RESUMEN
INTRODUCTION: Total ginsenosides (TG), the major active constituents of ginseng, have been proven to be beneficial in treatment of Alzheimer's disease (AD). However, the underlying mechanism of TG remains unclear. METHODS: APP/PS1 mice and N2a/APP695 cells were used as in vivo and in vitro model, respectively. Morris water maze (MWM) was used to investigate behavioral changes of mice; neuronal pathological changes were assessed by hematoxylin and eosin (H&E) and nissl staining; immunofluorescence staining was used to examine amyloid beta (Aß) deposition; Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to examine the expression of relative amyloidogenic genes and proteins. Moreover, the antagonist of PPARγ, GW9662, was used to determine whether the effects of TG on Aß production were associated with PPARγ activity. RESULTS: TG treatment increased the spatial learning and memory abilities of APP/PS1 mice while decreasing the Aß accumulation in the cortex and hippocampus. In N2a/APP695 cells, TG treatment attenuated the secretion of Aß1-40 and Aß1-42 acting as an PPARγ agonist by inhibiting the translocation of NF-κB p65. Additionally, TG treatment also decreased the expression of amyloidogenic pathway related gene BACE1, PS1 and PS2. CONCLUSIONS: TG treatment reduced the production of Aß both in vivo and in vitro. Activating PPARγ might be a potential therapeutic target of TG in facilitating Aß clearance and ameliorating cognitive deficiency in APP/PS1 mice.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Ginsenósidos , PPAR gamma , Animales , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Ginsenósidos/farmacología , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Transgénicos , Fragmentos de Péptidos/metabolismo , PPAR gamma/efectos de los fármacos , PPAR gamma/metabolismo , Presenilina-1/genéticaRESUMEN
OBJECTIVE: Previous studies have revealed that Propane-2-sulfonic acid octadec-9-enyl-amide(N15) exerts a protective role in the inflammatory response after ischemic stroke and in neuronal damage. However, little is known about N15 in Alzheimer's disease (AD). The aim of this study was to investigate the effects of N15 on AD and explore the underlying molecular mechanism. METHODS: AD mice model was established by lateral ventricular injection with Aß25-35. N15 was daily intraperitoneal administered for 28 days. Morris Water Maze was used to evaluate the neurocognitive function of the mice. The expression of PPARα/γ, brain-derived neurotrophic factor (BDNF), Neurotrophin-3 (NT3), ADAM10, PS1 and BACE1 were measured by qPCR. Aß amyloid in the hippocampus was measured by Congo red assay. Toluidine blue staining was used to detect the neuronal apoptosis. Protein levels of ADAM10, PS1 and BACE1 were determined using immunoblotting. RESULTS: N15 treatment significantly reduced neurocognitive dysfunction, which also significantly activated the expression of PPARα/γ at an optimal dose of 200 mg/kg. Administration of N15 alleviated the formation of Aß amyloid in the hippocampus of AD mice, enhanced the BDNF mRNA expression, decreased the mRNA and protein levels of PS1 and BACE1, upregulated ADAM10 mRNA and protein levels. CONCLUSION: N15 exerts its neuroprotective effects through the activation of PPARα/γ and may be a potential drug for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , PPAR alfa , Ácidos Sulfónicos , Animales , Masculino , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Fragmentos de Péptidos , PPAR alfa/agonistas , PPAR alfa/metabolismo , PPAR gamma/agonistas , PPAR gamma/metabolismo , Ácidos Sulfónicos/farmacología , Agonistas de PPAR-gamma/farmacologíaRESUMEN
Alzheimer's disease (AD) is a common type of neurodegenerative disease, which can only be symptomatically relieved but does not yet have a cure. Among the different Aß species, amyloid-ß 42 (Aß42) aggregates are proposed to be more neurotoxic than that of Aß40, and oligomeric Aß42 is thought to play a harmful role in the pathophysiology of AD. Therefore, the detection of Aß42 aggregation is very meaningful in the AD field. We herein report a conformationally-locked p- hydroxybenzylidene imidazolinone derivative, BDI, which exhibits selectivity and specificity towards Aß42 aggregation and remarkable fluorescent enhancement with a large Stokes shift (more than 100 nm). In the fluorescent co-localization study, BDI can sensitively detect a large population of Aß42 aggregation over that of Aß40 in the brain tissues of AD transgenic mouse models. Therefore, this new probe could provide a useful tool for the rapid detection of important Aß species in AD.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Animales , Ratones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/efectos de los fármacos , Colorantes , Fragmentos de Péptidos , Imidazoles/química , Imidazoles/farmacologíaRESUMEN
