induced AD model.
Asunto(s)
Enfermedad de Alzheimer , Escopolamina , Ratones , Animales , Escopolamina/toxicidad , Escopolamina/metabolismo , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Sistema de Señalización de MAP Quinasas , Zinc/metabolismo , Zinc/uso terapéutico , Sirtuina 1/metabolismo , Simulación del Acoplamiento Molecular , Solución Salina/metabolismo , Solución Salina/uso terapéutico , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/uso terapéutico , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , SinapsisRESUMEN
Alzheimer's disease (AD), also called senile dementia, is the most common neurological disorder. Around 50 million people, mostly of advanced age, are suffering from dementia worldwide and this is expected to reach 100-130 million between 2040 and 2050. AD is characterized by impaired glutamatergic and cholinergic neurotransmission, which is associated with clinical and pathological symptoms. AD is characterized clinically by loss of cognition and memory impairment and pathologically by senile plaques formed by Amyloid ß deposits or neurofibrillary tangles (NFT) consisting of aggregated tau proteins. Amyloid ß deposits are responsible for glutamatergic dysfunction that develops NMDA dependent Ca2+ influx into postsynaptic neurons generating slow excitotoxicity process leading to oxidative stress and finally impaired cognition and neuronal loss. Amyloid decreases acetylcholine release, synthesis and neuronal transport. The decreased levels of neurotransmitter acetylcholine, neuronal loss, tau aggregation, amyloid ß plaques, increased oxidative stress, neuroinflammation, bio-metal dyshomeostasis, autophagy, cell cycle dysregulation, mitochondrial dysfunction, and endoplasmic reticulum dysfunction are the factors responsible for the pathogenesis of AD. Acetylcholinesterase, NMDA, Glutamate, BACE1, 5HT6, and RAGE (Receptors for Advanced Glycation End products) are receptors targeted in treatment of AD. The FDA approved acetylcholinesterase inhibitors Donepezil, Galantamine and Rivastigmine and N-methyl-D-aspartate antagonist Memantine provide symptomatic relief. Different therapies such as amyloid ß therapies, tau-based therapies, neurotransmitter-based therapies, autophagy-based therapies, multi-target therapeutic strategies, and gene therapy modify the natural course of the disease. Herbal and food intake is also important as preventive strategy and recently focus has also been placed on herbal drugs for treatment. This review focuses on the molecular aspects, pathogenesis and recent studies that signifies the potential of medicinal plants and their extracts or chemical constituents for the treatment of degenerative symptoms related to AD.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides , Secretasas de la Proteína Precursora del Amiloide , Acetilcolina/fisiología , Acetilcolina/uso terapéutico , Acetilcolinesterasa/uso terapéutico , N-Metilaspartato/uso terapéutico , Ácido Aspártico Endopeptidasas/uso terapéuticoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Danggui Buxue decoction (DBD) is a classic herbal decoction consisting of Astragali Radix (AR) and Angelica Sinensis Radix (ASR) with a 5:1 wt ratio, which can supplement 'blood' and 'qi' (vital energy) for the treatment of clinical diseases. According to Traditional Chinese Medicine (TCM) theory, dementia is induced by Blood deficiency and Qi weakness, which causes a decline in cognition. However, the underlying mechanisms of DBD improving cognition deficits in neurodegenerative disease are no clear. AIM OF THE STUDY: This study aims at revealing the underlying mechanisms of DBD plays a protective role in the cognitive deficits and pathology process of Alzheimer's disease (AD). MATERIALS AND METHODS: The APP/PS1 (Mo/HuAPP695swe/PS1-dE9) double transgenic mice were adopted as an experimental model of AD. Qualitative and quantitative analysis of 3 compounds in DBT was analyzed by HPLC. Morris water maze test, Golgi staining and electrophysiology assays were used to evaluate the effects of DBD on cognitive function and synaptic plasticity in APP/PS1 mice. Western blot, immunofluorescence and Thioflavin S staining were used for the pathological evaluation of AD. Monitoring the level of ATP, mitochondrial membrane potential, SOD and MDA to evaluate the mitochondrial function, and with the usage of qPCR and CHIP for the changes of histone post-translational modification. RESULTS: In the current study, we found that DBD could effectively attenuate memory impairments and enhance long-term potentiation (LTP) with concurrent increased expression of memory-associated proteins. DBD