RESUMEN
RATIONALE AND OBJECTIVES: Prior to clinical presentations of Alzheimer's Disease (AD), neuropathological changes, such as amyloid-ß and brain atrophy, have accumulated at the earlier stages of the disease. The combination of such biomarkers assessed by multiple modalities commonly improves the likelihood of AD etiology. We aimed to explore the discriminative ability of Aß PET features and whether combining Aß PET and structural MRI features can improve the classification performance of the machine learning model in older healthy control (OHC) and mild cognitive impairment (MCI) from AD. MATERIAL AND METHODS: We collected 94 AD patients, 82 MCI patients, and 85 OHC from three different cohorts. 17 global/regional Aß features in Centiloid, 122 regional volume, and 68 regional cortical thickness were extracted as imaging features. Single or combined modality features were used to train the random forest model on the testing set. The top 10 features were sorted based on the Gini index in each binary classification. RESULTS: The results showed that AUC scores were 0.81/0.86 and 0.69/0.68 using sMRI/Aß PET features on the testing set in differentiating OHC and MCI from AD. The performance was improved while combining two-modality features with an AUC of 0.89 and an AUC of 0.71 in two classifications. Compared to sMRI features, particular Aß PET features contributed more to differentiating AD from others. CONCLUSION: Our study demonstrated the discriminative ability of Aß PET features in differentiating AD from OHC and MCI. A combination of Aß PET and structural MRI features can improve the RF model performance.
RESUMEN
Microglia, as resident macrophages in the central nervous system, play a multifunctional role in the pathogenesis of Alzheimer's disease (AD). Their clustering around amyloid-ß (Aß) deposits is a core pathological feature of AD. Recent advances in single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) have revealed dynamic changes in microglial phenotypes over time and across different brain regions during aging and AD progression. As AD advances, microglia primarily exhibit impaired phagocytosis of Aß and tau, along with the release of pro-inflammatory cytokines that damage synapses and neurons. Targeting microglia has emerged as a potential therapeutic approach for AD. Treatment strategies involving microglia can be broadly categorized into two aspects: (1) enhancing microglial function: This involves augmenting their phagocytic ability against Aß and cellular debris and (2) mitigating neuroinflammation: Strategies include inhibiting TNF-α signaling to reduce the neuroinflammatory response triggered by microglia. Clinical trials exploring microglia-related approaches for AD treatment have garnered attention. Additionally, natural products show promise in enhancing beneficial effects and suppressing inflammatory responses. Clarifying microglial dynamics, understanding their roles, and exploring novel therapeutic approaches will advance our fight against AD.
Asunto(s)
Enfermedad de Alzheimer , Microglía , Fagocitosis , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/terapia , Humanos , Microglía/metabolismo , Microglía/patología , Animales , Péptidos beta-Amiloides/metabolismoRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disease accompanied by irreversible cognitive impairment. A deleterious feedback loop between oxidative stress and neuroinflammation in early AD exacerbates AD-related pathology. Platycodon grandiflorum root extract (PGE) has antioxidant and anti-inflammatory effects in several organs. However, the mechanisms underlying the effects of PGE in the brain remain unclear, particularly regarding its impact on oxidative/inflammatory damage and Aß deposition. Thus, we aim to identify the mechanism through which PGE inhibits Aß deposition and oxidative stress in the brain by conducting biochemical and histological analyses. First, to explore the antioxidant mechanism of PGE in the brain, we induced oxidative stress in mice injected with scopolamine and investigated the effect of PGE on cognitive decline and oxidative damage. We also assessed the effect of PGE on reactive oxygen species (ROS) generation and the expressions of antioxidant enzymes and neurotrophic factor in H2O2- and Aß-treated HT22 hippocampal cells. Next, we investigated whether PGE, which showed antioxidant effects, could reduce Aß deposition by mitigating neuroinflammation, especially microglial phagocytosis. We directly verified the effect of PGE on microglial phagocytosis, microglial activation markers, and pro-inflammatory cytokines in Aß-treated BV2 microglial cells. Moreover, we examined the effect of PGE on neuroinflammation, inducing microglial responses in Aß-overexpressing 5XFAD transgenic mice. PGE exerts antioxidant effects in the brain, enhances microglial phagocytosis of Aß, and inhibits neuroinflammation and Aß deposition, ultimately preventing neuronal cell death in AD. Taken together, our findings indicate that the therapeutic potential of PGE in AD is mediated by its targeting of multiple pathological processes.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Antioxidantes , Microglía , Enfermedades Neuroinflamatorias , Estrés Oxidativo , Extractos Vegetales , Raíces de Plantas , Platycodon , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Ratones , Platycodon/química , Péptidos beta-Amiloides/metabolismo , Masculino , Raíces de Plantas/química , Microglía/efectos de los fármacos , Microglía/metabolismo , Antioxidantes/farmacología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Línea Celular , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Modelos Animales de Enfermedad , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Fagocitosis/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Ratones Transgénicos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patologíaRESUMEN