Phytocompounds therapy has recently emerged as an effective strategy to treat Alzheimer's disease. Herein, the protective effect of hesperidin methylchalcone (HMC) was evaluated through Alzheimer's disease models of Neuro-2a cells and Wistar rats. The in vitro results showed that HMC possesses significant ability to inhibit the acetylcholinesterase enzyme and exhibiting anti-aggregation and disaggregation properties. Furthermore, HMC could protect the Neuro-2a cells against Aß-induced neurotoxicity. Simultaneously, HMC treatment significantly improved the cognitive deficits caused by Aß-peptide on spatial memory in Wistar rats. HMC significantly enhanced the cholinergic effects by inhibiting AChE, BuChE, ß-secretase activity, caspase-3 activity, and attenuating macromolecular damages and apoptosis. Notably, HMC reduced the Aß-induced oxidative stress by activating the antioxidative defence enzymes. In addition, the HMC treatment suppressed the expression of immunocytokines such as p-NF-κB p65, p-IκBα, induced by Aß; whereas upregulating Nrf2, HO-1 in brain homogenate. These results suggest that HMC could attenuate Aß-induced neuroinflammation in brain via suppressing NF-κB signalling pathway and activating the Nrf2/HO-1 pathway, thereby improving memory and cognitive impairments in Wistar rats. Overall, the present study reports that HMC can act as a potent candidate with multi-faceted neuroprotective potential against Aß-induced memory dysfunction in Wistar rats for the treatment of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Factor 2 Relacionado con NF-E2 , Fármacos Neuroprotectores , Animales , Ratas , Acetilcolinesterasa/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Hemo-Oxigenasa 1/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismoRESUMEN
BACKGROUND: Deposition of amyloid beta (Aß) and hyperphosphorylated tau along with glial cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer's disease (AD). In recent years, impairment of autophagy has been identified as another important feature contributing to AD progression. Therefore, the potential of the autophagy activator spermidine, a small body-endogenous polyamine often used as dietary supplement, was assessed on Aß pathology and glial cell-mediated neuroinflammation. RESULTS: Oral treatment of the amyloid prone AD-like APPPS1 mice with spermidine reduced neurotoxic soluble Aß and decreased AD-associated neuroinflammation. Mechanistically, single nuclei sequencing revealed AD-associated microglia to be the main target of spermidine. This microglia population was characterized by increased AXL levels and expression of genes implicated in cell migration and phagocytosis. A subsequent proteome analysis of isolated microglia confirmed the anti-inflammatory and cytoskeletal effects of spermidine in APPPS1 mice. In primary microglia and astrocytes, spermidine-induced autophagy subsequently affected TLR3- and TLR4-mediated inflammatory processes, phagocytosis of Aß and motility. Interestingly, spermidine regulated the neuroinflammatory response of microglia beyond transcriptional control by interfering with the assembly of the inflammasome. CONCLUSIONS: Our data highlight that the autophagy activator spermidine holds the potential to enhance Aß degradation and to counteract glia-mediated neuroinflammation in AD pathology.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Espermidina , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Animales , Modelos Animales de Enfermedad , Ratones , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Espermidina/farmacología , Espermidina/uso terapéuticoRESUMEN
Most neurodegenerative diseases such as Alzheimer's disease are proteinopathies linked to the toxicity of amyloid oligomers. Treatments to delay or cure these diseases are lacking. Using budding yeast, we report that the natural lipid tripentadecanoin induces expression of the nitric oxide oxidoreductase Yhb1 to prevent the formation of protein aggregates during aging and extends replicative lifespan. In mammals, tripentadecanoin induces expression of the Yhb1 orthologue, neuroglobin, to protect neurons against amyloid toxicity. Tripentadecanoin also rescues photoreceptors in a mouse model of retinal degeneration and retinal ganglion cells in a Rhesus monkey model of optic atrophy. Together, we propose that tripentadecanoin affects p-bodies to induce neuroglobin expression and offers a potential treatment for proteinopathies and retinal neurodegeneration.
