RESUMEN
Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Histopathologically, AD presents two pathognomonic hallmarks: (1) neurofibrillary tangles, characterized by intracellular deposits of hyperphosphorylated tau protein, and (2) extracellular amyloid deposits (amyloid plaques) in the brain vasculature (cerebral amyloid angiopathy; CAA). It has been proposed that vascular amyloid deposits could trigger neurovascular unit (NVU) dysfunction in AD. The NVU is composed primarily of astrocytic feet, endothelial cells, pericytes, and basement membrane. Although physical exercise is hypothesized to have beneficial effects against AD, it is unknown whether its positive effects extend to ameliorating CAA and improving the physiology of the NVU. We used the triple transgenic animal model for AD (3xTg-AD) at 13 months old and analyzed through behavioral and histological assays, the effect of voluntary physical exercise on cognitive functions, amyloid angiopathy, and the NVU. Our results show that 3xTg-AD mice develop vascular amyloid deposits which correlate with cognitive deficits and NVU alteration. Interestingly, the physical exercise regimen decreases amyloid angiopathy and correlates with an improvement in cognitive function as well as in the underlying integrity of the NVU components. Physical exercise could represent a key therapeutic approach in cerebral amyloid angiopathy and NVU stability in AD patients.
Asunto(s)
Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , Placa Amiloide/metabolismo , Células Endoteliales/metabolismo , Ratones Transgénicos , Angiopatía Amiloide Cerebral/metabolismo , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Péptidos beta-Amiloides/metabolismoRESUMEN
Apolipoprotein E4 (ApoE4) is thought to increase the risk of developing Alzheimer's disease. Several studies have shown that ApoE4-Amyloid ß (Aß) interactions can increment amyloid depositions in the brain and that this can be augmented at low pH values. On the other hand, experimental studies in transgenic mouse models have shown that treatment with enoxaparin significantly reduces cortical Aß levels, as well as decreases the number of activated astrocytes around Aß plaques. However, the interactions between enoxaparin and the ApoE4-Aß proteins have been poorly explored. In this work, we combine molecular dynamics simulations, molecular docking, and binding free energy calculations to elucidate the molecular properties of the ApoE4-Aß interactions and the competitive binding affinity of the enoxaparin on the ApoE4 binding sites. In addition, we investigated the effect of the environmental pH levels on those interactions. Our results showed that under different pH conditions, the closed form of the ApoE4 protein, in which the C-terminal domain folds into the protein, remains stabilized by a network of hydrogen bonds. This closed conformation allowed the generation of six different ApoE4-Aß interaction sites, which were energetically favorable. Systems at pH5 and 6 showed the highest energetic affinity. The enoxaparin molecule was found to have a strong energetic affinity for ApoE4-interacting sites and thus can neutralize or disrupt ApoE4-Aß complex formation.
Asunto(s)
Enfermedad de Alzheimer , Apolipoproteína E4 , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Apolipoproteína E3/metabolismo , Apolipoproteína E4/metabolismo , Enoxaparina/farmacología , Concentración de Iones de Hidrógeno , Ratones , Simulación del Acoplamiento Molecular , Placa Amiloide/metabolismoRESUMEN
Genetic predispositions associated with metabolism of the amyloid-ß protein precursor underlie familial Alzheimer's disease; a form of dementia characterized by early disease onset and elevated levels of cortical amyloid-ß. Human exposure to aluminum is linked to the etiology of Alzheimer's disease and recent research measured a high content of aluminum in brain tissue in familial Alzheimer's disease. To elaborate upon this finding, we have obtained brain tissues from a Colombian cohort of donors with familial Alzheimer's disease. We have used established methods to measure the aluminum content of these tissues and we have compared the data with a recently measured dataset for control brain tissues. We report significantly higher levels of aluminum in brain tissues in donors with familial Alzheimer's disease than in control tissues from donors without neurological impairment or neurodegeneration. We have used aluminum-specific fluorescence microscopy along with complementary imaging for amyloid-ß to demonstrate a very high degree of co-localization of these two risk factors in brain tissue in familial Alzheimer's disease. Aluminum and amyloid-ß were co-located in senile plaques as well as vasculature, the latter resembling cerebral amyloid angiopathy. Aluminum was also found separately from amyloid-ß in intracellular compartments including glia and neuronal axons. The research has identified an arguably unique association between high brain aluminum content and amyloid-ß and allows postulation that genetic predispositions defining familial Alzheimer's disease underlie this relationship.
