RESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by several pathological hallmarks, including the deposition of amyloid-ß (Aß) plaques, neurofibrillary tangles, blood-brain barrier (BBB) dysfunction, increased oxidative stress, and neuroinflammation. Current treatment options include monoclonal antibody drugs, acetylcholinesterase, and n-methyl-d-aspartate (NMDA) antagonists. Although those treatments provide some improvements in patients' quality of life, they fail to prevent or cure AD. Current research aims to identify novel targets and tools for AD prevention and modification. In this context, several studies showed the beneficial effect of the Mediterranean diet in the prevention and treatment of AD. One integral component of the Mediterranean diet is olive oil and extra-virgin olive oil (EVOO), which is high in phenolic compounds. EVOO and other olive-related phenolic compounds have been shown to reduce the risk of developing mild cognitive impairment (MCI) and AD. In this review, we discuss the mechanisms by which EVOO and phenolic compounds exert neuroprotective effects, including modulation of AD pathologies and promotion of cognitive health. Findings indicate that EVOO and its phenolic constituents influence key pathological processes of AD, such as Aß aggregation, tau phosphorylation, and neuroinflammation, while also enhancing BBB integrity and reducing oxidative stress. The human studies cited reveal a consistent trend where the consumption of olive oil is associated with cognitive benefits and a decreased risk of AD and related dementias. In conclusion, EVOO and its phenolic compounds hold promising potential for the prevention and treatment of AD, representing a significant shift towards more effective strategies against this complex neurodegenerative disorder.
Asunto(s)
Enfermedad de Alzheimer , Animales , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/prevención & control , Aceite de Oliva/uso terapéutico , Acetilcolinesterasa , Enfermedades Neuroinflamatorias , Calidad de Vida , Péptidos beta-Amiloides , Fenoles/uso terapéuticoRESUMEN
The blood-brain barrier (BBB) is a unique and selective feature of the central nervous system's vasculature. BBB dysfunction has been observed as an early sign of Alzheimer's Disease (AD) before the onset of dementia or neurodegeneration. The intricate relationship between the BBB and the pathogenesis of AD, especially in the context of neurovascular coupling and the overlap of pathophysiology in neurodegenerative and cerebrovascular diseases, underscores the urgency to understand the BBB's role more deeply. Preserving or restoring the BBB function emerges as a potentially promising strategy for mitigating the progression and severity of AD. Molecular and genetic changes, such as the isoform ε4 of apolipoprotein E (ApoEε4), a significant genetic risk factor and a promoter of the BBB dysfunction, have been shown to mediate the BBB disruption. Additionally, receptors and transporters like the low-density lipoprotein receptor-related protein 1 (LRP1), P-glycoprotein (P-gp), and the receptor for advanced glycation end products (RAGEs) have been implicated in AD's pathogenesis. In this comprehensive review, we endeavor to shed light on the intricate pathogenic and therapeutic connections between AD and the BBB. We also delve into the latest developments and pioneering strategies targeting the BBB for therapeutic interventions, addressing its potential as a barrier and a carrier. By providing an integrative perspective, we anticipate paving the way for future research and treatments focused on exploiting the BBB's role in AD pathogenesis and therapy.