Asunto(s)
Amiloide , Lípidos , Agregación Patológica de Proteínas , Animales , Ratones , Enfermedad de Alzheimer , Amiloide/efectos de los fármacos , Amiloide/metabolismo , Péptidos beta-Amiloides/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Dioxigenasas , Hemoproteínas , Lípidos/farmacología , Mamíferos , Neuroglobina/efectos de los fármacos , Neuroglobina/metabolismo , Cuerpos de Procesamiento/efectos de los fármacos , Cuerpos de Procesamiento/metabolismo , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/metabolismo , Células Ganglionares de la Retina/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiaeRESUMEN
Alzheimer's disease (AD) is caused by various pathological mechanisms; therefore, it is necessary to develop drugs that simultaneously act on multiple targets. In this study, we investigated the effects of eugenitol, which has anti-amyloid ß (Aß) and anti-neuroinflammatory effects, in an AD mouse model. We found that eugenitol potently inhibited Aß plaque and oligomer formation. Moreover, eugenitol dissociated the preformed Aß plaques and reduced Aß-induced nero2a cell death. An in silico docking simulation study showed that eugenitol may interact with Aß1-42 monomers and fibrils. Eugenitol showed radical scavenging effects and potently reduced the release of proinflammatory cytokines from lipopolysaccharide-treated BV2 cells. Systemic administration of eugenitol blocked Aß aggregate-induced memory impairment in the Morris water maze test in a dose-dependent manner. In 5XFAD mice, prolonged administration of eugenitol ameliorated memory and hippocampal long-term potentiation impairment. Moreover, eugenitol significantly reduced Aß deposits and neuroinflammation in the hippocampus of 5XFAD mice. These results suggest that eugenitol, which has anti-Aß aggregation, Aß fibril dissociation, and anti-inflammatory effects, potently modulates AD-like pathologies in 5XFAD mice, and could be a promising candidate for AD therapy.
Asunto(s)
Péptidos beta-Amiloides , Trastornos de la Memoria , Enfermedades Neuroinflamatorias , Animales , Masculino , Ratones , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocinas/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Depuradores de Radicales Libres/metabolismo , Hipocampo/efectos de los fármacos , Trastornos de la Memoria/patología , Enfermedades Neuroinflamatorias/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Alzheimer's disease (AD) is characterized by amyloid beta (Aß) plaques and neurofibrillary tangles. AD drug development has been limited due to the presence of the blood-brain barrier (BBB), which prevents efficient uptake of therapeutics into the brain. To solve this problem, we used trans-activator of transcription (TAT)-transducing domain and added the human serum albumin (HSA) carrier to increase the half-life of the drug within the body. In addition, we included the protein of interest for lowering Aß deposition and/or neurofibrillary tangles. We made HSA fusion protein (designated AL04) which contains Cystatin C (CysC) as core mechanism of action moiety in the construct containing tandem repeat TAT (dTAT). After purification of 80KDa AL04, we investigate the therapeutic potential of AL04 in vitro and AD mouse model Tg2576. We evaluated the permeability of AL04 through the BBB using a cell-basedhuman BBB model and show that dTAT plays a role in facilitating the delivery of 80 kDa protein. We found out that AL04 attenuates Aß-induced neurotoxicity in PC12 cells. In Tg2576 mice brain, Aß plaques were dramatically reduced in AL04 treated mice. These data suggest that BBB-crossing albumin fusion protein AL04 with CysC active moiety can be a disease modifying treatment for AD.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides/efectos de los fármacos , Encéfalo/efectos de los fármacos , Cistatina C/farmacocinética , Portadores de Fármacos/farmacocinética , Albúmina Sérica Humana/farmacocinética , Animales , Barrera Hematoencefálica , Encéfalo/metabolismo , Encéfalo/patología , Cistatina C/administración & dosificación , Portadores de Fármacos/química , Productos del Gen tat/farmacocinética , Humanos , Ratones , Células PC12 , Ratas , Albúmina Sérica Humana/químicaRESUMEN