Asunto(s)
Aluminio/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/genética , Axones/metabolismo , Química Encefálica , Angiopatía Amiloide Cerebral/metabolismo , Estudios de Cohortes , Colombia , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Neuroglía/metabolismo , Placa Amiloide/metabolismo , Factores de RiesgoRESUMEN
Alzheimer's disease (AD) is associated to depressed brain energy supply and impaired cortical and hippocampal synaptic function. It was previously reported in McGill-R-Thy1-APP transgenic (Tg(+/+)) rats that Aß deposition per se is sufficient to cause abnormalities in glucose metabolism and neuronal connectivity. These data support the utility of this animal model as a platform for the search of novel AD biomarkers based on bioenergetic status. Recently, it has been proposed that energy dysfunction can be dynamically tested in platelets (PLTs) of nonhuman primates. PLTs are good candidates to find peripheral biomarkers for AD because they may reflect in periphery the bioenergetics deficits and the inflammatory and oxidative stress processes taking place in AD brain. In the present study, we carried out a PLTs bioenergetics screening in advanced-age (12-14 months old) control (WT) and Tg(+/+) rats. Results indicated that thrombin-activated PLTs of Tg(+/+) rats showed a significantly lower respiratory rate, as compared to that measured in WT animals, when challenged with the same dose of FCCP (an uncoupler of oxidative phosphorylation). In summary, our results provide original evidence that PLTs bioenergetic profiling may reflect brain bioenergetics dysfunction mediated by Aß plaque accumulation. Further studies on human PLTs from control and AD patients are required to validate the usefulness of PLTs bioenergetics as a novel blood-based biomarker for AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Plaquetas/metabolismo , Metabolismo Energético/fisiología , Hipocampo/metabolismo , Placa Amiloide/metabolismo , Animales , Mitocondrias/metabolismo , Ratas , Ratas TransgénicasRESUMEN
Alzheimer's disease (AD) is the leading cause of dementia worldwide. It compromises patients' daily activities owing to progressive cognitive deterioration, which has elevated direct and indirect costs. Although AD has several risk factors, aging is considered the most important. Unfortunately, clinical diagnosis is usually performed at an advanced disease stage when dementia is established, making implementation of successful therapeutic interventions difficult. Current biomarkers tend to be expensive, insufficient, or invasive, raising the need for novel, improved tools aimed at early disease detection. AD is characterized by brain atrophy due to neuronal and synaptic loss, extracellular amyloid plaques composed of amyloid-beta peptide (Aß), and neurofibrillary tangles of hyperphosphorylated tau protein. The visual system and central nervous system share many functional components. Thus, it is plausible that damage induced by Aß, tau, and neuroinflammation may be observed in visual components such as the retina, even at an early disease stage. This underscores the importance of implementing ophthalmological examinations, less invasive and expensive than other biomarkers, as useful measures to assess disease progression and severity in individuals with or at risk of AD. Here, we review functional and morphological changes of the retina and visual pathway in AD from pathophysiological and clinical perspectives.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Retina/fisiopatología , Trastornos de la Visión/fisiopatología , Vías Visuales/fisiopatología , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Progresión de la Enfermedad , Humanos , Placa Amiloide/metabolismo , Placa Amiloide/fisiopatología , Retina/metabolismo , Trastornos de la Visión/diagnóstico , Trastornos de la Visión/metabolismo , Vías Visuales/metabolismo , Proteínas tau/metabolismoRESUMEN