markedly decreased Aß accumulation in APP/PS1 mice by decreasing the phosphorylation of APP at the Thr668 level but not APP, PS1 or BACE1. Further studies demonstrated that DBD restored mitochondrial biogenesis deficits and mitochondrial dysfunction. Finally, the restored mitochondrial biogenesis and cognitive deficits are under HADC2-mediated histone H4 lysine 12 (H4K12) acetylation at the peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) and N-methyl-D-aspartate receptor type 2B (GluN2B) promoters. CONCLUSIONS: These findings reveal that DBD could ameliorate mitochondrial biogenesis and cognitive deficits by improving H4K12 acetylation. DBD might be a promising complementary drug candidate for AD treatment.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Ratones , Animales , Histonas/metabolismo , Lisina/metabolismo , Lisina/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide , Acetilación , Biogénesis de Organelos , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Ratones Transgénicos , Cognición , Procesamiento Proteico-Postraduccional , Precursor de Proteína beta-Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Modelos Animales de EnfermedadRESUMEN
This study aimed to demonstrate the potential benefits of donepezil (DPZ) and vitamin D (Vit D) in combination to counteract the neurodegenerative disorders induced by CuSO4 intake in experimental rats. Neurodegeneration (Alzheimer-like) was induced in twenty-four male Wistar albino rats by CuSO4 supplement to drinking water (10 mg/L) for 14 weeks. AD rats were divided into four groups: untreated AD group (Cu-AD) and three treated AD groups; orally treated for 4 weeks with either DPZ (10 mg/kg/day), Vit D (500 IU/kg/day), or DPZ + Vit D starting from the 10th week of CuSO4 intake. Another six rats were used as normal control (NC) group. The hippocampal tissue content of ß-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 and the cortical content of acetylcholine (Ach), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured. Cognitive function tests (Y-maze) and histopathology studies (hematoxylin and eosin and Congo red stains) and immunohistochemistry for neurofilament. Vit D supplementation alleviated CuSO4-induced memory deficits including significant reduction hippocampal BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α and cortical AChE and MDA. Vit D remarkably increased cortical Ach, TAC, and hippocampal Bcl-2. It also improved neurobehavioral and histological abnormalities. The effects attained by Vit D treatment were better than those attained by DPZ. Furthermore, Vit D boosted the therapeutic potential of DPZ in almost all AD associated behavioral and pathological changes. Vit D is suggested as a potential therapy to retard neurodegeneration.
Asunto(s)
Enfermedad de Alzheimer , Lesiones Encefálicas , Disfunción Cognitiva , Ratas , Masculino , Animales , Donepezilo/efectos adversos , Cobre , Sulfato de Cobre/efectos adversos , Sulfato de Cobre/metabolismo , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/farmacología , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Vitamina D/farmacología , Vitamina D/uso terapéutico , Acetilcolinesterasa/metabolismo , Sulfatos/metabolismo , Sulfatos/farmacología , Sulfatos/uso terapéutico , Proteína X Asociada a bcl-2/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ratas Wistar , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/farmacología , Ácido Aspártico Endopeptidasas/uso terapéutico , Lesiones Encefálicas/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antioxidantes/metabolismo , Vitaminas/farmacología , Encéfalo , Disfunción Cognitiva/inducido químicamenteRESUMEN
Alzheimer's disease (AD) is one of the neurodegenerative diseases, manifesting dementia, spatial disorientation, language, cognitive, and functional impairment, mainly affects the elderly population with a growing concern about the financial burden on society. Repurposing can improve the traditional progress of drug design applications and could speed up the identification of innovative remedies for AD. The pursuit of potent anti-BACE-1 drugs for AD treatment has become a pot boiler topic in the recent past and to instigate the design of novel improved inhibitors from the bee products. Drug-likeness characteristics (ADMET: absorption, distribution, metabolism, excretion, and toxicity), docking (AutoDock Vina), simulation (GROMACS), and free energy interaction (MM-PBSA, molecular mechanics Poisson-Boltzmann surface area) analyses were performed to identify the lead candidates from the bee products (500 bioactives from the honey, royal jelly, propolis, bee