PURPOSE: The Centiloid project helps calibrate the quantitative amyloid-ß (Aß) load into a unified Centiloid (CL) scale that allows data comparison across multi-site. How the smaller regional amyloid converted into CL has not been attempted. We first aimed to express regional Aß deposition in CL using [18F]Flutemetamol and evaluate regional Aß deposition in CL with that in standardized uptake value ratio (SUVr). Second, we aimed to determine the presence or absence of focal Aß deposition by measuring regional CL in equivocal cases showing negative global CL. METHODS: Following the Centiloid project pipeline, Level-1 replication, Level-2 calibration, and quality control were completed to generate corresponding Centiloid conversion equations to convert SUVr into Centiloid at regional levels. In equivocal cases, the regional CL was compared with visual inspection to evaluate regional Aß positivity. RESULTS: 14 out of 16 regional conversions from [18F]Flutemetamol SUVr to Centiloid successfully passed the quality control, showing good reliability and relative variance, especially precuneus/posterior cingulate and prefrontal regions with good stability for Centiloid scaling. The absence of focal Aß deposition could be detected by measuring regional CL, showing a high agreement rate with visual inspection. The regional Aß positivity in the bilateral anterior cingulate cortex was most prevalent in equivocal cases. CONCLUSION: The expression of regional brain Aß deposition in CL with [18F]Flutemetamol has been attempted in this study. Equivocal cases had focal Aß deposition that can be detected by measuring regional CL.
Asunto(s)
Péptidos beta-Amiloides , Compuestos de Anilina , Benzotiazoles , Tomografía de Emisión de Positrones , Radiofármacos , Humanos , Péptidos beta-Amiloides/metabolismo , Femenino , Masculino , Anciano , Tomografía de Emisión de Positrones/métodos , Reproducibilidad de los Resultados , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Persona de Mediana Edad , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , CalibraciónRESUMEN
Blunt and diffuse injury is a highly prevalent form of traumatic brain injury (TBI) which can result in microstructural alterations in the brain. The blunt impact on the brain can affect the immediate contact region but can also affect the vulnerable regions like hippocampus, leading to functional impairment and long-lasting cognitive deficits. The hippocampus of the moderate weight drop injured male rats was longitudinally assessed for microstructural changes using in vivo MR imaging from 4 h to Day 30 post-injury (PI). The DTI analysis found a prominent decline in the apparent diffusion coefficient (ADC), radial diffusivity (RD), and axial diffusivity (AD) values after injury. The perturbed DTI scalars accompanied histological changes in the hippocampus, wherein both the microglia and astrocytes showed changes in the morphometric parameters at all timepoints. Along with this, the hippocampus showed presence of Aß positive fibrils and neurite plaques after injury. Therefore, this study concludes that TBI can lead to a complex morphological, cellular, and structural alteration in the hippocampus which can be diagnosed using in vivo MR imaging techniques to prevent long-term functional deficits.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Imagen de Difusión Tensora , Ratas , Masculino , Animales , Imagen de Difusión Tensora/métodos , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen de Difusión por Resonancia Magnética , Hipocampo/patologíaRESUMEN
Uncovering the molecular changes at the site where Aß is deposited plays a critical role in advancing the diagnosis and treatment of Alzheimer's disease. However, there is currently a lack of a suitable label-free imaging method with a high spatial resolution for brain tissue analysis. In this study, we propose a modified desorption electrospray ionization (DESI) mass spectrometry imaging (MSI) method, called segmented temperature-controlled DESI (STC-DESI), to achieve high-resolution and high-sensitivity spatial metabolomics observation by precisely controlling desorption and ionization temperatures. By concentrating the spray plume and accelerating solvent evaporation at different temperatures, we achieved an impressive spatial resolution of 20 µm that enables direct observation of the heterogeneity around a single cell or an individual Aß plaque and an exciting sensitivity that allows a variety of low-abundance metabolites and less ionizable neutral lipids to be detected. We applied this STC-DESI method to analyze the brains of transgenic AD mice and identified molecular changes associated with individual Aß aggregates. More importantly, our study provides the first evidence that carnosine is significantly depleted and 5-caffeoylquinic acid (5-CQA) levels rise sharply around Aß deposits. These observations highlight the potential of carnosine as a sensitive molecular probe for clinical magnetic resonance imaging diagnosis and the potential of 5-CQA as an efficient therapeutic strategy for Aß clearance in the early AD stage. Overall, our findings demonstrate the effectiveness of our STC-DESI method and shed light on the potential roles of these molecules in AD pathology, specifically in cellular endocytosis, gray matter network disruption, and paravascular Aß clearance.