Alzheimer's disease (AD) is the most common cause of dementia worldwide. Despite advances in our understanding of the molecular milieu driving AD pathophysiology, no effective therapy is currently available. Moreover, various clinical trials have continued to fail, suggesting that our approach to AD must be revised. Accordingly, the development and validation of new models are highly desirable. Over the last decade, we have been working with Octodon degus (degu), a Chilean rodent, which spontaneously develops AD-like neuropathology, including increased amyloid-ß (Aß) aggregates, tau hyperphosphorylation, and postsynaptic dysfunction. However, for proper validation of degu as an AD model, the aggregation properties of its Aß peptide must be analyzed. Thus, in this study, we examined the capacity of the degu Aß peptide to aggregate in vitro. Then, we analyzed the age-dependent variation in soluble Aß levels in the hippocampus and cortex of third- to fifth-generation captive-born degu. We also assessed the appearance and spatial distribution of amyloid plaques in O. degus and compared them with the plaques in two AD transgenic mouse models. In agreement with our previous studies, degu Aß was able to aggregate, forming fibrillar species in vitro. Furthermore, amyloid plaques appeared in the anterior brain structures of O. degus at approximately 32 months of age and in the whole brain at 56 months, along with concomitant increases in Aß levels and the Aß42/Aß40 ratio, indicating that O. degus spontaneously develops AD-like pathology earlier than other spontaneous models. Based on these results, we can confirm that O. degus constitutes a valuable model to improve AD research.
Asunto(s)
Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Amiloide/metabolismo , Encéfalo/patología , Placa Amiloide/patología , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Octodon , Placa Amiloide/metabolismo , Agregado de Proteínas , Proteínas tau/metabolismoRESUMEN
The study of brain pathology by fluorescence microscopy finds in the autofluorescence of the tissue an additional difficulty for the recognition of markers of interest. In particular, in the immunofluorescence study of brains from Alzheimer's disease (AD) patients, several approaches have been attempted to eliminate or mask the presence of autofluorescent aggregates. In the present work, we propose a method to characterize by fluorescent microscopy senile plaques discriminating them from autofluorescent aggregates, such as lipofuscin granules.This work describes four protocols carried out in human brain tissue of patients with AD, covering adequate tissue preparation, immunofluorescence acquisition, and data analysis: 1. Tissues processing of frozen samples for optimal epitope conservation. 2. Analysis of the fluorescence emission spectrum of the tissue by performing a confocal microscopy λ-scan. 3. Analysis of fluorescence emission of both intact and formic acid-treated tissues in four channels corresponding to the emission in blue, green, near red, and far-red regions. 4. Analysis a specific immunostaining of amyloid beta in senile plaques, using fluorescent-labeled antibodies by using specific emission channels to avoid detection of tissue autofluorescence.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Lipofuscina/química , Placa Amiloide/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Técnica del Anticuerpo Fluorescente , Humanos , Microscopía Confocal , Microscopía Fluorescente , Placa Amiloide/metabolismo , Conservación de TejidoAsunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Investigación Biomédica , Terapia Molecular Dirigida/tendencias , Tomografía de Emisión de Positrones , Proteínas tau/metabolismo , Adolescente , Adulto , Edad de Inicio , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Colombia , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Placa Amiloide/tratamiento farmacológico , Placa Amiloide/genética , Placa Amiloide/metabolismo , Tomografía de Emisión de Positrones/métodos , Proteínas tau/análisisRESUMEN