Asunto(s)
Enfermedad de Alzheimer , Trastornos Cerebrovasculares , Humanos , Enfermedad de Alzheimer/metabolismo , Barrera Hematoencefálica/metabolismo , Péptidos beta-Amiloides/metabolismo , Transporte Biológico/fisiología , Trastornos Cerebrovasculares/metabolismoRESUMEN
A surgically implantable device is an inevitable treatment option for millions of people worldwide suffering from diseases arising from orthopedic injuries. A global paradigm shift is currently underway to tailor and personalize replacement or reconstructive joints. Additive manufacturing (AM) has provided dynamic outflow to the customized fabrication of orthopedic implants by enabling need-based design and surface modification possibilities. Surgical grade 316L Stainless Steel (316L SS) is promising with its cost, strength, composition, and corrosion resistance to fabricate 3D implants. This work investigates the possibilities of application of the laser powder bed fusion (L-PBF) technique to fabricate 3D-printed (3DP) implants, which are functionalized with a multilayered antimicrobial coating to treat potential complications arising due to postsurgical infections (PSIs). Postsurgical implant-associated infection is a primary reason for implantation failure and is complicated mainly by bacterial colonization and biofilm formation at the installation site. PLGA (poly-d,l-lactide-co-glycolide), a biodegradable polymer, was utilized to impart multiple layers of coating using the airbrush spray technique on 3DP implant surfaces loaded with gentamicin (GEN). Various PLGA-based polymers were tested to optimize the ideal lactic acid: glycolic acid ratio and molecular weight suited for our investigation. 3D-Printed PLGA-GEN substrates sustained the release of gentamicin from the surface for approximately 6 weeks. The 3DP surface modification with PLGA-GEN facilitated cell adhesion and proliferation compared to control surfaces. The cell viability studies showed that the implants were safe for application. The 3DP PLGA-GEN substrates showed good concentration-dependent antibacterial efficacy against the common PSI pathogen Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis). The GEN-loaded substrates demonstrated antimicrobial longevity and showed significant biofilm growth inhibition compared to control. The substrates offered great versatility regarding the in vitro release rates, antimicrobial properties, and biocompatibility studies. These results radiate great potential in future human and veterinary clinical applications pertinent to complications arising from PSIs, focusing on personalized sustained antibiotic delivery.
Asunto(s)
Antiinfecciosos , Gentamicinas , Humanos , Gentamicinas/farmacología , Gentamicinas/química , Staphylococcus aureus , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Staphylococcus epidermidis , Polímeros , Impresión TridimensionalRESUMEN
Aging is a major risk factor for Alzheimer's disease (AD). AD mouse models are frequently used to assess pathology, behavior, and memory in AD research. While the pathological characteristics of AD are well established, our understanding of the changes in the metabolic phenotypes with age and pathology is limited. In this work, we used the Promethion cage systems® to monitor changes in physiological metabolic and behavioral parameters with age and pathology in wild-type and 5xFAD mouse models. Then, we assessed whether these parameters could be altered by treatment with oleocanthal, a phenolic compound with neuroprotective properties. Findings demonstrated metabolic parameters such as body weight, food and water intake, energy expenditure, dehydration, and respiratory exchange rate, and the behavioral parameters of sleep patterns and anxiety-like behavior are altered by age and pathology. However, the effect of pathology on these parameters was significantly greater than normal aging, which could be linked to amyloid-ß deposition and blood-brain barrier (BBB) disruption. In addition, and for the first time, our findings suggest an inverse correlation between sleep hours and BBB breakdown. Treatment with oleocanthal improved the assessed parameters and reduced anxiety-like behavior symptoms and sleep disturbances. In conclusion, aging and AD are associated with metabolism and behavior changes, with the changes being greater with the latter, which were rectified by oleocanthal. In addition, our findings suggest that monitoring changes in metabolic and behavioral phenotypes could provide a valuable tool to assess disease severity and treatment efficacy in AD mouse models.
Asunto(s)
Enfermedad de Alzheimer , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Péptidos beta-Amiloides/metabolismo , Fenotipo , Modelos Animales de Enfermedad , Ratones TransgénicosRESUMEN
The blood-brain barrier (BBB) is a complex network of tightly regulated cells and transport proteins that separate the circulating blood from the brain tissue [...].