Asunto(s)
Enfermedad de Alzheimer , Carnosina , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Placa Amiloide/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Ratones Transgénicos , Encéfalo/metabolismo , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
BACKGROUND: Alzheimer's disease (AD) is a degenerative neurological disorder. Recent studies have indicated that histone deacetylases (HDACs) are among the most prominent epigenetic therapy targets and that HDAC inhibitors have therapeutic effects on AD. Here, we identified sodium valproate (VPA), a pan-HDAC inhibitor, and WT161, a novel HDAC6 selective inhibitor, as potential therapeutic agents for AD. Underlying molecular mechanisms were investigated. METHODS: A cellular model, N2a-APPswe, was established via lentiviral infection, and the APPswe/PSEN1dE9 transgenic mouse model was employed in the study. LC-MS/MS was applied to quantify the concentration of WT161 in the mouse brain. Western blotting, immunohistochemical staining, thioflavin-S staining and ELISA were applied to detect protein expression in cells, tissues, or serum. RNA interference was utilized to knockdown the expression of specific genes in cells. The cognitive function of mice was assessed via the nest-building test, novel object recognition test and Morris water maze test. RESULTS: Previous studies have focused mainly on the impact of HDAC inhibitors on histone deacetylase activity. Our study discovered that VPA and WT161 can downregulate the expression of multiple HDACs, such as HDAC1 and HDAC6, in both AD cell and mouse models. Moreover, they also affect the expression of APP and APP secretases (BACE1, PSEN1, ADAM10). RNA interference and subsequent vitamin C induction further confirmed that the expression of APP and APP secretases is indeed regulated by HDAC1 and HDAC6, with the JNK pathway being the intermediate link in this regulatory process. Through the above pathways, VPA and WT161 effectively reduced Aß deposition in both AD cell and mouse models and significantly improved cognitive function in AD mice. CONCLUSIONS: In general, we have discovered that the HDAC6-JNK-APP secretases cascade is an important pathway for VPA and WT161 to exert their therapeutic effects on AD. Investigations into the safety and efficacy of VPA and WT161 were also conducted, providing essential preclinical evidence for assessing these two epigenetic drugs for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Ácidos Hidroxámicos , Compuestos de Terfenilo , Ratones , Animales , Enfermedad de Alzheimer/genética , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Cromatografía Liquida , Ácido Aspártico Endopeptidasas/metabolismo , Espectrometría de Masas en Tándem , Ratones Transgénicos , Modelos Animales de Enfermedad , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismoRESUMEN
Introduction: Iron oxide nanoparticles (Fe2O3-NPs) are small magnetic particles that are widely used in different aspects of biology and medicine in modern life. Fe2O3-NP accumulated in the living cells due to the absence of an active system to excrete the iron ions and damages cellular organelles by high reactivity. Methods: Herein cytotoxic effects of Fe2O3-NP with a size of 50 nm on the primary culture of neonatal rat hippocampus were investigated using 2,5-diphenyltetrazolium bromide (MTT) assay. Pathophysiological signs of Alzheimer's disease such as amyloid precursor protein (APP) expression, Aß aggregation, soluble APPα, and APPß secretion were also investigated in hippocampal cells treated with various concentrations of nanoparticle (NP) for different exposure times. Results: Our results revealed that Fe2O3-NP treatment causes oxidative stress in cells which is accompanied by upregulation of the APP and Aß in a concentration-dependent manner. NP exposure also leads to more secretion of sAPPß rather than sAPPα, leading to increased activation of ß-secretase in NP-received cells. All the harmful effects accumulate in neurons that cannot be renovated, leading to neurodegeneration in Alzheimer's disease. Conclusion: This study approved iron-based NPs could help to develop Alzheimer's and related neurological disorders and explained why some of the iron chelators have therapeutic potential in Alzheimer's disease. Highlights: Fe2O3-NP induced oxidative stress in hippocampal cells in a concentration dependent manner.Fe2O3-NP imposed up-regulation of APP in hippocampal cells.Fe2O3-NP activated ß-secretase and elevated sAPPß/sAPPα ratio.Cumulative effects of Fe2O3-NP damages increased cell death in neurons. Plain Language Summary: The most common type of dementia is Alzheimer's disease (AD), which is characterized by chronic neurodegeneration, impairment of memory, and disturbed planning, language, and thinking ability. In recent years, the use of nanoparticles has been increased in all aspects of life. Among these nanoparticles, iron oxide nanoparticles (Fe2O3-NP) are vital in biological sciences, medicine, magnetic resonance imaging, ultrasound, and optical imaging. Considering the general application and high reactivity of iron, growing concerns exist about the Fe2O3-NP application harms, especially in the central nervous system. Hippocampus tissue is one of the affected tissues in AD, which is widely investigated in recent years. This study aimed to investigate the cytotoxic effects of Fe2O3-NP on the primary culture of the hippocampus as one of the main tissues damaged in patients with AD. Our results revealed that treatment with different concentrations of Fe2O3-NP caused cellular damage in hippocampal cells. Exposure to Fe2O3-NP also caused oxidative stress. Our results showed a close association between oxidative stress and AD's pathological symptoms. The Fe2O3-NP application in medicine and biology should be limited.