The main amyloid-beta (Aß) variants detected in the human brain are full-length Aß1-40 and Aß1-42 peptides; however, a significant proportion of AD brain Aß consists also of N-terminal truncated/modified species. The majority of the previous immunotherapeutic strategies targeted the N-terminal immunodominant epitope of the full-length Aß; however, most of the pathological N-truncated forms of Aß lack this critical B cell epitope. Recently, virus-like particles (VLPs), self-assembled structures with highly ordered repetitive patterns on their surface and capable of inducing robust immune responses, were applied as a promising platform for various antigen expressions. In this study, we expressed in plants two chimeric HPV16 L1 capsid proteins obtained by introduction of the ß-amyloid 11-28 epitope (Aß 11-28) into the h4 helix or into the coil regions of the L1 protein. The Aß 11-28 epitope was chosen because it is present in the full-length Aß 1-42 as well as in the truncated/modified amyloid peptide species. After expression, we assembled the chimerical L1/Aß 11-28 into a VLP in which the Aß 11-28 epitope is exposed at very high density (360 times) on the surface of the VLP. The chimeric VLPs elicited in mice Aß-specific antibodies binding to ß-amyloid plaques in APP-tg mouse and AD brains. Our study is the first to demonstrate a successful production in plants and immunogenic properties in mice of chimeric HPV16 L1 VLPs bearing Aß epitope that may be of potential relevance for the development of multivalent vaccines for a multifactorial disease such as AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Epítopos/metabolismo , Papillomavirus Humano 16/metabolismo , Fragmentos de Péptidos/metabolismo , Virus de Plantas/metabolismo , Placa Amiloide/metabolismo , Vacunas de Partículas Similares a Virus/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Secuencia de Aminoácidos , Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Anticuerpos Antivirales/genética , Anticuerpos Antivirales/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Quimera/genética , Quimera/metabolismo , Epítopos/genética , Papillomavirus Humano 16/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fragmentos de Péptidos/genética , Virus de Plantas/genética , Placa Amiloide/tratamiento farmacológico , Placa Amiloide/genética , Vacunas de Partículas Similares a Virus/farmacología , Vacunas de Partículas Similares a Virus/uso terapéuticoRESUMEN
Down syndrome (DS), trisomy of chromosome 21, is the most common genetic form of intellectual disability. The neuropathology of DS involves multiple molecular mechanisms, similar to AD, including the deposition of beta-amyloid (Aß) into senile plaques and tau hyperphosphorylationg in neurofibrillary tangles. Interestingly, many genes encoded by chromosome 21, in addition to being primarily linked to amyloid-beta peptide (Aß) pathology, are responsible for increased oxidative stress (OS) conditions that also result as a consequence of reduced antioxidant system efficiency. However, redox homeostasis is disturbed by overproduction of Aß, which accumulates into plaques across the lifespan in DS as well as in AD, thus generating a vicious cycle that amplifies OS-induced intracellular changes. The present review describes the current literature that demonstrates the accumulation of oxidative damage in DS with a focus on the lipid peroxidation by-product, 4-hydroxy-2-nonenal (HNE). HNE reacts with proteins and can irreversibly impair their functions. We suggest that among different post-translational modifications, HNE-adducts on proteins accumulate in DS brain and play a crucial role in causing the impairment of glucose metabolism, neuronal trafficking, protein quality control and antioxidant response. We hypothesize that dysfunction of these specific pathways contribute to accelerated neurodegeneration associated with AD neuropathology.
Asunto(s)
Aldehídos/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Síndrome de Down/metabolismo , Procesamiento Proteico-Postraduccional , Proteínas tau/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Síndrome de Down/genética , Síndrome de Down/patología , Glucosa/metabolismo , Humanos , Peroxidación de Lípido , Mitocondrias/metabolismo , Mitocondrias/patología , Ovillos Neurofibrilares/genética , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Neuronas/metabolismo , Neuronas/patología , Estrés Oxidativo , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patología , Proteínas tau/genéticaRESUMEN