Alzheimer's disease (AD) is a complex neurodegenerative disease characterized by functional disruption, death of cholinergic neurons (ChNs) because of intracellular and extracellular Aß aggregates, and hyperphosphorylation of protein TAU (p-TAU). To date, there are no efficient therapies against AD. Therefore, new therapies for its treatment are in need. The goal of this investigation was to evaluate the effect of the polyphenol epigallocatechin-3-gallate (EGCG) on cholinergic-like neurons (ChLNs) bearing the mutation E280A in PRESENILIN 1 (PSEN1 E280A). To this aim, wild-type (WT) and PSEN1 E280A ChLNs were exposed to EGCG (5-50 µM) for 4 days. Untreated or treated neurons were assessed for biochemical and functional analysis. We found that EGCG (50 µM) significantly inhibited the aggregation of (i)sAPPßf, blocked p-TAU, increased ∆Ψm, decreased oxidation of DJ-1 at residue Cys106-SH, and inhibited the activation of transcription factor c-JUN and P53, PUMA, and CASPASE-3 in mutant ChLNs compared to WT. Although EGCG did not reduce (e)Aß42, the polyphenol reversed Ca2+ influx dysregulation as a response to acetylcholine (ACh) stimuli in PSEN1 E280A ChLNs, inhibited the activation of transcription factor NF-κB, and reduced the secretion of pro-inflammatory IL-6 in wild-type astrocyte-like cells (ALCs) when exposed to mutant ChLNs culture supernatant. Taken together, our findings suggest that the EGCG might be a promising therapeutic approach for the treatment of FAD.
Asunto(s)
Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/química , Catequina/análogos & derivados , Neuronas Colinérgicas/citología , Presenilina-1/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/efectos de los fármacos , Péptidos beta-Amiloides/toxicidad , Catequina/farmacología , Células Cultivadas , Neuronas Colinérgicas/efectos de los fármacos , Neuronas Colinérgicas/metabolismo , Femenino , Redes Reguladoras de Genes/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/metabolismo , Microscopía Fluorescente , Modelos Biológicos , Mutación , Agregado de Proteínas/efectos de los fármacosRESUMEN
Declines in physiological functions are the predominant risk factors for age-related diseases, such as cancers and neurodegenerative diseases. Therefore, delaying the aging process is believed to be beneficial in preventing the onset of age-related diseases. Previous studies have demonstrated that Graptopetalum paraguayense (GP) extract inhibits liver cancer cell growth and reduces the pathological phenotypes of Alzheimer's disease (AD) in patient IPS-derived neurons. Here, we show that GP extract suppresses ß-amyloid pathology in SH-SYS5Y-APP695 cells and APP/PS1 mice. Moreover, AMP-activated protein kinase (AMPK) activity is enhanced by GP extract in U87 cells and APP/PS1 mice. Intriguingly, GP extract enhances autophagy in SH-SYS5Y-APP695 cells, U87 cells, and the nematode Caenorhabditis elegans, suggesting a conserved molecular mechanism by which GP extract might regulate autophagy. In agreement with its role as an autophagy activator, GP extract markedly diminishes mobility decline in polyglutamine Q35 mutants and aged wild-type N2 animals in C. elegans. Furthermore, GP extract significantly extends lifespan in C. elegans.