RESUMEN
BACKGROUND: Ankle-brachial index (ABI), an indicator of atherosclerosis or arterial stiffness, has been associated with Alzheimer's disease (AD) dementia and related cognitive impairment. Nevertheless, only limited information is available regarding its contribution to brain alterations leading to cognitive decline in late-life. OBJECTIVE: We aimed to investigate the relationship of ABI with in vivo AD pathologies and cerebrovascular injury in cognitively impaired older adults. METHODS: Total 127 cognitively impaired (70 mild cognitive impairment and 57 AD dementia) individuals, who participated in an ongoing prospective cohort study, were included. All participants underwent comprehensive clinical and neuropsychological assessment, ABI measurement, apolipoprotein E (APOE) É4 genotyping, and multi-modal brain imaging including [11C] Pittsburgh Compound B (PiB)-positron emission tomography (PET) and [18F] fludeoxyglucose (FDG)-PET, and MRI. RESULTS: General linear model analysis showed significant relationship between ABI strata (low ABI: <1.00, normal ABI: 1.00-1.29, and high ABI: ≥1.30) and AD-signature region cerebral glucose metabolism (AD-CM), even after controlling age, sex, clinical dementia rating-sum of box, and APOE É4 positivity (pâ=â0.029). Post hoc comparison revealed that low ABI had significantly lower AD-CM than middle and high ABI, while no difference of AD-CM was found between middle and high ABI. There was no significant difference of global Aß deposition, AD-signature region cortical thickness, and white matter hyperintensity volume between the three ABI strata. CONCLUSION: Our findings suggest that lower ABI, likely related to atherosclerosis, may contribute to the aggravation of AD-related regional neurodegeneration in cognitively impaired older adults.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Índice Tobillo Braquial , Estudios Prospectivos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Apolipoproteínas E/metabolismo , Glucosa/metabolismo , Tomografía de Emisión de Positrones/métodos , Imagen por Resonancia MagnéticaRESUMEN
Cerebral amyloid angiopathy (CAA) is characterized by the cerebrovascular amyloid-ß (Aß) accumulation, and always accompanied by Alzheimer's disease (AD). Mitochondrial dysfunction-associated cellular events including cell death, inflammation and oxidative stress are implicated in the progression of CAA. Unfortunately, the molecular mechanisms revealing CAA pathogenesis are still obscure, thus requiring further studies. Mitochondrial calcium uptake 3 (MICU3), a regulator of the mitochondrial Ca2+ uniporter (MCU), mediates various biological functions, but its expression and influence on CAA are largely unknown. In the present study, we found that MICU3 expression was gradually declined in cortex and hippocampus of Tg-SwDI transgenic mice. Using stereotaxic operation with AAV9 encoding MICU3, we showed that AAV-MICU3 improved the behavioral performances and cerebral blood flow (CBF) in Tg-SwDI mice, along with markedly reduced Aß deposition through mediating Aß metabolism process. Importantly, we found that AAV-MICU3 remarkably improved neuronal death and mitigated glial activation and neuroinflammation in cortex and hippocampus of Tg-SwDI mice. Furthermore, excessive oxidative stress, mitochondrial impairment and dysfunction, decreased ATP and mitochondrial DNA (mtDNA) were detected in Tg-SwDI mice, while being considerably ameliorated upon MICU3 over-expression. More importantly, our in vitro experiments suggested that MICU3-attenuated neuronal death, activation of glial cells and oxidative stress were completely abrogated upon PTEN induced putative kinase 1 (PINK1) knockdown, indicating that PINK1 was required for MICU3 to perform its protective effects against CAA. Mechanistic experiment confirmed an interaction between MICU3 and PINK1. Together, these findings demonstrated that MICU3-PINK1 axis may serve as a key target for CAA treatment mainly through improving mitochondrial dysfunction.