An emerging view on Alzheimer disease's (AD) pathogenesis considers amyloid-ß (Aß) oligomers as a key factor in synaptic impairment and rodent spatial memory decline. Alterations in the α7-nicotinic acetylcholine receptor (α7-nAChR) have been implicated in AD pathology. Herein, we report that nicotine, an unselective α7-nAChR agonist, protects from morphological and synaptic impairments induced by Aß oligomers. Interestingly, nicotine prevents both early postsynaptic impairment and late presynaptic damage induced by Aß oligomers through the α7-nAChR/phosphatidylinositol-3-kinase (PI3K) signaling pathway. On the other hand, a cross-talk between α7-nAChR and the Wnt/ß-catenin signaling pathway was revealed by the following facts: (1) nicotine stabilizes ß-catenin, in a concentration-dependent manner; (2) nicotine prevents Aß-induced loss of ß-catenin through the α7-nAChR; and (3) activation of canonical Wnt/ß-catenin signaling induces α7-nAChR expression. Analysis of the α7-nAChR promoter indicates that this receptor is a new Wnt target gene. Taken together, these results demonstrate that nicotine prevents memory deficits and synaptic impairment induced by Aß oligomers. In addition, nicotine improves memory in young APP/PS1 transgenic mice before extensive amyloid deposition and senile plaque development, and also in old mice where senile plaques have already formed. Activation of the α7-nAChR/PI3K signaling pathway and its cross-talk with the Wnt signaling pathway might well be therapeutic targets for potential AD treatments.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides/toxicidad , Nicotina/farmacología , Fragmentos de Péptidos/toxicidad , Receptor Nicotínico de Acetilcolina alfa 7/fisiología , Péptidos beta-Amiloides/síntesis química , Precursor de Proteína beta-Amiloide/genética , Androstadienos/farmacología , Animales , Bungarotoxinas/farmacología , Células Cultivadas , Dendritas/efectos de los fármacos , Dendritas/ultraestructura , Homólogo 4 de la Proteína Discs Large , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Péptidos y Proteínas de Señalización Intracelular/análisis , Aprendizaje por Laberinto/efectos de los fármacos , Proteínas de la Membrana/análisis , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuritas/ultraestructura , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/ultraestructura , Nicotina/uso terapéutico , Técnicas de Placa-Clamp , Fragmentos de Péptidos/síntesis química , Fosfatidilinositol 3-Quinasas/fisiología , Placa Amiloide/metabolismo , Presenilina-1/genética , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/ultraestructura , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes de Fusión/genética , Transducción de Señal , Sinapsinas/análisis , Proteínas Wnt/fisiología , Vía de Señalización Wnt , Wortmanina , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Receptor Nicotínico de Acetilcolina alfa 7/biosíntesis , Receptor Nicotínico de Acetilcolina alfa 7/genética , beta Catenina/fisiologíaRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-ß peptide (Aß) accumulation, neurofibrillary tangle deposition, synaptic alterations, and oxidative injury. In AD patients, acetylcholinesterase (AChE) activity is low in most regions of the brain, but increased within and around amyloid plaques, where it accelerates the Aß assembly into oligomers and fibrils, increasing its neurotoxicity. Tetrahydrohyperforin (THH), a semi-synthetic derivative of hyperforin, reduces tau phosphorylation and Aß accumulation in AD mouse models. In the present study, we examined the effects of THH on Aß-AChE complexes, α7-nicotinic acetylcholine receptors (α7-nAChR), 4-hydroxynonenal (4-HNE) adducts, caspase-3 activation, and spatial memory in young AßPPSwe/PSEN1ΔE9 (AßPP/PS1) transgenic mice, in order to evaluate its potential preventive effects on the development of the disease. We report here that treatment with THH prevents the association of AChE to different types of amyloid plaques; partially restores the brain distribution of AChE molecular forms; increases α7-nAChR levels in the hippocampus of treated mice; decreases the amount of these receptors in amyloid plaques; and reduces the oxidative damage, evidenced by 4-HNE adduct formation and caspase-3 activation on AßPP/PS1 mice brain; demonstrating the neuroprotective properties of THH. Finally, we found that the acute treatment of hippocampal neurons with THH, in the presence of Aß-AChE complexes, prevents 4-HNE adduct formation and caspase-3 activation. Our data support a therapeutic potential of THH for the treatment of AD.