bread, bee wax, and bee venom) for Alzheimer's disease as novel inhibitors of BACE-1 (beta-site amyloid precursor protein cleaving enzyme (1) receptor using appropriate bioinformatics tools. Forty-four bioactive lead compounds were screened from the bee products through high throughput virtual screening on the basis of their pharmacokinetic and pharmacodynamics characteristics, showing favorable intestinal and oral absorption, bioavailability, blood brain barrier penetration, less skin permeability, and no inhibition of cytochrome P450 inhibitors. The docking score of the forty-four ligand molecules was found to be between -4 and -10.3 kcal/mol, respectively, exhibiting strong binding affinity to BACE1 receptor. The highest binding affinity was observed in the rutin (-10.3 kcal/mol), 3,4-dicaffeoylquinic acid (-9.5 kcal/mol), nemorosone (-9.5 kcal/mol), and luteolin (-8.9 kcal/mol). Furthermore, these compounds demonstrated high total binding energy -73.20 to -105.85 kJ/mol), and low root mean square deviation (0.194-0.202 nm), root mean square fluctuation (0.0985-0.1136 nm), radius of gyration (2.12 nm), number of H-bonds (0.778-5.436), and eigenvector values (2.39-3.54 nm2) in the molecular dynamic simulation, signifying restricted motion of Cα atoms, proper folding and flexibility, and highly stable with compact of the BACE1 receptor with the ligands. Docking and simulation studies concluded that rutin, 3,4-dicaffeoylquinic acid, nemorosone, and luteolin are plausibly used as novel inhibitors of BACE1 to combat AD, but further in-depth experimental investigations are warranted to prove these in silico findings.
Asunto(s)
Enfermedad de Alzheimer , Anciano , Abejas , Humanos , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Ligandos , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Reposicionamiento de Medicamentos , Luteolina , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/uso terapéuticoRESUMEN
Alzheimer's disease (AD) is a neurodegenerative, progressive, and fatal disorder characterized by marked atrophy of the cerebral cortex and loss of basal forebrain cholinergic neurons. The main pathological features of AD are related to neuronal degeneration and include extracellular deposition of amyloid beta plaques (Aß plaques), intracellular formation of neurofibrillary tangles (NFTs), and neuroinflammation. So far, drugs used to treat AD have symptomatic and palliative pharmacological effects, disappearing with continued use due to neuron degeneration and death. Therefore, there are still problems with an effective drug for treating AD. Few approaches evaluate the action of natural products other than alkaloids on the molecular targets of ß-amyloid protein (Aß protein) and/or tau protein, which are important targets for developing neuroprotective drugs that will effectively contribute to finding a prophylactic drug for AD. This review gathers and categorizes classes of natural products, excluding alkaloids, which in silico analysis (molecular docking) and in vitro and/or in vivo assays can inhibit the BACE1 and GSK-3ß enzymes involved in AD.
Asunto(s)
Enfermedad de Alzheimer , Productos Biológicos , Humanos , Péptidos beta-Amiloides/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Simulación del Acoplamiento Molecular , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Ácido Aspártico Endopeptidasas/uso terapéutico , Enfermedad de Alzheimer/metabolismo , Proteínas tau/metabolismo , Proteínas tau/uso terapéuticoRESUMEN
Alzheimer's Disease (AD) is a common neurodegenerative disorder that is almost incurable with the existing therapeutic interventions. Due to the high-risk factors associated with this disease, there is a global pursuit of new anti-AD agents. Herein, we explore the biochemical pathways which are responsible for the initiation/propagation of the disease. It is observed that out of the two isoforms of ß-secretase, ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) and ß-site amyloid precursor protein cleaving enzyme 2 (BACE2) present in the brain, BACE1 plays the predominant role in the commencement of AD. Moreover, the catalytic activities of acetylcholinesterase and butyrylcholinesterase regulate the concentration of neurotransmitters, and they are needed to be kept under control during the signs of AD. Hence, these two enzymes also serve as potential targets for the treatment of AD patients. Keeping in view the multifactorial nature of the disease, we also reviewed the multitarget approach for the treatment of AD. It is tried to identify the common structural features of those molecules which act on different cellular targets during AD therapy.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/uso terapéutico , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/uso terapéutico , Acetilcolinesterasa , ButirilcolinesterasaRESUMEN