Asunto(s)
Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Animales , Ratones , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Calcio/metabolismo , Angiopatía Amiloide Cerebral/genética , Angiopatía Amiloide Cerebral/metabolismo , Angiopatía Amiloide Cerebral/patología , Inflamación/metabolismo , Ratones Transgénicos , Mitocondrias/metabolismo , Neuroglía/metabolismo , Proteínas Quinasas/metabolismoRESUMEN
We synthesized a series of novel pyromeconic acid-styrene hybrid compounds and measured their activities in inhibiting Aß1-42 self-aggregation and promoting disaggregation, and their anti-inflammatory and antioxidant properties. The most potent compound, compound 30, had IC50 values of 11.15 µM and 6.87 µM for inhibition of fibril aggregation and promotion of fibril disaggregation, respectively. Because of its redox metal chelating property, 30 also inhibited Cu2+-induced Aß1-42 fibril aggregation and promoted fibril disaggregation with IC50 of 3.69 µM and 3.35 µM, respectively. Molecular docking demonstrated that 30 interacted with key amino acids of Aß1-42, and the reliability of the complex was confirmed by molecular dynamics. In addition, 30 displayed excellent antioxidative activity (oxygen radical absorbance capacity = 2.65 Trolox equivalents) and moderate anti-inflammatory activity and neuroprotection in cell culture assays. Compound 30 was safe in acute toxicity test in mice, and it exhibited favorable pharmacokinetic properties, particularly, accumulation in the hippocampus (maximum ratio of hippocampus to plasma = 7.12). Compound 30 alleviated cognitive deficits in scopolamine-induced amnesia mice; this property may have been attributed to reducing neuroinflammation by inhibiting ionized calcium binding adapter molecule 1 and glial fibrillary acidic protein expression and reducing oxidative stress by activating the Nrf2/HO-1 signaling pathway. In view of its many properties, we envision that 30 is a promising lead for the treatment of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer , Fármacos Neuroprotectores , Ratones , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Simulación del Acoplamiento Molecular , Neuroprotección , Reproducibilidad de los Resultados , Inhibidores de la Colinesterasa/farmacología , Antioxidantes/química , Oxidación-Reducción , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Fármacos Neuroprotectores/química , Acetilcolinesterasa/metabolismoRESUMEN
AIMS: This study aimed to clarify that breviscapine combined with bone marrow mesenchymal stem cells (BMSCs) treatment can reduce Aß deposition in Alzheimer's disease (AD) patients. BACKGROUND: AD is a common degenerative disease of the central nervous system. Aß protein deposition in the cerebral cortex and hippocampus causes neuronal peroxidation damage, synaptic dysfunction, neuroinflammation, and nerve cell apoptosis, and ultimately leads to AD. OBJECTIVE: To investigate whether breviscapine combined with BMSCs treatment can reduce Aß deposition in AD. METHODS: The AD rat model was successfully induced by Aß1-42. The expression of protein and mRNA was detected by western blot and reverse transcription-quantitative PCR (RT-qPCR), respectively. RESULTS: In AD rat brain tissue, the expression of circular RNA ciRS-7 (ciRS-7), ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), and NF-kappaB p65 was significantly downregulated, and the expression of ß-amyloid precursor protein (APP), ß-site APPcleaving enzyme 1 (BAEC1), and Aß was upregulated. The expression of ciRS-7, UCHL1, and p65 was significantly upregulated after breviscapine or BMSCs treatment, and there was increased APP and BAEC1 degradation. Notably, breviscapine combined with BMSCs treatment was more effective than either treatment alone. In SH-SY5Y cells, overexpression of ciRS-7 reduced Aß deposition by upregulating UCHL1 to degrade APP and BAEC1, but these effects were reversed with inhibition of NF-kB signaling. Finally, knockdown of ciRS-7 elevated Aß, APP, and BAEC1 expression in each group of rats compared with the control. CONCLUSION: Breviscapine combined with BMSCs treatment can reduce Aß deposition in AD rats and promote the degradation of APP and BAEC1 by activating NF-kB to promote UCHL1 expression.
