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1.
Zhongguo Zhen Jiu ; 41(3): 295-302, 2021 Mar 12.
Artículo en Chino | MEDLINE | ID: mdl-33798313

RESUMEN

OBJECTIVE: To screen protein target in prevention and treatment with electroacupuncture (EA) for Alzheimer's disease (AD) and explore the potential mechanism of EA in prevention of AD. METHODS: A total of 40 APP/PS1 transgenic young male mice, 1.5-month old, were randomized into an EA group and a model group, 20 mice in each one, and 20 C57BL/6J mice were chosen as the normal control group. After adaptive housing for 1 week, the mice in the EA group were stimulated with EA at "Baihui" (GV 20), "Fengfu" (GV 16) and "Shenshu" (BL 23), with intermittent wave, 10 Hz in frequency and 2 mA in electric intensity. EA was given once daily, 20 min each time. There was 1 day at interval after EA for 6 days each week. Totally, the intervention lasted for 16 weeks. On day 3 after the end of EA intervention, Morris water maze test was adopted to detect learning and memory abilities of mice in each group. After water maze test, the label-free method was used to measure the difference expressions in cerebral cortex and hippocampus. Using Western blot method, the expressions of guanylate binding protein beta 5 (GNB 5) and histone-H 3 in cerebral cortex and hippocampus were verified. Using immunohistochemical method, the expressions of amyloid beta protein (Aß) in cerebral cortex and hippocampus were detected. RESULTS: Compared with the normal control group, the escape latency (on day 2, 3 and 4) was prolonged, the frequency of crossing platform and the duration of platform stay were decreased in the mice of the model group (P<0.05). Compared with the model group, the escape latency (on day 3 and 4) was shortened, the frequency of crossing platform and the duration of platform stay were increased in the mice of the EA group (P<0.05). By the comparison among the three groups, the high mobility group nucleosome-binding domain-containing protein 5, band 3 anion transport protein, histone-H 3, epoxide hydrolase 4 (fragment), neurolysin (mitochondria), phosphoglycerate mutase 2, GNB5 and Aß were the differential proteins with the larger fold-change difference in expression. Compared with the normal control group, the expression of histone-H 3 in cerebral cortex and hippocampus was reduced (P<0.001) and the expressions of GNB 5 and Aß were increased (P<0.001, P<0.01) in the mice of the model group. Compared with the model group, the expression of histone-H 3 in cerebral cortex and hippocampus was increased (P<0.001) and the expressions of GNB 5 and Aßwere reduced (P<0.001, P<0.05) in the mice of the EA group. CONCLUSION: The intervention with EA effectively prevents from the decline of learning and memory ability and the formation of Aß senile plaques in cerebral cortex and hippocampus in young mouse models of AD after growing up. Besides, EA plays a regulatory function for protein expression differences induced by AD model.


Asunto(s)
Enfermedad de Alzheimer , Electroacupuntura , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/genética , Animales , Modelos Animales de Enfermedad , Hipocampo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteómica
2.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(2): 300-305, 2021 Mar.
Artículo en Chino | MEDLINE | ID: mdl-33829706

RESUMEN

Objective: A predictive model of Alzheimer's disease (AD) was established based on brain surface meshes and geometric deep learning, and its performance was evaluated. Methods: Seventy-six clinically diagnosed AD patients and 83 healthy older adults were enrolled and randomly assigned to the training set and the test set according to a 4-to-1 ratio. Brain surface mesh was constructed from 3-D T1-weighted high-resolution structural MR volumes of each participant. After applying a series of simplification to the surface meshes, the training set was fed into the geometric deep neural network for training. The performance of the prediction model was evaluated with the test set, and the evaluation metrics included accuracy, sensitivity and specificity. Results: The prediction model trained on the right brain surface meshes with 6 000 faces achieved the best performance, with accuracy reaching 93.8%, sensitivity, 91.7%, and specificity, 94.1%. The evolution of the brain surface meshes during convolution and pooling revealed that AD patients had diffuse brain tissue loss compared with healthy older adults. Conclusion: Morphological brain analysis based on mesh data and geometric deep learning has great potential in the differential diagnosis of AD.