The seed embryo of Nelumbo nucifera Gaertn. is a famous traditional Chinese medicine and food which is considered conducive to the prevention of Alzheimer's disease (AD). In this study, the effect and mechanism of TASENN (total alkaloids from the seed embryo of Nelumbo nucifera Gaertn.) on AD mice and amyloid-ß (Aß) injured PC12 cells were evaluated. HPLC-UV analysis showed that the extracted TASENN (purity = 95.6%) mainly contains Liensinine, Isoliensinine, and Neferine (purity was 23.01, 28.02, and 44.57%, respectively). In vivo, oral treatment with TASENN (50 mg/kg/day for 28 days) improved the learning and memory functions of APP/PS1 transgenic mice, ameliorated the histopathological changes of cortical and hippocampal neurons, and inhibited neuronal apoptosis. We found that TASENN reduced the phosphorylation of Tau and the formation of neurofibrillary tangles (NFTs) in APP/PS1 mouse brain. Moreover, TASENN down-regulated the expression of APP and BACE1, ameliorated Aß deposition, and inhibited microglial proliferation and aggregation. The elevated protein expression of CaM and p-CaMKII in APP/PS1 mouse brain was also reduced by TASENN. In vitro, TASENN inhibited the apoptosis of PC12 cells injured by Aß25-35 and increased the cell viability. Aß25-35-induced increase of cytosolic free Ca2+ level and high expression of CaM, p-CaMKII, and p-Tau were decreased by TASENN. Our findings indicate that TASENN has a potential therapeutic effect on AD mice and a protective effect on PC12 cells. The anti-AD activity of TASENN may be closely related to its negative regulation of the CaM pathway.
Asunto(s)
Alcaloides , Enfermedad de Alzheimer , Disfunción Cognitiva , Nelumbo , Ratones , Animales , Ratas , Nelumbo/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/uso terapéutico , Células PC12 , Ácido Aspártico Endopeptidasas/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/metabolismo , Ratones Transgénicos , Alcaloides/uso terapéutico , Modelos Animales de Enfermedad , Precursor de Proteína beta-Amiloide/genéticaRESUMEN
Alzheimer's disease is a neurodegenerative disease caused by excessive amyloid ß protein-induced neurotoxicity. However, drugs targeting amyloid ß protein production face many problems, such as the low utilization rate of drugs by cells and the difficulty of drugs in penetrating the blood-brain barrier. A tetrahedral framework nucleic acid is a new type of nanonucleic acid structure that functions as a therapy and drug carrier. Here, we synthesized a BACE1 aptamer-modified tetrahedral framework nucleic acid and tested its therapeutic effect on Alzheimer's disease in vitro and in vivo. Our results demonstrated that the tetrahedral framework nucleic acid could be used as a carrier to deliver the BACE1 aptamer to the brain to reduce the production of amyloid ß proteins. It also played an antiapoptotic role by reducing the production of reactive oxygen species. Thus, this nanomaterial is a potential drug for Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Ácidos Nucleicos , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/uso terapéutico , Modelos Animales de Enfermedad , Portadores de Fármacos/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Ácidos Nucleicos/uso terapéutico , Especies Reactivas de OxígenoRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is clinically characterized by the impairment of memory and cognition. Accumulation of ß-amyloid (Aß) in the brain is considered as a key process in the development of AD because it impairs the synapses' function to impair memory formation. Recent research studies have indicated that a group of edible plant-derived Thymelaeaceae compounds known as coumarin may exert particularly powerful actions on alleviating learning and memory impairment. 7,8-Dithydroxycoumarin (7,8-DHC), a bioactive component of coumarin derived from Thymelaeaceae, showed its function in neuroprotection before. In this study, we found that 7,8-DHC was able to mitigate Aß accumulation via reducing the level of BACE1 and increasing the level of ADAM17 and ADAM10. More importantly, we found that 7,8-DHC could mitigate memory impairment, promote the dendrite branch density, and increase synaptic protein expression via activating PI3K-Akt-CREB-BDNF signaling. Hence, these results suggested that 7,8-DHC represented a novel bioactive therapeutic agent in mitigating Aß deposition and synaptic loss in the process of treating AD.