Asunto(s)
Barrera Hematoencefálica , Encéfalo , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Transporte Biológico , Proteínas Portadoras/metabolismoRESUMEN
Alzheimer's disease (AD) is characterized by several pathological hallmarks, including the deposition of amyloid-ß (Aß) plaques, neurofibrillary tangles, blood-brain barrier (BBB) dysfunction, and neuroinflammation. Growing evidence support the neuroprotective effects of extra-virgin olive oil (EVOO) and oleocanthal (OC). In this work, we aimed to evaluate and compare the beneficial effects of equivalent doses of OC-low EVOO (0.5 mg total phenolic content/kg) and OC (0.5 mg OC/kg) on Aß and related pathology and to assess their effect on neuroinflammation in a 5xFAD mouse model with advanced pathology. Homozygous 5xFAD mice were fed with refined olive oil (ROO), OC-low EVOO, or OC for 3 months starting at the age of 3 months. Our findings demonstrated that a low dose of 0.5 mg/kg EVOO-phenols and OC reduced brain Aß levels and neuroinflammation by suppressing the nuclear factor-κB (NF-κB) pathway and reducing the activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes. On the other hand, only OC suppressed the receptor for advanced glycation endproducts/high-mobility group box 1 (RAGE/HMGB1) pathway. In conclusion, our results indicated that while OC-low EVOO demonstrated a beneficial effect against Aß-related pathology in 5xFAD mice, EVOO rich with OC could provide a higher anti-inflammatory effect by targeting multiple mechanisms. Collectively, diet supplementation with EVOO or OC could prevent, halt progression, and treat AD.
Asunto(s)
Enfermedad de Alzheimer , Ratones , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Aceite de Oliva/farmacología , Enfermedades Neuroinflamatorias , Receptor para Productos Finales de Glicación Avanzada , Ratones Endogámicos NOD , Péptidos beta-Amiloides/metabolismo , Fenoles/farmacología , Fenoles/uso terapéuticoRESUMEN
Mild cognitive impairment (MCI) and early Alzheimer's disease (AD) are characterized by blood-brain barrier (BBB) breakdown leading to abnormal BBB permeability ahead of brain atrophy or dementia. Previous findings in AD mouse models have reported the beneficial effect of extra-virgin olive oil (EVOO) against AD, which improved BBB and memory functions and reduced brain amyloid-ß (Aß) and related pathology. This work aimed to translate these preclinical findings to humans in individuals with MCI. We examined the effect of daily consumption of refined olive oil (ROO) and EVOO for 6 months in MCI subjects on BBB permeability (assessed by contrast-enhanced MRI), and brain function (assessed using functional-MRI) as the primary outcomes. Cognitive function and AD blood biomarkers were also assessed as the secondary outcomes. Twenty-six participants with MCI were randomized with 25 participants completed the study. EVOO significantly improved clinical dementia rating (CDR) and behavioral scores. EVOO also reduced BBB permeability and enhanced functional connectivity. While ROO consumption did not alter BBB permeability or brain connectivity, it improved CDR scores and increased functional brain activation to a memory task in cortical regions involved in perception and cognition. Moreover, EVOO and ROO significantly reduced blood Aß42/Aß40 and p-tau/t-tau ratios, suggesting that both altered the processing and clearance of Aß. In conclusion, EVOO and ROO improved CDR and behavioral scores; only EVOO enhanced brain connectivity and reduced BBB permeability, suggesting EVOO biophenols contributed to such an effect. This proof-of-concept study justifies further clinical trials to assess olive oil's protective effects against AD and its potential role in preventing MCI conversion to AD and related dementias.