Asunto(s)
Enfermedad de Alzheimer , Aprendizaje Profundo , Anciano , Enfermedad de Alzheimer/diagnóstico , Encéfalo/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Redes Neurales de la Computación
3.
Sensors (Basel) ; 21(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803913

RESUMEN

The most frequent form of dementia is Alzheimer's Disease (AD), a severe progressive neurological pathology in which the main cognitive functions of an individual are compromised. Recent studies have found that loneliness and living in isolation are likely to cause an acceleration in the cognitive decline associated with AD. Therefore, understanding social behaviours of AD patients is crucial to promote sociability, thus delaying cognitive decline, preserving independence, and providing a good quality of life. In this work, we analyze the localization data of AD patients living in assisted care homes to gather insights about the social dynamics among them. We use localization data collected by a system based on iBeacon technology comprising two components: a network of antennas scattered throughout the facility and a Bluetooth bracelet worn by the patients. We redefine the Relational Index to capture wandering and casual encounters, these being common phenomena among AD patients, and use the notions of Relational and Popularity Indexes to model, visualize and understand the social behaviour of AD patients. We leverage the data analyses to build predictive tools and applications to enhance social activities scheduling and sociability monitoring and promotion, with the ultimate aim of providing patients with a better quality of life. Predictions and visualizations act as a support for caregivers in activity planning to maximize treatment effects and, hence, slow down the progression of Alzheimer's disease. We present the Community Behaviour Prediction Table (CBPT), a tool to visualize the estimated values of sociability among patients and popularity of places within a facility. Finally, we show the potential of the system by analyzing the Coronavirus Disease 2019 (COVID-19) lockdown time-frame between February and June 2020 in a specific facility. Through the use of the indexes, we evaluate the effects of the pandemic on the behaviour of the residents, observing no particular impact on sociability even though social distancing was put in place.


Asunto(s)
Enfermedad de Alzheimer , Sistemas de Identificación de Pacientes , Conducta Social , Enfermedad de Alzheimer/diagnóstico , Control de Enfermedades Transmisibles , Humanos , Calidad de Vida
4.
Am J Alzheimers Dis Other Demen ; 36: 1533317521996147, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33719595

RESUMEN

Alzheimer's Disease (AD) is pathologically characterized by the accumulation of soluble oligomers causing extracellular beta-amyloid deposits in form of neuritic plaques and tau-containing intraneuronal neurofibrillary tangles in brain. One proposed mechanism explaining the formation of these proteins is impaired phagocytosis by microglia/macrophages resulting in defective clearance of soluble oligomers of beta-amyloid stimulating aggregation of amyloid plaques subsequently causing AD. However, research indicates that activating macrophages in M2 state may reduce toxic oligomers. NEU1 mutation is associated with a rare disease, sialidosis. NEU1 deficiency may also cause AD-like amyloidogenic process. Amyloid plaques have successfully been reduced using NEU1.Thus, NEU1 is suggested to have therapeutic potential for AD, with lysosomal exocytosis being suggested as underlying mechanism. Studies however demonstrate that NEU1 may activate macrophages in M2 state, which as noted earlier, is crucial to reducing toxic oligomers. In this review, authors discuss the potential therapeutic role of NEU1 in AD via immune system.


Asunto(s)
Enfermedad de Alzheimer , Neuraminidasa , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Humanos , Sistema Inmunológico/metabolismo , Placa Amiloide
5.
Methods Mol Biol ; 2212: 169-179, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33733356

RESUMEN

In biology, the term "epistasis" indicates the effect of the interaction of a gene with another gene. A gene can interact with an independently sorted gene, located far away on the chromosome or on an entirely different chromosome, and this interaction can have a strong effect on the function of the two genes. These changes then can alter the consequences of the biological processes, influencing the organism's phenotype. Machine learning is an area of computer science that develops statistical methods able to recognize patterns from data. A typical machine learning algorithm consists of a training phase, where the model learns to recognize specific trends in the data, and a test phase, where the trained model applies its learned intelligence to recognize trends in external data. Scientists have applied machine learning to epistasis problems multiple times, especially to identify gene-gene interactions from genome-wide association study (GWAS) data. In this brief survey, we report and describe the main scientific articles published in data mining and epistasis. Our article confirms the effectiveness of machine learning in this genetics subfield.