Asunto(s)
Enfermedad de Alzheimer , Células Madre Mesenquimatosas , Neuroblastoma , Humanos , Animales , Ratas , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/terapia , ARN Circular/genética , FN-kappa B/genéticaRESUMEN
BACKGROUND/OBJECTIVE: AD-associated PSEN1 mutations exhibit high clinical heterogeneity. The discovery of these mutations and the analysis of their associations with cases such as EOAD should be critical to understanding AD's pathogenesis. METHODS: We performed clinical analysis, neuroimaging, target region capture and high-throughput sequencing, and Sanger sequencing in a family of 3 generations. The underlying Alzheimer's pathology was evaluated using biomarker evidence obtained from cerebrospinal fluid (CSF) amyloid testing and 18F-florbetapir (AV-45) PET imaging. RESULTS: Target region capture sequencing revealed a novel heterozygous C to T missense point mutation at the base position 284 (c.850 C>T) located in exon 8 of the PSEN1 gene, resulting in a Prolineto- Serine substitution (P284S) at codon position 850. The mutation was also identified by Sanger sequencing in 2 family members, including proband and her daughter and was absent in the other 4 unaffected family members and 50 control subjects. Cerebrospinal fluid (CSF) amyloid test exhibited biomarker evidence of underlying Alzheimer's pathology. 18F-florbetapir (AV-45) PET imaging indicated extensive cerebral cortex and cerebellar Aß deposition. CONCLUSIONS: We discovered a novel PSEN1 pathogenic mutation, P284S, observed for the first time in a Chinese family with early-onset AD.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Humanos , Femenino , Péptidos beta-Amiloides/genética , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Presenilina-1/genética , Mutación/genética , Biomarcadores/líquido cefalorraquídeoRESUMEN
BACKGROUND: Ginsenoside Rg1 (Rg1), an active ingredient in ginseng, may be a potential agent for the treatment of Alzheimer's disease (AD). However, the protective effect of Rg1 on neurodegeneration in AD and its mechanism of action are still incompletely understood. METHODS: Wild type (WT) and APP/PS1 AD mice, from 6 to 9 months old, were used in the experiment. The open field test (OFT) and Morris water maze (MWM) were used to detect behavioral changes. Neuronal damage was assessed by hematoxylin and eosin (H&E) and Nissl staining. Immunofluorescence, western blotting, and quantitative real-time polymerase chain reaction (q-PCR) were used to examine postsynaptic density 95 (PSD95) expression, amyloid beta (Aß) deposition, Tau and phosphorylated Tau (p-Tau) expression, reactive oxygen species (ROS) production, and NAPDH oxidase 2 (NOX2) expression. RESULTS: Rg1 treatment for 12 weeks significantly ameliorated cognitive impairments and neuronal damage and decreased the p-Tau level, amyloid precursor protein (APP) expression, and Aß generation in APP/PS1 mice. Meanwhile, Rg1 treatment significantly decreased the ROS level and NOX2 expression in the hippocampus and cortex of APP/PS1 mice. CONCLUSIONS: Rg1 alleviates cognitive impairments, neuronal damage, and reduce Aß deposition by inhibiting NOX2 activation in APP/PS1 mice.
RESUMEN
Alzheimer's disease (AD) is a fatal neurodegenerative disease for which currently no cure is available. Electroacupuncture (EA) has been widely used in China as an alternative therapeutic approach for neurological diseases. The cognitive decline in patients with AD has been reported to be closely related to the deposition of amyloid-ß (Aß) in the hippocampus of the brain, and the Morris water maze (MWM) test is a widely used method for assessing the behavior of animal models. In this study, the MWM test was performed to evaluate the effects of EA treatment on cognitive function and memory, and the micro-positron emission tomography scan was used to assess the hippocampal Aß deposition. The results showed that the cognitive function of APP/PS1 mice was significantly improved and the rate of [18F]AV-45 uptake was reduced in the EA group, compared with the AD group. Our study suggested that EA can exert a therapeutic effect in AD by improving spatial learning and memory and inhibiting the hippocampal Aß deposition.