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Animales , Ratones , Humanos , Aceite de Oliva/farmacología , Barrera Hematoencefálica/metabolismo , Enfermedad de Alzheimer/prevención & control , Disfunción Cognitiva/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismoRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disorder; it is the most common cause of dementia and has no treatment. It is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aß) and the intraneuronal deposits of Neurofibrillary tangles (NFTs). Yet, those two hallmarks do not explain the full pathology seen with AD, suggesting the involvement of other mechanisms. Neuroinflammation could offer another explanation for the progression of the disease. This review provides an overview of recent advances on the role of the immune cells' microglia and astrocytes in neuroinflammation. In AD, microglia and astrocytes become reactive by several mechanisms leading to the release of proinflammatory cytokines that cause further neuronal damage. We then provide updates on neuroinflammation diagnostic markers and investigational therapeutics currently in clinical trials to target neuroinflammation.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Citocinas , Humanos , Microglía/patología , Neuroglía/patología , Enfermedades NeuroinflamatoriasRESUMEN
Alzheimer's disease (AD) is the most common form of dementia among several neurodegenerative disorders afflicting the elderly. AD is characterized by the deposition of extracellular amyloid-ß (Aß) plaques, disrupted blood-brain barrier (BBB), and neuroinflammation. Several studies have demonstrated the health benefits of olive oil and olive leaf extract (OLE) due to their polyphenolic content. The main phenolic compound in OLE is glycosylated oleuropein (OLG), while the aglycon form of oleuropein (OLA) exists in much lower amounts. This work aimed to evaluate the effect of a low dose of OLG-rich OLE and the mechanism(s) that contributed to the observed beneficial effects against Aß pathology in the homozygous 5xFAD mouse model. Mice were fed with OLE-enriched diet (695 µg/kg body weight/day) for 3 months, starting at 3 months old. Overall findings demonstrated that OLE reduced neuroinflammation by inhibiting the NF-κB pathway and suppressing the activation of NLRP3 inflammasomes and RAGE/HMGB1 pathways. In addition, OLE reduced total Aß brain levels due to increased clearance and reduced production of Aß and enhanced BBB integrity and function, which collectively improved the memory function. Thus, the consumption of OLE as a dietary supplement is expected to stop and/or slow the progression of AD.
Asunto(s)
Enfermedad de Alzheimer , Olea , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Glucósidos Iridoides , Ratones , Enfermedades Neuroinflamatorias , Olea/metabolismo , Extractos VegetalesRESUMEN
Since the first discovery of its ibuprofen-like anti-inflammatory activity in 2005, the olive phenolic (-)-oleocanthal gained great scientific interest and popularity due to its reported health benefits. (-)-Oleocanthal is a monophenolic secoiridoid exclusively occurring in extra-virgin olive oil (EVOO). While several groups have investigated oleocanthal pharmacokinetics (PK) and disposition, none was able to detect oleocanthal in biological fluids or identify its PK profile that is essential for translational research studies. Besides, oleocanthal could not be detected following its addition to any fluid containing amino acids or proteins such as plasma or culture media, which could be attributed to its unique structure with two highly reactive aldehyde groups. Here, we demonstrate that oleocanthal spontaneously reacts with amino acids, with high preferential reactivity to glycine compared to other amino acids or proteins, affording two products: an unusual glycine derivative with a tetrahydropyridinium skeleton that is named oleoglycine, and our collective data supported the plausible formation of tyrosol acetate as the second product. Extensive studies were performed to validate and confirm oleocanthal reactivity, which were followed by PK disposition studies in mice, as well as cell culture transport studies to determine the ability of the formed derivatives to cross physiological barriers such as the blood-brain barrier. To the best of our knowledge, we are showing for the first time that (-)-oleocanthal is biochemically transformed to novel products in amino acids/glycine-containing fluids, which were successfully monitored in vitro and in vivo, creating a completely new perspective to understand the well-documented bioactivities of oleocanthal in humans.