Asunto(s)
Envejecimiento/efectos de los fármacos , Crassulaceae/química , Extractos Vegetales/farmacología , Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Péptidos beta-Amiloides/efectos de los fármacos , Animales , Autofagia/efectos de los fármacos , Caenorhabditis elegans/efectos de los fármacos , Técnicas de Cultivo de Célula , Modelos Animales de Enfermedad , Humanos , Longevidad/efectos de los fármacos , Ratones , Ratones TransgénicosRESUMEN
Our previous study found that low molecular weight chondroitin sulfate (LMWCS) had neuroprotective effects against the toxicity of amyloid-ß (Aß) peptides both in vitro and in vivo, and we speculated that the effects might be related with its anti-oxidative activities. In this study, the anti-Alzheimer's disease (AD) activity of LMWCS was further studied in 5XFAD transgenic mice. After 4-month gavage, the levels of Aß1-42 level, amyloid precursor protein (APP) and presenilin 1 (PS1) were significantly decreased in the brains of 5XFAD mice, indicating the alteration of APP metabolism by LMWCS. Besides, LMWCS inhibited the secretions of pro-inflammatory cytokines, including interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and IL-6. Furthermore, the suppression of neuroinflammation by LMWCS was supported by the decreased expressions of glial fibrillary acidic protein (GFAP) and toll-like receptor 2 (TLR2) in the brains. LMWCS also reduced the production of reactive oxygen species (ROS) and the level of phospho-tau (Ser404) in the brains. Nevertheless, the changes in the behavior tests were moderate. In conclusion, LMWCS administration ameliorated APP metabolism, neuroinflammation, ROS production and tau protein abnormality in the brains of 5XFAD mice, displaying the potential to improve the pathological changes of AD mouse brain. LMWCS could be considered as a promising anti-AD drug candidate, nonetheless, the therapy regimen need to be optimized to improve its pharmacotherapy efficacy.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Sulfatos de Condroitina/farmacología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/inmunología , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/inmunología , Péptidos beta-Amiloides/efectos de los fármacos , Precursor de Proteína beta-Amiloide/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Sulfatos de Condroitina/administración & dosificación , Citocinas/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Peso Molecular , Enfermedades Neuroinflamatorias/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Presenilina-1/efectos de los fármacos , Proteínas tau/efectos de los fármacosRESUMEN
Finding an effective therapeutic to prevent or cure AD has been difficult due to the complexity of the brain and limited experimental models. This study utilized unmodified and genetically modified Saccharomyces cerevisiae as model organisms to find potential natural bioactive compounds capable of reducing intracellular amyloid beta 42 (Aß42) and associated oxidative damage. Eleven natural bioactive compounds including mangiferin, quercetin, rutin, resveratrol, epigallocatechin gallate (EGCG), urolithin A, oleuropein, rosmarinic acid, salvianolic acid B, baicalein and trans-chalcone were screened for their ability to reduce intracellular green fluorescent protein tagged Aß42 (GFP-Aß42) levels. The two most effective compounds from the screens were combined in varying concentrations of each to study the combined capacity to reduce GFP-Aß42. The most effective combinations were examined for their effect on growth rate, turnover of native Aß42 and reactive oxygen species (ROS). The bioactive compounds except mangiferin and urolithin A significantly reduced intracellular GFP-Aß42 levels. Baicalein and trans-chalcone were the most effective compounds among those that were screened. The combination of baicalein and trans-chalcone synergistically reduced GFP-Aß42 levels. A combination of 15 µM trans-chalcone and 8 µM baicalein was found to be the most synergistic combination. The combination of the two compounds significantly reduced ROS and Aß42 levels in yeast cells expressing native Aß42 without affecting growth of the cells. These findings suggest that the combination of baicalein and trans-chalcone could be a promising multifactorial therapeutic strategy to cure or prevent AD. However, further studies are recommended to look for similar cytoprotective activity in humans and to find an optimal dosage.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Chalcona/farmacología , Flavanonas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Chalcona/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Flavanonas/metabolismo , Humanos , Modelos Biológicos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Fragmentos de Péptidos/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Sustancias Protectoras/farmacología , Especies Reactivas de Oxígeno/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismoAsunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/efectos de los fármacos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores , Ensayos Clínicos como Asunto/normas , Aprobación de Drogas , Humanos , Estados Unidos , United States Food and Drug AdministrationRESUMEN
BACKGROUND: Diabetes is a risk factor for Alzheimer's disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC). OBJECTIVE: This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications. METHODS: Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total Nâ=â118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aß1-42. Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index. RESULTS: Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aß1-42 (-0.57 (CI: -1.12, -0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aß1-42 compared to nonusers (-0.15 (CI: -0.28, -0.02), -0.31 (CI: -0.54, -0.07), respectively). CONCLUSION: Some evidence exists that diabetes medications are associated with lower levels of Aß1-42, but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD.