Asunto(s)
Biología Computacional/métodos , Minería de Datos/métodos , Epistasis Genética , Aprendizaje Automático , Carácter Cuantitativo Heredable , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Crohn/genética , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/patología , Genoma Humano , Estudio de Asociación del Genoma Completo , Humanos , Patrón de Herencia , Degeneración Macular/genética , Degeneración Macular/metabolismo , Degeneración Macular/patología , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Fenotipo , Plantas/genética , Polimorfismo de Nucleótido Simple
6.
Molecules ; 26(5)2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33668128

RESUMEN

The remarkable prevalence of pyrazole scaffolds in a versatile array of bioactive molecules ranging from apixaban, an anticoagulant used to treat and prevent blood clots and stroke, to bixafen, a pyrazole-carboxamide fungicide used to control diseases of rapeseed and cereal plants, has encouraged both medicinal and organic chemists to explore new methods in developing pyrazole-containing compounds for different applications. Although numerous synthetic strategies have been developed in the last 10 years, there has not been a comprehensive overview of synthesis and the implication of recent advances for treating neurodegenerative disease. This review first presents the advances in pyrazole scaffold synthesis and their functionalization that have been published during the last decade (2011-2020). We then narrow the focus to the application of these strategies in the development of therapeutics for neurodegenerative diseases, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD).


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Pirazoles/uso terapéutico , Animales , Humanos , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química
7.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652925

RESUMEN

Two new minor Amaryllidaceae alkaloids were isolated from Hippeastrum × hybridum cv. Ferrari and Narcissus pseudonarcissus cv. Carlton. The chemical structures were identified by various spectroscopic (one- and two-dimensional (1D and 2D) NMR, circular dichroism (CD), high-resolution mass spectrometry (HRMS) and by comparison with literature data of similar compounds. Both isolated alkaloids were screened for their human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) inhibition activity. One of the new compounds, a heterodimer alkaloid of narcikachnine-type, named narciabduliine (2), showed balanced inhibition potency for both studied enzymes, with IC50 values of 3.29 ± 0.73 µM for hAChE and 3.44 ± 0.02 µM for hBuChE. The accommodation of 2 into the active sites of respective enzymes was predicted using molecular modeling simulation.


Asunto(s)
Alcaloides/química , Alcaloides de Amaryllidaceae/química , Inhibidores de la Colinesterasa/química , Colinesterasas/ultraestructura , Alcaloides/farmacología , Enfermedad de Alzheimer , Alcaloides de Amaryllidaceae/farmacología , Butirilcolinesterasa/química , Butirilcolinesterasa/ultraestructura , Dominio Catalítico/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Colinesterasas/química , Dicroismo Circular , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad
8.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652938

RESUMEN

PET of ß-Amyloid plaques (Aß) using [18F]florbetaben ([18F]FBB) and [18F]fluorodeoxyglucose ([18F]FDG) increasingly aid clinicians in early diagnosis of dementia, including Alzheimer's disease (AD), frontotemporal disease, dementia with Lewy bodies, and vascular dementia. The aim of this retrospective analysis was to evaluate clinical relevance of [18F]FBB, [18F]FDG PET and complimentary CSF measurements in patients with suspected dementia. In this study, 40 patients with clinically suspected or history of dementia underwent (1) measurement of Aß peptides, total tau, and p-tau protein levels in the cerebrospinal fluid (CSF) compared with healthy controls (HC); (2) clinical and neuropsychological assessment, which included Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery (CERAD-NAB); (3) [18F]FBB and [18F]FDG PET imaging within an average of 3 weeks. The subjects were within 15 days stratified using PET, CSF measurements as HC, mild cognitive impaired (MCI) and dementia including Alzheimer´s disease. The predictive dementia-related cognitive decline values were supporting the measurements. PET images were evaluated visually and quantitatively using standard uptake value ratios (SUVR). Twenty-one (52.5%) subjects were amyloid-positive (Aß+), with a median neocortical SUVR of 1.80 for AD versus 1.20 relative to the respective 19 (47.5 %) amyloid-negative (Aß-) subjects. Moreover, the [18F]FDG and [18F]FBB confirmed within a sub-group of 10 patients a good complimentary role by correlation between amyloid pathology and brain glucose metabolism in 8 out of 10 subjects. The results suggest the clinical relevance for [18F]FBB combined with [18F]FDG PET retention and CFS measurements serving the management of our patients with dementia. Therefore, [18F]FBB combined with [18F]FDG PET is a helpful tool for differential diagnosis, and supports the patients' management as well as treatment.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Demencia/diagnóstico por imagen , Fluorodesoxiglucosa F18/administración & dosificación , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/aislamiento & purificación , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/fisiopatología , Demencia/diagnóstico , Demencia/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Proteínas tau/genética , Proteínas tau/aislamiento & purificación
9.
Braz J Med Biol Res ; 54(5): e9665, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33729395