Asunto(s)
Aldehídos/metabolismo , Encéfalo/efectos de los fármacos , Caspasa 3/metabolismo , Floroglucinol/análogos & derivados , Placa Amiloide/metabolismo , Terpenos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Encéfalo/patología , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Hipocampo/química , Hipocampo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Ratones , Ratones Transgénicos , Floroglucinol/farmacología , Placa Amiloide/prevención & control , Receptores Nicotínicos/análisis , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/metabolismoRESUMEN
Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) pathology was also explored. Exposed urbanites displayed differential (>2-fold) regulation of 134 genes. Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% had amyloid-ß (Aß) diffuse plaques compared with 0% in controls. APOE4 carriers had greater hyperphosphorylated tau and diffuse Aß plaques versus E3 carriers (Q = 7.82, p = 0.005). Upregulated gene network clusters included IL1, NFκB, TNF, IFN, and TLRs. A 15-fold frontal down-regulation of the prion-related protein (PrP(C)) was seen in highly exposed subjects. The down-regulation of the PrP(C) is critical given its important roles for neuroprotection, neurodegeneration, and mood disorder states. Elevation of indices of neuroinflammation and oxidative stress, down-regulation of the PrP(C) and AD-associated pathology are present in young megacity residents. The inducible regulation of gene expression suggests they are evolving different mechanisms in an attempt to cope with the constant state of inflammation and oxidative stress related to their environmental exposures. Together, these data support a role for air pollution in CNS damage and its impact upon the developing brain and the potential etiology of AD and mood disorders.
Asunto(s)
Contaminación del Aire/efectos adversos , Encefalitis/metabolismo , Placa Amiloide/metabolismo , Priones/metabolismo , Proteínas tau/metabolismo , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Estudios de Cohortes , Regulación hacia Abajo , Encefalitis/patología , Femenino , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Redes Reguladoras de Genes , Humanos , Lactante , Masculino , México , Fosforilación , Placa Amiloide/patología , Adulto JovenRESUMEN
Alzheimer's disease (AD) is the 3rd most costly disease and the leading cause of dementia. It can linger for many years, but ultimately is fatal, the 6th leading cause of death. Alzheimer's disease (AD) is fatal and affected individuals can sometimes linger many years. Current treatments are palliative and transient, not disease modifying. This article reviews progress in the search to identify the primary AD-causing toxins. We summarize the shift from an initial focus on amyloid plaques to the contemporary concept that AD memory failure is caused by small soluble oligomers of the Aß peptide, toxins that target and disrupt particular synapses. Evidence is presented that links Aß oligomers to pathogenesis in animal models and humans, with reference to seminal discoveries from cell biology and new ideas concerning pathogenic mechanisms, including relationships to diabetes and Fragile X. These findings have established the oligomer hypothesis as a new molecular basis for the cause, diagnosis, and treatment of AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Trastornos de la Memoria/metabolismo , Sinapsis/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/patología , Humanos , Trastornos de la Memoria/patología , Neuronas/metabolismo , Neuronas/patología , Placa Amiloide/metabolismo , Placa Amiloide/patología , Sinapsis/patologíaRESUMEN
Alzheimer's disease and inclusion body myositis (IBM) are disorders frequently found in the elderly and characterized by the presence of amyloid-ß peptide (Aß) aggregates. We used Caenorhabditis elegans that express Aß in muscle cells as a model of IBM, with the aim of analyzing Aß-induced muscle pathology and evaluating the consequences of modulating Aß aggregation. First, we tested whether the altered motility we observed in the Aß transgenic strain could be the result of a compromised neuromuscular synapse. Our pharmacological analyses show that synaptic transmission is defective in our model and suggest a specific defect on nicotine-sensitive acetylcholine receptors (AChRs). Through GFP-coupled protein visualization, we found that synaptic dysfunction correlates with mislocalization of ACR-16, the AChR subunit essential for nicotine-triggered currents. Histological and biochemical analysis allowed us to determine that copper treatment increases the amyloid deposits and decreases Aß oligomers in this model. Furthermore, copper treatment improves motility, ACR-16 localization, and synaptic function and delays Aß-induced paralysis. Our results indicate that copper modulates Aß-induced pathology and suggest that Aß oligomers are triggering neuromuscular dysfunction. Our findings emphasize the importance of neuromuscular synaptic dysfunction and the relevance of modulating the amyloidogenic component as an alternative therapeutic approach for this debilitating disease.