Asunto(s)
Enfermedad de Alzheimer , Electroacupuntura , Enfermedades Neurodegenerativas , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Modelos Animales de Enfermedad , Electroacupuntura/métodos , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Presenilina-1/genéticaRESUMEN
Aluminum is an environmental neurotoxin that comes extensively in contact with human beings. Animal and human studies demonstrated that aluminum exposure increases the deposition of beta amyloid proteins in the brain as it was observed in Alzheimer's disease. The purpose of this study was to investigate whether miR-29a/b1 affected the expression of beta-secrete enzymes (BACE1) in the process of amyloid ß-protein (Aß) deposition caused by aluminum exposure. The study was performed using two different cell lines. Our results showed that after rat primary cortical neurons were exposed to aluminum, BACE1 gene and protein levels increased to different degrees, and the expression level of Aß1-42 increased. In aluminum-exposed groups, the expression of miR-29a and miR-29b1 decreased, while the expression of amyloid protein Aß1-42 and BACE1 increased. In miRs transfection groups, the expression of amyloid protein Aß1-42 and BACE1 decreased. Aluminum may affect the expression of BACE1 by lowering miR-29a and miR-29b1. AEK293 cells were utilized in this research since they present elevated levels of miR-29a and miR-29b1. After HEK293 cells were exposed to aluminum alone, BACE1 mRNA and BACE1 protein expression levels increased with the increase of aluminum exposure dose (p < 0.05), and the level of Aß1-42 also increased (p < 0.05). Compared with the group exposed to aluminum alone at the same doses, the expression levels of BACE1 mRNA and BACE1 protein in the miRs transfected plus aluminum-exposed groups significantly decreased (p < 0.05), and the level of Aß1-42 also decreased (p < 0.05). This result is consistent with the investigation in rat primary neurons. The results of two types of cells showed that aluminum may cause abnormal down-regulation of the expressions of miR-29a and miR-29b1, thus negatively regulating the increase of BACE1 expression and finally leading to the increase of Aß.
Asunto(s)
Enfermedad de Alzheimer , MicroARNs , Aluminio/toxicidad , Secretasas de la Proteína Precursora del Amiloide/genética , Péptidos beta-Amiloides , Animales , Ácido Aspártico Endopeptidasas/genética , Células HEK293 , Humanos , MicroARNs/genética , RatasRESUMEN
Genome-scale metabolic models (GEMs) are used extensively for analysis of mechanisms underlying human diseases and metabolic malfunctions. However, the lack of comprehensive and high-quality GEMs for model organisms restricts translational utilization of omics data accumulating from the use of various disease models. Here we present a unified platform of GEMs that covers five major model animals, including Mouse1 (Mus musculus), Rat1 (Rattus norvegicus), Zebrafish1 (Danio rerio), Fruitfly1 (Drosophila melanogaster), and Worm1 (Caenorhabditis elegans). These GEMs represent the most comprehensive coverage of the metabolic network by considering both orthology-based pathways and species-specific reactions. All GEMs can be interactively queried via the accompanying web portal Metabolic Atlas. Specifically, through integrative analysis of Mouse1 with RNA-sequencing data from brain tissues of transgenic mice we identified a coordinated up-regulation of lysosomal GM2 ganglioside and peptide degradation pathways which appears to be a signature metabolic alteration in Alzheimer's disease (AD) mouse models with a phenotype of amyloid precursor protein overexpression. This metabolic shift was further validated with proteomics data from transgenic mice and cerebrospinal fluid samples from human patients. The elevated lysosomal enzymes thus hold potential to be used as a biomarker for early diagnosis of AD. Taken together, we foresee that this evolving open-source platform will serve as an important resource to facilitate the development of systems medicines and translational biomedical applications.