RESUMEN

This study aimed to explore the effect of microRNA (miR)-146a inhibition on regulating cell apoptosis, total neurite outgrowth, inflammation, and STAT1/MYC pathway in Alzheimer's disease (AD). PC12 and cortical neuron cellular AD models were constructed by Aß1-42 insult. For the former model, nerve growth factor (NGF) stimulation was previously conducted. miR-146a inhibitor and negative-control (NC) inhibitor were transfected into the two cellular AD models, and then cells were named miR-inhibitor group and NC-inhibitor group, respectively. After transfection, cell apoptosis, total neurite outgrowth, supernatant inflammation cytokines, and STAT1/MYC pathway were detected. miR-146a expression was similar between PC12 cellular AD model and control cells (NGF-stimulated PC12 cells), while miR-146a expression was increased in cortical neuron cellular AD model compared with control cells (rat embryo primary cortical neurons). In both PC12 and cortical neuron cellular AD models, miR-146a expression was reduced in miR-inhibitor group compared with NC-inhibitor group after transfection. Furthermore, cell apoptosis was attenuated, while total neurite outgrowth was elevated in miR-inhibitor group compared with NC-inhibitor group. As for supernatant inflammatory cytokines, tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-17 levels were lower in miR-inhibitor group than in NC-inhibitor group. Additionally, STAT1 and c-Myc mRNA and protein expressions were attenuated in miR-inhibitor group compared with NC-inhibitor group. In conclusion, miR-146a potentially represented a viable therapeutic target for AD.


Asunto(s)
Enfermedad de Alzheimer , MicroARNs , Enfermedad de Alzheimer/genética , Animales , Apoptosis , Inflamación , MicroARNs/genética , Proyección Neuronal , Neuronas , Células PC12 , Ratas , Factor de Transcripción STAT1
10.
Nat Commun ; 12(1): 1903, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33771994

RESUMEN

Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of Alzheimer's disease (AD), but most abnormally expressed miRNAs found in AD are not regulated by synaptic activity. Here we report that dysfunction of miR-135a-5p/Rock2/Add1 results in memory/synaptic disorder in a mouse model of AD. miR-135a-5p levels are significantly reduced in excitatory hippocampal neurons of AD model mice. This decrease is tau dependent and mediated by Foxd3. Inhibition of miR-135a-5p leads to synaptic disorder and memory impairments. Furthermore, excess Rock2 levels caused by loss of miR-135a-5p plays an important role in the synaptic disorder of AD via phosphorylation of Ser726 on adducin 1 (Add1). Blocking the phosphorylation of Ser726 on Add1 with a membrane-permeable peptide effectively rescues the memory impairments in AD mice. Taken together, these findings demonstrate that synaptic-related miR-135a-5p mediates synaptic/memory deficits in AD via the Rock2/Add1 signaling pathway, illuminating a potential therapeutic strategy for AD.


Asunto(s)
Enfermedad de Alzheimer/genética , Proteínas del Citoesqueleto/genética , Trastornos de la Memoria/genética , MicroARNs/genética , Sinapsis/metabolismo , Quinasas Asociadas a rho/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Células Cultivadas , Proteínas del Citoesqueleto/metabolismo , Modelos Animales de Enfermedad , Hipocampo/citología , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neuronas/metabolismo , Neuronas/fisiología , Fosforilación , Transducción de Señal/genética , Transducción de Señal/fisiología , Sinapsis/fisiología , Quinasas Asociadas a rho/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
11.
Molecules ; 26(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669839