Asunto(s)
Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/efectos de los fármacos , Autopsia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Fragmentos de Péptidos/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Biguanidas/uso terapéutico , Femenino , Humanos , Masculino , Ovillos Neurofibrilares/patología , Neuropatología , Estudios Prospectivos , Compuestos de Sulfonilurea/uso terapéuticoRESUMEN
BACKGROUND: Alzheimer's disease (AD) is a degenerative brain disorder. Due to the relationship between the functional loss of astrocytes and AD, the present study aims to evaluate the effects of the low dose of methamphetamine (METH) on primary fetal human astrocytes under a stress paradigm as a possible model for AD. METHODS AND RESULTS: The groups in this study included Aß (Group 1), METH (Group 2), Aß + METH (METH after adding Aß for 24 h) (Group 3 as treated group), METH + Aß (Aß after adding METH for 24 h) (Group 4 as prevention group), and control group. Then, the gene expression of Bax, Bcl-X, PKCα, GSK3ß, and Cdk5 was evaluated. In addition, phosphorylated tau, p-GSK3ß, GSK3ß, and GSK3α proteins were assessed by western blotting. Further, cell cycle arrest and apoptosis were checked by flow cytometry and Hoechst staining. Based on the results, the expression of GSK3ß, Cdk5, and PKCα genes decreased in the prevention group, while GSK3ß and Cdk5 were amplified in the treatment group. Furthermore, the level of GSK3α and GSK3ß proteins in the treatment group increased, while it decreased in the prevention group. Additionally, a decrease occurred in the percentage of necrosis and early apoptosis in the treatment and prevention groups. The results of the cell cycle indicated that G1 increased, while G2 decreased in the prevention group. CONCLUSION: The pure form of METH can prevent from activating GSK-3ß and CdK-5, as well as enhanced activity of PKCα to inhibit phosphorylated tau protein. Therefore, a low dose of METH may have a protective effect or reducing role in the pathway of tau production in reactive astrocytes.
Asunto(s)
Péptidos beta-Amiloides/genética , Astrocitos/metabolismo , Metanfetamina/efectos adversos , Fragmentos de Péptidos/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/efectos de los fármacos , Apoptosis/genética , Astrocitos/efectos de los fármacos , Encéfalo , Sistema Nervioso Central/metabolismo , Quinasa 5 Dependiente de la Ciclina , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Glucógeno Sintasa Quinasa 3 beta , Hipocampo/metabolismo , Humanos , Metanfetamina/metabolismo , Metanfetamina/farmacología , Neuronas/metabolismo , Fragmentos de Péptidos/efectos de los fármacos , Proteína Quinasa C-alfa , Transcriptoma/efectos de los fármacos , Transcriptoma/genética , Proteína X Asociada a bcl-2 , Proteína bcl-XAsunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Aprobación de Drogas , Placa Amiloide/tratamiento farmacológico , United States Food and Drug Administration , Enfermedad de Alzheimer/etiología , Péptidos beta-Amiloides/efectos de los fármacos , Biomarcadores , Ensayos Clínicos como Asunto , Conflicto de Intereses , Aprobación de Drogas/legislación & jurisprudencia , Industria Farmacéutica/ética , Etiquetado de Medicamentos , Humanos , Placa Amiloide/complicaciones , Estados Unidos , United States Food and Drug Administration/ética , United States Food and Drug Administration/legislación & jurisprudenciaRESUMEN
OBJECTIVE: Nicotine, a main active compound in tobacco, has been shown to attenuate amyloid-ß (Aß) mediated neurotoxicity. However, the detailed underlying mechanisms remains to be elucidated. In this study, nematode Caenorhabditis elegans (C. elegans) had been chosen as the model animal for dissecting the role of nicotine in the prevention of Aß-induced toxicity in vivo. METHODS: CL2120 and CL4176 transgenic worms of Alzheimer's disease (AD) models were treated with different concentrations of nicotine, and worm paralysis was monitored. Next, the effects of nicotine on Aß deposits, Aß oligomers, reactive oxygen species (ROS) and the oxidative stress resistance in worms were measured. Moreover, the pathway responsible for nicotine alleviating Aß-induced toxicity in vivo was explored by observing the oxidative stress resistance of