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Cobre/uso terapéutico , Miositis por Cuerpos de Inclusión/tratamiento farmacológico , Unión Neuromuscular/efectos de los fármacos , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans , Cobre/administración & dosificación , Cobre/metabolismo , Modelos Animales de Enfermedad , Miositis por Cuerpos de Inclusión/metabolismo , Miositis por Cuerpos de Inclusión/patología , Unión Neuromuscular/metabolismo , Unión Neuromuscular/patología , Placa Amiloide/metabolismo , Placa Amiloide/patologíaRESUMEN
Alzheimer's disease is a neurodegenerative disorder involving extracellular plaques (amyloid-ß) and intracellular tangles of tau protein. Recently, tangle formation has been identified as a major event involved in the neurodegenerative process, due to the conversion of either soluble peptides or oligomers into insoluble filaments. At present, the current therapeutic strategies are aimed at natural phytocomplexes and polyphenolics compounds able to either inhibit the formation of tau filaments or disaggregate them. However, only a few polyphenolic molecules have emerged to prevent tau aggregation, and natural drugs targeting tau have not been approved yet. Fulvic acid, a humic substance, has several nutraceutical properties with potential activity to protect cognitive impairment. In this work we provide evidence to show that the aggregation process of tau protein, forming paired helical filaments (PHFs) in vitro, is inhibited by fulvic acid affecting the length of fibrils and their morphology. In addition, we investigated whether fulvic acid is capable of disassembling preformed PHFs. We show that the fulvic acid is an active compound against preformed fibrils affecting the whole structure by diminishing length of PHFs and probably acting at the hydrophobic level, as we observed by atomic force techniques. Thus, fulvic acid is likely to provide new insights in the development of potential treatments for Alzheimer's disease using natural products.
Asunto(s)
Enfermedad de Alzheimer/patología , Benzopiranos/farmacología , Ovillos Neurofibrilares/efectos de los fármacos , Ovillos Neurofibrilares/metabolismo , Placa Amiloide/metabolismo , Proteínas tau/metabolismo , Enfermedad de Alzheimer/metabolismo , Humanos , Microscopía de Fuerza Atómica , Microscopía Electrónica de Transmisión , Placa Amiloide/ultraestructura , Proteínas tau/efectos de los fármacos , Proteínas tau/ultraestructuraRESUMEN
Amyloid-beta plaques and neurodegeneration are hallmarks of Alzheimer's disease, where glial cells are responsible for sustained neuroinflammation. Here we show that hippocampal-microglia co-cultures exposed to proinflammatory mediators, amyloid-beta- and amyloid-beta protein precursor construct-conjugated beads increased their production of nitrites. In contrast, inflammation was unable to significantly induce cell death by itself, whereas inflammation plus amyloid-beta or amyloid-beta protein precursor induced a significant increment of cell death and a 6-fold increase of production of Interleukin 1beta. Those effects were not observed in the absence of microglia or when hippocampal cells were co-cultured with microglia for one day. In contrast, a 2-fold increase of transforming growth factor beta1 was observed in hippocampal cultures exposed to inflammatory stimuli for 4 days, whereas induction of transforming growth factor beta1 by inflammation plus amyloid-beta and amyloid-beta protein precursor was nearly abolished by microglia. Our results indicate that neurotoxicity induced by amyloid-beta or amyloid-beta protein precursor was a slow process depending on activated microglia and additional stimuli. The observed cytotoxicity could be consequence of a vicious cycle in which elevated concentrations of Interleukin 1beta and radical species along with decreased secretion of neuroprotective cytokines such as transforming growth factor beta1 support persistent activation of glial cells and cell damage.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/metabolismo , Muerte Celular/fisiología , Hipocampo/metabolismo , Hipocampo/patología , Microglía/metabolismo , Microglía/patología , Nitritos/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patología , Enfermedad de Alzheimer/embriología , Animales , Western Blotting , Modelos Animales de Enfermedad , Hipocampo/embriología , Inmunohistoquímica , Ratas , Ratas Sprague-Dawley , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