RESUMEN

Despite Alzheimer's disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm "one target-one drug-one disease" in delivering effective medications for AD, polypharmacology appears to be a most viable therapeutic strategy. Polypharmacology can involve combinations of multiple drugs and/or single chemical entities modulating multiple targets. Taking inspiration from an ongoing clinical trial, this work aims to convert a promising cromolyn-ibuprofen drug combination into single-molecule "codrugs." Such codrugs should be able to similarly modulate neuroinflammatory and amyloid pathways, while showing peculiar pros and cons. By exploiting a linking strategy, we designed and synthesized a small set of cromolyn-ibuprofen conjugates (4-6). Preliminary plasma stability and neurotoxicity assays allowed us to select diamide 5 and ethanolamide 6 as promising compounds for further studies. We investigated their immunomodulatory profile in immortalized microglia cells, in vitro anti-aggregating activity towards Aß42-amyloid self-aggregation, and their cellular neuroprotective effect against Aß42-induced neurotoxicity. The fact that 6 effectively reduced Aß-induced neuronal death, prompted its investigation into an in vivo model. Notably, 6 was demonstrated to significantly increase the longevity of Aß42-expressing Drosophila and to improve fly locomotor performance.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Cromolin Sódico/uso terapéutico , Ibuprofeno/uso terapéutico , Polifarmacología , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/toxicidad , Animales , Conducta Animal/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cromolin Sódico/síntesis química , Cromolin Sódico/química , Cromolin Sódico/farmacología , Drosophila/efectos de los fármacos , Diseño de Fármacos , Endocitosis/efectos de los fármacos , Ibuprofeno/síntesis química , Ibuprofeno/química , Ibuprofeno/farmacología , Inmunomodulación/efectos de los fármacos , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Neurotoxinas/toxicidad , Agregado de Proteínas/efectos de los fármacos , Ratas Wistar
12.
Molecules ; 26(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670164

RESUMEN

Neurodegenerative diseases are chronic, progressive disorders that occur in the central nervous system (CNS). They are characterized by the loss of neuronal structure and function and are associated with inflammation. Inflammation of the CNS is called neuroinflammation, which has been implicated in most neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Much evidence indicates that these different conditions share a common inflammatory mechanism: the activation of the inflammasome complex in peripheral monocytes and in microglia, with the consequent production of high quantities of the pro-inflammatory cytokines IL-1ß and IL-18. Inflammasomes are a group of multimeric signaling complexes that include a sensor Nod-like receptor (NLR) molecule, the adaptor protein ASC, and caspase-1. The NLRP3 inflammasome is currently the best-characterized inflammasome. Multiple signals, which are potentially provided in combination and include endogenous danger signals and pathogens, trigger the formation of an active inflammasome, which, in turn, will stimulate the cleavage and the release of bioactive cytokines including IL-1ß and IL-18. In this review, we will summarize results implicating the inflammasome as a pivotal player in the pathogenesis of neurodegenerative diseases and discuss how compounds that hamper the activation of the NLRP3 inflammasome could offer novel therapeutic avenues for these diseases.


Asunto(s)
Inflamasomas/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Enfermedades Neurodegenerativas/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Humanos , Interleucina-18/genética , Interleucina-1beta/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Enfermedades Neurodegenerativas/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Transducción de Señal/genética
13.
Int J Nanomedicine ; 16: 2311-2322, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33776435

RESUMEN

Background: Alzheimer's disease (AD) is a neurodegenerative chronic disorder that causes dementia and problems in thinking, cognitive impairment and behavioral changes. Amyloid-beta (Aß) is a peptide involved in AD progression, and a high level of Aß is highly correlated with severe AD. Identifying and quantifying Aß levels helps in the early treatment of AD and reduces the factors associated with AD. Materials and Methods: This research introduced a dual probe detection system involving aptamers and antibodies to identify Aß. Aptamers and antibodies were attached to the gold (Au) urchin and hybrid on the carbon nanohorn-modified surface. The nanohorn was immobilized on the sensor surface by using an amine linker, and then a Au urchin dual probe was immobilized. Results: This dual probe-modified surface enhanced the current flow during Aß detection compared with the surface with antibody as the probe. This dual probe interacted with higher numbers of Aß peptides and reached the detection limit at 10 fM with R2=0.992. Furthermore, control experiments with nonimmune antibodies, complementary aptamer sequences and control proteins did not display the current responses, indicating the specific detection of Aß. Conclusion: Aß-spiked artificial cerebrospinal fluid showed a similar response to current changes, confirming the selective identification of Aß.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Oro/química , Sondas Moleculares/química , Nanopartículas/química , Péptidos beta-Amiloides/metabolismo , Electrodos , Humanos , Límite de Detección , Modelos Lineales , Nanopartículas/ultraestructura , Fragmentos de Péptidos , Multimerización de Proteína , Reproducibilidad de los Resultados , Espectrometría por Rayos X , Propiedades de Superficie
14.
Adv Exp Med Biol ; 1286: 183-198, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33725354