RESUMEN
In Alzheimer's disease (AD), several studies have reported blood-brain barrier (BBB) breakdown with compromised function. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are transport proteins localized at the BBB luminal membrane and play an important role in the clearance of amyloid-ß (Aß). The purpose of this study was to investigate the effect of pharmacological inhibition of Aß efflux transporters on BBB function and Aß accumulation and related pathology. Recently, we have developed an in vitro high-throughput screening assay to screen for compounds that modulate the integrity of a cell-based BBB model, which identified elacridar as a disruptor of the monolayer integrity. Elacridar, an investigational compound known for its P-gp and BCRP inhibitory effect and widely used in cancer research. Therefore, it was used as a model compound for further evaluation in a mouse model of AD, namely TgSwDI. TgSwDI mouse is also used as a model for cerebral amyloid angiopathy (CAA). Results showed that P-gp and BCRP inhibition by elacridar disrupted the BBB integrity as measured by increased IgG extravasation and reduced expression of tight junction proteins, increased amyloid deposition due to P-gp, and BCRP downregulation and receptor for advanced glycation end products (RAGE) upregulation, increased CAA and astrogliosis. Further studies revealed the effect was mediated by activation of NF-κB pathway. In conclusion, results suggest that BBB disruption by inhibiting P-gp and BCRP exacerbates AD pathology in a mouse model of AD, and indicate that therapeutic drugs that inhibit P-gp and BCRP could increase the risk for AD.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Acridinas/farmacología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Barrera Hematoencefálica/metabolismo , Encéfalo/efectos de los fármacos , Tetrahidroisoquinolinas/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Acridinas/administración & dosificación , Enfermedad de Alzheimer/patología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Barrera Hematoencefálica/patología , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular , Modelos Animales de Enfermedad , Inmunoglobulina G/metabolismo , Inmunohistoquímica , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Transgénicos , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Tetrahidroisoquinolinas/administración & dosificación , Uniones Estrechas/metabolismoRESUMEN
Alzheimer disease (AD) is usually accompanied by two prominent pathological features, cerebral accumulation of amyloid-ß (Aß) plaques and presence of MAPT/tau neurofibrillary tangles. Dysregulated clearance of Aß largely contributes to its accumulation and plaque formation in the brain. Macroautophagy/autophagy is a lysosomal degradative process, which plays an important role in the clearance of Aß. Failure of autophagic clearance of Aß is currently acknowledged as a contributing factor to increased accumulation of Aß in AD brains. In this study, we have identified crocetin, a pharmacologically active constituent from the flower stigmas of Crocus sativus, as a potential inducer of autophagy in AD. In the cellular model, crocetin induced autophagy in N9 microglial and primary neuron cells through STK11/LKB1 (serine/threonine kinase 11)-mediated AMP-activated protein kinase (AMPK) pathway activation. Autophagy induction by crocetin significantly increased Aß clearance in N9 cells. Moreover, crocetin crossed the blood-brain barrier and induced autophagy in the brains' hippocampi of wild-type male C57BL/6 mice. Further studies in transgenic male 5XFAD mice, as a model of AD, revealed that one-month treatment with crocetin significantly reduced Aß levels and neuroinflammation in the mice brains and improved memory function by inducing autophagy that was mediated by AMPK pathway activation. Our findings support further development of crocetin as a pharmacological inducer of autophagy to prevent, slow down progression, and/or treat AD.Abbreviations: Aß: amyloid-ß; ABCB1/P-gp/P-glycoprotein: ATP-binding cassette, subfamily B (MDR/TAP), member 1; AD: Alzheimer disease; AMPK/PRKAA: AMP-activated protein kinase; APP: amyloid beta (A4) precursor protein; ATG: autophagy related; BBB: blood-brain barrier; BECN1: beclin 1, autophagy related; CAMKK2/CaMKKß: calcium/calmodulin-dependent protein kinase kinase 2, beta; CSE: Crocus sativus extract; CTSB: cathepsin B; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; GFAP: glial fibrillary acidic protein; GSK3B/GSK3ß: glycogen synthase kinase 3 beta; Kp: brain partition coefficient; LRP1: low density lipoprotein receptor-related protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAP2: microtubule-associated protein 2; MAPK/ERK: mitogen-activated protein kinase; MAPT/tau: microtubule-associated protein tau; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTOR: mechanistic target of rapamycin kinase; MWM: Morris water maze; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NMDA: N-methyl-d-aspartic acid; RPTOR: regulatory associated protein of MTOR; RPS6KB1/p70S6K: ribosomal protein S6 kinase 1; SQSTM1: sequestosome 1; SRB: sulforhodamine B; STK11/LKB1: serine/threonine kinase 11; TFEB: transcription factor EB; TSC2: TSC complex subunit 2; ULK1: unc-51 like kinase 1.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Autofagia/efectos de los fármacos , Carotenoides/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Vitamina A/análogos & derivados , Péptidos beta-Amiloides/metabolismo , Animales , Línea Celular , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Vitamina A/farmacologíaRESUMEN
This comment is intended to discuss errors observed in the title paper, doi:10.3390/pharmaceutics12020134. When this paper was published, the authors of this commentary were excited to read it. However, the more we read, the more pitfalls were observed, which necessitated a response to revise the many errors and misleading information included in this publication.
RESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Aim: Additively manufactured (3D printed), stainless steel implants were coated with dexamethasone using gelatin, chondroitin sulfate for use in bone graft surgeries. Materials & methods: The drug and polymers were deposited on the implants with a rough surface using a high precision air brush. The gelatin-chondroitin sulfate layers were cross-linked using glutaraldehyde. Results: The drug content uniformity was within 100 ± 5%, and the thickness of the polymer layer was 410 ± 5.2 µm. The in vitro release studies showed a biphasic pattern with an initial burst release followed by slow release up to 3 days. Conclusion: These results are very promising as the slow release implants can be further tested in vivo in large animals, such as cattle and horses to prevent the inflammatory cascade following surgeries.
Asunto(s)
Huesos/lesiones , Dexametasona , Gelatina , Prótesis e Implantes , Animales , Bovinos , Caballos , Polímeros , Impresión TridimensionalRESUMEN
A major characteristic of Alzheimer's disease (AD) is the accumulation of misfolded amyloid-ß (Aß) peptide. Several studies linked AD with type 2 diabetes due to similarities between Aß and human amylin. This study investigates the effect of amylin and pramlintide on Aß pathogenesis and the predisposing molecular mechanism(s) behind the observed effects in TgSwDI mouse, a cerebral amyloid angiopathy (CAA) and AD model. Our findings showed that thirty days of intraperitoneal injection with amylin or pramlintide increased Aß burden in mice brains. Mechanistic studies revealed both peptides altered the amyloidogenic pathway and increased Aß production by modulating amyloid precursor protein (APP) and γ-secretase levels in lipid rafts. In addition, both peptides increased levels of B4GALNT1 enzyme and GM1 ganglioside, and only pramlintide increased the level of GM2 ganglioside. Increased levels of GM1 and GM2 gangliosides play an important role in regulating amyloidogenic pathway proteins in lipid rafts. Increased brain Aß burden by amylin and pramlintide was associated with synaptic loss, apoptosis, and microglia activation. In conclusion, our findings showed amylin or pramlintide increase Aß levels and related pathology in TgSwDI mice brains, and suggest that increased amylin levels or the therapeutic use of pramlintide could increase the risk of AD.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Microdominios de Membrana/metabolismo , Procesamiento Proteico-Postraduccional , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Angiopatía Amiloide Cerebral/genética , Angiopatía Amiloide Cerebral/metabolismo , Angiopatía Amiloide Cerebral/patología , Gangliósido G(M1)/genética , Gangliósido G(M1)/metabolismo , Gangliósido G(M2)/genética , Gangliósido G(M2)/metabolismo , Microdominios de Membrana/genética , Microdominios de Membrana/patología , Ratones , Ratones Transgénicos , N-Acetilgalactosaminiltransferasas/genética , N-Acetilgalactosaminiltransferasas/metabolismoRESUMEN
Alzheimer's disease (AD) is characterized by a compromised blood-brain barrier (BBB) and disrupted intracellular calcium homeostasis in the brain. Therefore, rectifying the BBB integrity and restoring calcium homeostasis could provide an effective strategy to treat AD. Recently, we developed a high throughput-screening assay to screen for compounds that enhance a cell-based BBB model integrity, which identified multiple hits among which is granisetron, a Food and Drug Administration approved drug. Here, we evaluated the therapeutic potential of granisetron against AD. Granisetron was tested in C57Bl/6J young and aged wild-type mice, and in a transgenic mouse model of AD namely TgSwDI for its effect on BBB intactness and amyloid-ß (Aß)-related pathology. Our study findings showed that granisetron enhanced BBB integrity in both aged and TgSwDI mice. This effect was associated with an overall reduction in Aß load and neuroinflammation in TgSwDI mice brains. In addition, and supported by proteomics analysis, granisetron significantly reduced Aß induced calcium influx in vitro, and rectified calcium dyshomeostasis in TgSwDI mice brains by restoring calmodulin-dependent protein kinase II/cAMP-response element binding protein pathway, which was associated with cognitive improvement. These results support granisetron repurposing as a potential drug to hold, slow, and/or treat AD.