In recent years, we have used a variety of tau immunological markers combined with the dye thiazin red (TR), an accurate marker to differentiate the fibrillar from the nonfibrillar state of both amyloid-beta and tau in Alzheimer's disease (AD). In this study, we used TR as a potential diagnostic marker of AD in frozen-thawed (F-T) brain tissue and imprint cytology. Control experiments included the use of Thioflavin-S staining, fixed tissue, and some double-labeled material with TR and selected tau markers, including AT100, MC1, Alz-50, TG-3, Tau-C3, and S396. Our results indicate that TR retains its strong affinity for both tangles and plaques in unfixed F-T tissue and imprint cytology. This information provides a potential use of TR as an accurate diagnostic tool for the rapid postmortem diagnosis of AD neuropathology. This study shows the advantages of TR on cytology mainly because tools for the fast postmortem diagnosis of AD are practically nonexistent. In addition, we observed Tau-C3 immunoreactivity in extracellular tangles, suggesting that the Tau-C3 epitope is characteristically stable. Moreover, this study demonstrates that chemical fixation is not necessarily required for tau immunoreactivity on histological sections.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Encéfalo/patología , Neuronas/patología , Placa Amiloide/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Benzotiazoles , Encéfalo/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente/métodos , Humanos , Inmunohistoquímica , Masculino , Microscopía Confocal , Persona de Mediana Edad , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Neuronas/metabolismo , Compuestos Orgánicos/metabolismo , Placa Amiloide/metabolismo , Cambios Post Mortem , Tinción con Nitrato de Plata/métodos , Tiazoles/metabolismo , Proteínas tau/metabolismoRESUMEN
It was proposed that insulin-degrading enzyme (IDE) participates in the clearance of amyloid beta (Abeta) in the brain, and its low expression or activity may be relevant for the progression of Alzheimer disease. We performed a longitudinal study of brain level, activity, and distribution of IDE in transgenic mice (Tg2576) expressing the Swedish mutation in human Abeta precursor protein. At 16 months of age, Tg2576 showed a significant 2-fold increment in IDE protein level as compared with 4.5- and 11-month-old animals. The peak of IDE was in synchrony with the sharp accumulation of sodium dodecyl sulfate-soluble Abeta and massive Abeta deposition into plaques. At this stage, IDE appeared surrounding Abeta fibrillar deposits within glial fibrillar acidic protein-positive astrocytes, suggesting that it was locally overexpressed during the Abeta-mediated inflammation process. When primary astrocytes were exposed to fibrillar Abeta in vitro, IDE protein level increased as compared with control, and this effect was reduced by the addition of U0126, a specific inhibitor of the ERK1/2 mitogen-activated protein kinase cascade. We propose that in Tg2576 mice and in contrast to its behavior in Alzheimer brains, active IDE increases with age around plaques as a component of astrocyte activation as a result of Abeta-triggered inflammation.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Corteza Cerebral/metabolismo , Insulisina/biosíntesis , Placa Amiloide/metabolismo , Factores de Edad , Enfermedad de Alzheimer/patología , Animales , Astrocitos/metabolismo , Western Blotting , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Ratones , Ratones Transgénicos , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
In the past two decades, a large body of evidence has established a causative role for the beta-amyloid peptide (Abeta) in Alzheimer's disease (AD). However, recent debate has focused on whether amyloid fibrils or soluble oligomers of Abeta are the main neurotoxic species that contribute to neurodegeneration and dementia. Considerable early evidence has indicated that amyloid fibrils are toxic, but some recent studies support the notion that Abeta oligomers are the primary neurotoxins. While this crucial aspect of AD pathogenesis remains controversial, effective therapeutic strategies should ideally target both oligomeric and fibrillar species of Abeta. Here, we describe the anti-amyloidogenic and neuroprotective actions of some di- and tri-substituted aromatic compounds. Inhibition of the formation of soluble Abeta oligomers was monitored using a specific antibody-based assay that discriminates between Abeta oligomers and monomers. Thioflavin T and electron microscopy were used to screen for inhibitors of fibril formation. Taken together, these results led to the identification of compounds that more effectively block Abeta oligomerization than fibrillization. It is significant that such compounds completely blocked the neurotoxicity of Abeta to rat hippocampal neurons in culture. These findings provide a basis for the development of novel small molecule Abeta inhibitors with potential applications in AD.