skn-1 or daf-16 mutants in the presence of nicotine. Furthermore, the worm paralysis and Aß deposits were further checked in CL4176 worms with skn-1 RNA interference under the condition of nicotine. RESULTS: Nicotine (5 µM) attenuated AD-like symptoms of worm paralysis in CL2120 and CL4176 transgenic C. elegans. Nicotine did not inhibit Aß aggregation in vitro, however it suppressed Aß deposits and reduced the Aß oligomers to alleviate the toxicity induced by Aß overexpression in C. elegans. Although nicotine did not possess apparent intrinsic anti-oxidative activity, it decreased in vivo reactive oxygen species (ROS). Nicotine enhanced the oxidative stress resistance of C. elegans, which was mediated by SKN-1 but not DAF-16 signaling. Furthermore, skn-1 RNAi abrogated the effect of nicotine reducing Aß deposits in vivo and completely blocked nicotine preventing Aß induced worm paralysis. CONCLUSIONS: Nicotine reduces Aß oligomer formation and alleviates Aß-induced paralysis of C. elegans, which is mediated by SKN-1 signaling.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/toxicidad , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Unión al ADN/metabolismo , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Factores de Transcripción/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/efectos de los fármacos , Animales , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Proteínas de Unión al ADN/genética , Nicotina/uso terapéutico , Agonistas Nicotínicos/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Factores de Transcripción/genéticaRESUMEN
One of the treatment strategies for Alzheimer's disease (AD) is based on the use of pharmacological agents capable of binding to beta-amyloid (Aß) and blocking its aggregation in the brain. Previously, we found that intravenous administration of the synthetic tetrapeptide Acetyl-His-Ala-Glu-Glu-Amide (HAEE), which is an analogue of the 35-38 region of the α4 subunit of α4ß2 nicotinic acetylcholine receptor and specifically binds to the 11-14 site of Aß, reduced the development of cerebral amyloidogenesis in a mouse model of AD. In the current study on three types of laboratory animals, we determined the biodistribution and tissue localization patterns of HAEE peptide after single intravenous bolus administration. The pharmacokinetic parameters of HAEE were established using uniformly tritium-labeled HAEE. Pharmacokinetic data provided evidence that HAEE goes through the blood-brain barrier. Based on molecular modeling, a role of LRP1 in receptor-mediated transcytosis of HAEE was proposed. Altogether, the results obtained indicate that the anti-amyloid effect of HAEE, previously found in a mouse model of AD, most likely occurs due to its interaction with Aß species directly in the brain.
Asunto(s)
Péptidos/farmacología , Péptidos/farmacocinética , Receptores Nicotínicos/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Animales , Transporte Biológico , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/farmacología , Péptidos/genética , Conejos , Ratas , Ratas Wistar , Receptores Nicotínicos/fisiologíaRESUMEN
Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Sever cognitive and memory impairments, huge increase in the prevalence of the disease, and lacking definite cure have absorbed worldwide efforts to develop therapeutic approaches. Since many drugs have failed in the clinical trials due to multifactorial nature of AD, symptomatic treatments are still in the center attention and now, nootropic medicinal plants have been found as versatile ameliorators to reverse memory disorders. In this work, anti-Alzheimer's activity of aqueous extract of areca nuts (Areca catechu L.) was investigated via in vitro and in vivo studies. It depicted good amyloid ß (Aß) aggregation inhibitory activity, 82% at 100 µg/mL. In addition, it inhibited beta-secretase 1 (BACE1) with IC50 value of 19.03 µg/mL. Evaluation of neuroprotectivity of the aqueous extract of the plant against H2O2-induced cell death in PC12 neurons revealed 84.5% protection at 1 µg/mL. It should be noted that according to our results obtained from Morris Water Maze (MWM) test, the extract reversed scopolamine-induced memory deficit in rats at concentrations of 1.5 and 3 mg/kg.
La enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo relacionado con la edad. Los severos deterioros cognitivos y de la memoria, el enorme aumento de la prevalencia de la enfermedad y la falta de una cura definitiva han absorbido los esfuerzos mundiales para desarrollar enfoques terapéuticos. Dado que muchos fármacos han fallado en los ensayos clínicos debido a la naturaleza multifactorial de la EA, los tratamientos sintomáticos siguen siendo el centro de atención y ahora, las plantas medicinales nootrópicas se han encontrado como mejoradores versátiles para revertir los trastornos de la memoria. En este trabajo, se investigó la actividad anti-Alzheimer del extracto acuoso de nueces de areca (Areca catechu L.) mediante estudios in vitro e in vivo. Representaba una buena actividad inhibidora de la agregación de amiloide ß (Aß), 82% a 100 µg/mL. Además, inhibió la beta-secretasa 1 (BACE1) con un valor de CI50 de 19,03 µg/mL. La evaluación de la neuroprotección del extracto acuoso de la planta contra la muerte celular inducida por H2O2 en neuronas PC12 reveló una protección del 84,5% a 1 µg/mL. Cabe señalar que, de acuerdo con nuestros resultados obtenidos de la prueba Morris Water Maze (MWM), el extracto revirtió el déficit de memoria inducido por escopolamina en ratas a concentraciones de 1,5 y 3 mg/kg.
Asunto(s)
Animales , Ratas , Areca/química , Extractos Vegetales/administración & dosificación , Enfermedad de Alzheimer/tratamiento farmacológico , beta-Amilasa/antagonistas & inhibidores , Péptidos beta-Amiloides/efectos de los fármacos , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/efectos de los fármacos , Fármacos Neuroprotectores , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/efectos de los fármacos , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/prevención & control , Prueba del Laberinto Acuático de Morris , Medicina TradicionalRESUMEN
Alzheimer's disease, characterized by brain deposits of amyloid-ß plaques and neurofibrillary tangles, is also linked to neurovascular dysfunction and blood-brain barrier breakdown, affecting the passage of substances into and out of the brain. We hypothesized that treatment of neurovascular alterations could be beneficial in Alzheimer's disease. Annexin A1 (ANXA1) is a mediator of glucocorticoid anti-inflammatory action that can suppress microglial activation and reduce blood-brain barrier leakage. We have reported recently that treatment with recombinant human ANXA1 (hrANXA1) reduced amyloid-ß levels by increased degradation in neuroblastoma cells and phagocytosis by microglia. Here, we show the beneficial effects of hrANXA1 in vivo by restoring efficient blood-brain barrier function and decreasing amyloid-ß and tau pathology in 5xFAD mice and Tau-P301L mice. We demonstrate that young 5xFAD mice already suffer cerebrovascular damage, while acute pre-administration of hrANXA1 rescued the vascular defects. Interestingly, the ameliorated blood-brain barrier permeability in young 5xFAD mice by hrANXA1 correlated with reduced brain amyloid-ß load, due to increased clearance and degradation of amyloid-ß by insulin degrading enzyme (IDE). The systemic anti-inflammatory properties of hrANXA1 were also observed in 5xFAD mice, increasing IL-10 and reducing TNF-α expression. Additionally, the prolonged treatment with hrANXA1 reduced the memory deficits and increased synaptic density in young 5xFAD mice. Similarly, in Tau-P301L mice, acute hrANXA1 administration restored vascular architecture integrity, affecting the distribution of tight junctions, and reduced tau phosphorylation. The combined data support the hypothesis that blood-brain barrier breakdown early in Alzheimer's disease can be restored by hrANXA1 as a potential therapeutic approach.