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Granisetrón/farmacología , Fármacos Neuroprotectores/farmacología , Transducción de Señal/efectos de los fármacos , Enfermedad de Alzheimer/genética , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones TransgénicosRESUMEN
Mutations exclusively in equilibrative nucleoside transporter 3 (ENT3), the only intracellular nucleoside transporter within the solute carrier 29 (SLC29) gene family, cause an expanding spectrum of human genetic disorders (e.g., H syndrome, PHID syndrome, and SHML/RDD syndrome). Here, we identify adult stem cell deficits that drive ENT3-related abnormalities in mice. ENT3 deficiency alters hematopoietic and mesenchymal stem cell fates; the former leads to stem cell exhaustion, and the latter leads to breaches of mesodermal tissue integrity. The molecular pathogenesis stems from the loss of lysosomal adenosine transport, which impedes autophagy-regulated stem cell differentiation programs via misregulation of the AMPK-mTOR-ULK axis. Furthermore, mass spectrometry-based metabolomics and bioenergetics studies identify defects in fatty acid utilization, and alterations in mitochondrial bioenergetics can additionally propel stem cell deficits. Genetic, pharmacologic and stem cell interventions ameliorate ENT3-disease pathologies and extend the lifespan of ENT3-deficient mice. These findings delineate a primary pathogenic basis for the development of ENT3 spectrum disorders and offer critical mechanistic insights into treating human ENT3-related disorders.
Asunto(s)
Células Madre Adultas/metabolismo , Proteínas de Transporte de Nucleósidos/metabolismo , Adenosina/metabolismo , Adenilato Quinasa/metabolismo , Células Madre Adultas/ultraestructura , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Animales , Autofagia , Transporte Biológico , Diferenciación Celular , Autorrenovación de las Células , Metabolismo Energético , Ácidos Grasos/metabolismo , Células HEK293 , Humanos , Metabolismo de los Lípidos , Lisosomas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Fenotipo , Ribonucleótidos/farmacología , Transducción de Señal , Análisis de Supervivencia , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by multiple hallmarks including extracellular amyloid (Aß) plaques, neurofibrillary tangles, dysfunctional blood-brain barrier (BBB), neuroinflammation, and impaired autophagy. Thus, novel strategies that target multiple disease pathways would be essential to prevent, halt, or treat the disease. A growing body of evidence including our studies supports a protective effect of oleocanthal (OC) and extra-virgin olive oil (EVOO) at early AD stages before the onset of pathology. In addition, we reported previously that OC and EVOO exhibited such effect by restoring the BBB function; however, the mechanism(s) by which OC and EVOO exert such an effect and whether this effect extends to a later stage of AD remain unknown. In this work, we sought first to test the effect of OC-rich EVOO consumption at an advanced stage of the disease in TgSwDI mice, an AD mouse model, starting at the age of 6 months for 3 months treatment, and then to elucidate the mechanism(s) by which OC-rich EVOO exerts the observed beneficial effect. Overall findings demonstrated that OC-rich EVOO restored the BBB function and reduced AD-associated pathology by reducing neuroinflammation through inhibition of NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome and inducing autophagy through activation of AMP-activated protein kinase (AMPK)/Unc-51-like autophagy activating kinase 1 (ULK1) pathway. Thus, diet supplementation with OC-rich EVOO could provide beneficial effect to slow or halt the progression of AD.