RESUMEN

Alzheimer's disease (AD) is a neurodegenerative disorder in which the death of brain cells causes memory loss and cognitive decline. Existing drugs only suppress symptoms or delay further deterioration but do not address the cause of the disease. In spite of screening numerous drug candidates against various molecular targets of AD, only a few candidates, such as acetylcholinesterase inhibitors, are currently utilized as an effective clinical therapy. Currently, nano-based therapies can make a difference, providing new therapeutic options by helping drugs to cross the blood-brain barrier and enter the brain more effectively. The main aim of this review was to highlight advances in research on the development of nano-based therapeutics for improved treatment of AD.


Asunto(s)
Enfermedad de Alzheimer , Envejecimiento , Enfermedad de Alzheimer/tratamiento farmacológico , Barrera Hematoencefálica , Encéfalo , Sistemas de Liberación de Medicamentos , Humanos
15.
Adv Exp Med Biol ; 1286: 213-223, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33725356

RESUMEN

Age-related neurodegenerative diseases have detrimental consequences on health of many patients and result in mortality. The current treatment options are limited and usually fail to correct the underlying pathology. AAV-based gene therapies have proved to be safe based on the data available on clinical trials for several monogenic diseases. Therefore, such therapies can pave the way to treat neurodegenerative diseases likes Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Here, the advantages of AAV-based gene therapies are discussed with emphasis on efforts of developing novel capsids with superior therapeutic efficacy. Furthermore, the results of clinical trials on AD, PD, and ALS are summarized.


Asunto(s)
Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/terapia , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/terapia , Terapia Genética , Humanos , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/terapia , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia
16.
Adv Exp Med Biol ; 1286: 251-264, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33725358

RESUMEN

Psychiatric and neurodegenerative disorders such as schizophrenia (SCZ), Parkinson's disease (PD), and Alzheimer's disease (AD) continue to grow around the world with a high impact on health, social, and economic outcomes for the patient and society. Despite efforts, the etiology and pathophysiology of these disorders remain unclear. Omics technologies have contributed to the understanding of the molecular mechanisms that underlie these complex disorders and have suggested novel potential targets for treatment and diagnostics. Here, we have highlighted the unique and common pathways shared between SCZ, PD, and AD and highlight the main proteomic findings over the last 5 years using in vitro models, postmortem brain samples, and cerebrospinal fluid (CSF) or blood of patients. These studies have identified possible therapeutic targets and disease biomarkers. Further studies including target validation, the use of large sample sizes, and the integration of omics findings with bioinformatics tools are required to provide a better comprehension of pharmacological targets.


Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Biomarcadores , Humanos , Enfermedades Neurodegenerativas/genética , Proteómica
17.
Arq Neuropsiquiatr ; 79(1): 8-14, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33656114

RESUMEN

BACKGROUND: Swallowing and feeding problems may occur with the progression of behavioral variant frontotemporal dementia (bvFTD) and can impair the anticipatory and oral preparatory phases of swallowing. OBJECTIVE: To characterize swallowing problems and the feeding situation of patients with bvFTD and to correlate the swallowing problems with functionality, executive functions, cognitive and behavioral features. METHODS: Consecutive outpatients with bvFTD in mild, moderate and severe dementia stages were recruited along with their caregivers. Patients and caregivers were screened with the following scales: "Mini-Mental State Examination", "Severe Mini-Mental State Examination", "FTLD-modified Clinical Dementia Rating", "Neuropsychiatric Inventory", "Frontal Assessment Battery", "Index of Independence in Activities of Daily Living", "Swallowing Rating Scale" and "Assessment of Feeding and Swallowing Difficulties in Dementia". RESULTS: Overall, thirty patients with bvFTD were included along with their caregivers. Patients with bvFTD showed feeding and swallowing difficulties such as: messy to eat, passivity, coughing and choking, difficulty with some food consistencies and with specific food. Swallowing problems in bvFTD correlated with impaired functionality (p<0.05) and cognition (p<0.05), executive dysfunction (p<0.01) and behavioral features (p<0.01). Caregivers had great difficulty in managing the feeding situation during mealtime, with different characteristics in each dementia stage. CONCLUSION: Patients with bvFTD had inappropriate speed eating, passivity, coughing and choking starting in the mild dementia stage, and these problems worsen in the severe stage. Such difficulties affected caregiver performance during mealtime. The correlations indicated that swallowing difficulties tend to follow cognitive and behavioral decline in patients with bvFTD.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Demencia Frontotemporal , Actividades Cotidianas , Deglución , Humanos , Pruebas Neuropsicológicas
18.
Int J Nanomedicine ; 16: 1901-1911, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33707945

