ABSTRACT
Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Sever cognitive and memory impairments, huge increase in the prevalence of the disease, and lacking definite cure have absorbed worldwide efforts to develop therapeutic approaches. Since many drugs have failed in the clinical trials due to multifactorial nature of AD, symptomatic treatments are still in the center attention and now, nootropic medicinal plants have been found as versatile ameliorators to reverse memory disorders. In this work, anti-Alzheimer's activity of aqueous extract of areca nuts (Areca catechu L.) was investigated via in vitro and in vivo studies. It depicted good amyloid ß (Aß) aggregation inhibitory activity, 82% at 100 µg/mL. In addition, it inhibited beta-secretase 1 (BACE1) with IC50 value of 19.03 µg/mL. Evaluation of neuroprotectivity of the aqueous extract of the plant against H2O2-induced cell death in PC12 neurons revealed 84.5% protection at 1 µg/mL. It should be noted that according to our results obtained from Morris Water Maze (MWM) test, the extract reversed scopolamine-induced memory deficit in rats at concentrations of 1.5 and 3 mg/kg.
La enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo relacionado con la edad. Los severos deterioros cognitivos y de la memoria, el enorme aumento de la prevalencia de la enfermedad y la falta de una cura definitiva han absorbido los esfuerzos mundiales para desarrollar enfoques terapéuticos. Dado que muchos fármacos han fallado en los ensayos clínicos debido a la naturaleza multifactorial de la EA, los tratamientos sintomáticos siguen siendo el centro de atención y ahora, las plantas medicinales nootrópicas se han encontrado como mejoradores versátiles para revertir los trastornos de la memoria. En este trabajo, se investigó la actividad anti-Alzheimer del extracto acuoso de nueces de areca (Areca catechu L.) mediante estudios in vitro e in vivo. Representaba una buena actividad inhibidora de la agregación de amiloide ß (Aß), 82% a 100 µg/mL. Además, inhibió la beta-secretasa 1 (BACE1) con un valor de CI50 de 19,03 µg/mL. La evaluación de la neuroprotección del extracto acuoso de la planta contra la muerte celular inducida por H2O2 en neuronas PC12 reveló una protección del 84,5% a 1 µg/mL. Cabe señalar que, de acuerdo con nuestros resultados obtenidos de la prueba Morris Water Maze (MWM), el extracto revirtió el déficit de memoria inducido por escopolamina en ratas a concentraciones de 1,5 y 3 mg/kg.
Subject(s)
Animals , Rats , Areca/chemistry , Plant Extracts/administration & dosage , Alzheimer Disease/drug therapy , beta-Amylase/antagonists & inhibitors , Amyloid beta-Peptides/drug effects , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/drug effects , Neuroprotective Agents , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/drug effects , Alzheimer Disease/enzymology , Alzheimer Disease/prevention & control , Morris Water Maze Test , Medicine, TraditionalABSTRACT
RESUMO A doença neurodegenerativa mais comum no mundo é a doença de Alzheimer (DA), e 10% dos casos apresentam sintomas antes dos 65 anos, quase todos com associação genética, com hereditariedade autossômica dominante e penetrância entre 92 a 100% dos portadores. Na presente revisão, realizamos uma busca sobre as variantes genéticas associadas à doença de Alzheimer de início precoce (DAIP), enfatizando as características associadas mais importantes e as principais mutações já descritas. Os genes mais comumente relacionados com o surgimento da DAIP são APP, PSEN1, PSEN2 e MAPT, e mutações nestes afetam o metabolismo e a estrutura destas proteínas, resultando em acúmulos de peptídeo Aβ que causam inflamação e toxicidade no cérebro, levando à ativação da micróglia e promovendo a liberação de fatores neurotóxicos e pró-inflamatórios que aceleram a neurodegeneração. O gene PSEN1 é responsável por 70% das mutações conhecidas da DAIP, sendo a L166P associada à idade de ocorrência da doença abaixo dos 30 anos. Mutações em APP levam à agregação da proteína em placas neurodegenerativas. Todas as mutações descritas para MAPT estão associadas a um aumento dos emaranhados neurofibrilares. O polimorfismo E4 da Apolipoproteína E (APOE) influencia o aumento no risco de DAIP elevando as chances em três vezes para portadores heterozigotos e entre oito a dez vezes para os homozigotos. Apenas 5% das mutações associadas à DAIP são conhecidas, e novos estudos apresentam outros genes candidatos, bem como a importância de alterações epigenéticas na gênese desta doença.