Asunto(s)
Enfermedad de Alzheimer/patología , Biomarcadores/análisis , Modelos Animales de Enfermedad , Redes Reguladoras de Genes , Redes y Vías Metabólicas , Proteoma , Transcriptoma , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Animales , Caenorhabditis elegans , Drosophila melanogaster , Genoma , Humanos , Ratones , Ratones Transgénicos , Ratas , Pez CebraRESUMEN
Several genetic studies have identified a rare variant of triggering receptor expressed on myeloid cells 2 (TREM2) as a risk factor for Alzheimer's disease (AD). However, findings on the effects of TREM2 on Aß deposition are quite inconsistent in animal studies, requiring further investigation. In this study, we investigated whether elevation of TREM2 mitigates Aß pathology in TgCRND8 mice. We found that peripheral nerve injury resulted in a robust elevation of TREM2 exclusively in reactive microglia in the ipsilateral spinal cord of aged TgCRND8 mice at the age of 20 months. TREM2 expression appeared on day 1 post-injury and the upregulation was maintained for at least 28 days. Compared to the contralateral side, neither amyloid beta plaque load nor soluble Aß40 and Aß42 levels were attenuated upon TREM2 induction. We further showed direct evidence that TREM2 elevation in reactive microglia did not affect amyloid-ß pathology in plaque-bearing TgCRND8 mice by applying anti-TREM2 neutralizing antibody to selectively block TREM2. Our results question the ability of TREM2 to ameliorate established Aß pathology, discouraging future development of disease-modifying pharmacological treatments targeting TREM2 in the late stage of AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Glicoproteínas de Membrana/metabolismo , Microglía/metabolismo , Microglía/patología , Receptores Inmunológicos/metabolismo , Envejecimiento/patología , Animales , Plexo Braquial , Proteínas de Unión al Calcio/metabolismo , Modelos Animales de Enfermedad , Masculino , Ratones Transgénicos , Proteínas de Microfilamentos/metabolismo , Nervios Periféricos/patología , Médula Espinal/metabolismo , Médula Espinal/patología , Asta Dorsal de la Médula Espinal/patologíaRESUMEN
Postoperative cognitive dysfunction (POCD) is a neurological complication of surgery especially common in elderly patients. In this study, we investigated the role of NONMMUT055714 in POCD via regulation of miR-7684-5p. In a POCD mouse model, we induced overexpression of NONMUTT055714 via transfection of lentivrus into the hippocampus, and used the Morris water maze for assessment of cognitive function. Silencing of NONMUTT055714 and miR-7684-5p was induced in primary hippocampal neurons to observe the effects of these regulatory RNAs on cellular processes. Bioinformatics analysis and a double luciferase reporter experiment were performed to further explore the relationship between NONMMUT055714, miR-7684-5p, and SORLA. Cell and animal rescue experiments were performed to verify the ability of miR-7684-5p to reverse the protective effects of NONMMUT055714 overexpression in POCD. We observed that NONMMUT055714 has decreased expression in the POCD mouse model. Overexpression of NONMMUT055714 protected against cognitive impairment of the POCD mouse model in vivo. We identified miR-7684-5p as a NONMMUT055714-related miRNA and in turn as an upstream regulator of SORLA. We found that NONMMUT055714 downregulation is associated with decreased SORLA, increased Aß and p-tau expression, increased inflammatory biomarkers, increased markers of oxidative stress, and increased neuronal apoptosis in vitro. The effects of NONMMUT055714 downregulation were reversed by silencing miR-7684-5p in vitro and in vivo. Taken together, our findings suggest that NONMMUT055714 is protective against the development of POCD via its function as a ceRNA (or miRNA sponge) in the regulation of miR-7684-5p and SORLA. We therefore propose NONMMUT055714 as a novel target for the investigation and prevention of POCD.
Asunto(s)
Disfunción Cognitiva/genética , MicroARNs/genética , Complicaciones Cognitivas Postoperatorias/genética , ARN Largo no Codificante/genética , Animales , Proliferación Celular/genética , Disfunción Cognitiva/etiología , Hipocampo/metabolismo , Masculino , Ratones Endogámicos C57BL , MicroARNs/metabolismoRESUMEN
BACKGROUND: Although it is known that the brain communicates with the gastrointestinal (GI) tract via the well-established gut-brain axis, the influence exerted by chronic intestinal inflammation on brain changes in Alzheimer's disease (AD) is not fully understood. We hypothesized that increased gut inflammation would alter brain pathology of a mouse model of AD. OBJECTIVE: Determine whether colitis exacerbates AD-related brain changes. METHODS: To test this idea, 2% dextran sulfate sodium (DSS) was dissolved in the drinking water and fed ad libitum to male C57BL/6 wild type and AppNL-G-F mice at 6-10 months of age for two cycles of three days each. DSS is a negatively charged sulfated polysaccharide which results in bloody diarrhea and weight loss, changes similar to human inflammatory bowel disease (IBD). RESULTS: Both wild type and AppNL-G-F mice developed an IBD-like condition. Brain histologic and biochemical assessments demonstrated increased insoluble Aß1-40/42 levels along with the decreased microglial CD68 immunoreactivity in DSS treated AppNL-G-F mice compared to vehicle treated AppNL-G-F mice. CONCLUSION: These data demonstrate that intestinal dysfunction is capable of altering plaque deposition and glial immunoreactivity in the brain. This study increases our knowledge of the impact of peripheral inflammation on Aß deposition via an IBD-like model system.