RESUMEN

Purpose: Developing a sensitive SERS-based method to quantitatively detect serum biomarkers (Aß1-42 and P-Tau-181) for the early diagnosis of Alzheimer's disease (AD). Methods: In this study, a novel SERS-based sandwich immunoassay, which consists of tannin-capped silver nanoparticles and magnetic graphene oxide (Fe3O4@GOs), was developed. We firstly applied this method for the detection of protein standards in buffer solution, obtaining the regression equation. Then, its potential value on real serum samples of AD was further explored. Results: The detection linear range of Aß1-42 and P-Tau-181 protein standards were observed to range from 100 pg mL-1 to 10 fg mL-1, 100 pg mL-1 to 1 fg mL-1 respectively. We finally explored clinical application of the proposed method in 63 serum samples. As a result, P-tau-181 differentiated AD from non-AD dementia patients (AUC = 0.770), with a more favored ROC than Aß1-42 (AUC = 0.383). Conclusion: The developed SERS-based immunoassay is successfully applied to the determination of Aß1-42 and P-Tau-181 in human serum specimens, which provides a promising tool for the early diagnosis of AD.


Asunto(s)
Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/sangre , Inmunoensayo/métodos , Sondas Moleculares/química , Plata/química , Espectrometría Raman/métodos , Péptidos beta-Amiloides/sangre , Benzoatos/química , Calibración , Femenino , Grafito/química , Humanos , Límite de Detección , Masculino , Nanopartículas del Metal/química , Nanopartículas del Metal/ultraestructura , Compuestos de Sulfhidrilo/química , Difracción de Rayos X , Proteínas tau/sangre
19.
Sensors (Basel) ; 21(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670317

RESUMEN

Alzheimer's disease is the most prevalent dementia among the elderly population. Early detection is critical because it can help with future planning for those potentially affected. This paper uses a three-dimensional DenseNet architecture to detect Alzheimer's disease in magnetic resonance imaging. Our work is restricted to the use of freely available tools. We constructed a deep neural network classifier with metrics of 0.86¯ mean accuracy, 0.86¯ mean sensitivity (micro-average), 0.86¯ mean specificity (micro-average), and 0.91¯ area under the receiver operating characteristic curve (micro-average) for the task of discriminating between five different disease stages or classes. The use of tools available for free ensures the reproducibility of the study and the applicability of the classification system in developing countries.


Asunto(s)
Enfermedad de Alzheimer , Redes Neurales de la Computación , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Diagnóstico Precoz , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Curva ROC , Reproducibilidad de los Resultados
20.
Nat Commun ; 12(1): 1882, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33767197

RESUMEN

Single-cell RNA-sequencing (scRNA-Seq) is widely used to reveal the heterogeneity and dynamics of tissues, organisms, and complex diseases, but its analyses still suffer from multiple grand challenges, including the sequencing sparsity and complex differential patterns in gene expression. We introduce the scGNN (single-cell graph neural network) to provide a hypothesis-free deep learning framework for scRNA-Seq analyses. This framework formulates and aggregates cell-cell relationships with graph neural networks and models heterogeneous gene expression patterns using a left-truncated mixture Gaussian model. scGNN integrates three iterative multi-modal autoencoders and outperforms existing tools for gene imputation and cell clustering on four benchmark scRNA-Seq datasets. In an Alzheimer's disease study with 13,214 single nuclei from postmortem brain tissues, scGNN successfully illustrated disease-related neural development and the differential mechanism. scGNN provides an effective representation of gene expression and cell-cell relationships. It is also a powerful framework that can be applied to general scRNA-Seq analyses.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , RNA-Seq/métodos , Análisis de la Célula Individual/métodos , Transcriptoma/genética , Encéfalo/citología , Encéfalo/patología , Análisis por Conglomerados , Biología Computacional , Aprendizaje Profundo , Humanos , Secuenciación del Exoma Completo
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