SUMMARY The most common neurodegenerative disease in the world is Alzheimer's Disease (AD). Ten percent of Alzheimer patients experience symptoms before the age of 65, and almost all of them present genetic features of autosomal dominant inheritance nature, and penetrance of 92 to 100%. In the present review, we searched for genetic variants associated with early onset Alzheimer's disease (EOAD), emphasizing the most important characteristics and the main mutations. The genes most commonly related to the onset of EOAD are APP, PSEN1, PSEN2 and MAPT, whose mutations affect the metabolism and structure of these proteins. This process results in accumulations of Aβ peptide that leads to activation of the microglia and release of neurotoxic and pro-inflammatory factors that accelerate neurodegeneration. The PSEN1 gene is responsible for 70% of the known mutations in EOAD, while L166P is associated with below 30 years as the starting age of occurrence. APP mutations lead to protein aggregation in neurodegenerative plaques. All of the mutations described for MAPT are associated with an increase in neurofibrillary tangles. The E4 polymorphism of Apolipoprotein E (APOE) influences an increased risk of EOAD increasing up to three times the chances for heterozygous, and between eight and ten times for homozygotes carriers. Only 5% of the mutations associated with EOAD are known; new studies will show other candidate genes, as well as the importance of epigenetic factors changes in the etio-pathogenesis of this disease.
ABSTRACT
The hypotheses currently considered the most likely causes of Alzheimer's disease (AD) are amyloid beta peptide deposition in the cerebral cortex and hyperphosphorylation of the Tau protein, with the consequent formation of neurofibrillary tangles. In clinical practice, although not accurate, AD diagnosis is based on the exclusion of other diseases, behavioural assessments and complementary examinations, such as imaging and blood tests. Advances in the field of biotechnology have created exciting prospects for the early detection of AD via biomarker assessment, which is considered a safer and more efficient procedure. Molecules recognised as biomarkers can be expressed in some body fluids, including cerebrospinal fluid, saliva and blood. The presence of amyloid beta peptide and Tau can be confirmed in saliva, which is also an easily and non-invasively collectable material with an accessible cost. The objective was evaluate the concentrations of the t-Tau protein and Ab42 peptide in the saliva of elderly individuals with and without dementia of the AD type Method: The objective of this case-control study, involving a total of 120 individuals, was to analyse whether a correlation exists between variations in the concentrations of the t-Tau and Ab42 biomarkers in the saliva of patients with confirmed AD and individuals in the inclusion group but without AD . We found that t-Tau expression in AD patients is significantly lower than that in individuals without AD, whereas the salivary concentration of Ab42 is higher in patients with AD but not significantly different from that of the group without AD. Conclusion: Thus, we demonstrate the feasibility of using salivary biomarkers as predictive markers for diagnosis of Alzheimer's disease.
Las hipótesis consideradas actualmente como las causas más probables de la enfermedad de Alzheimer (EA) son la deposición de péptido beta amiloide en la corteza cerebral y la hiperfosforilación de la proteína Tau, con la consiguiente formación de ovillos neurofibrilares. En la práctica clínica, aunque no es precisa, el diagnóstico de la EA se basa en la exclusión de otras enfermedades, evaluaciones de comportamiento y exámenes complementarios, como imágenes y análisis de sangre. Los avances en el campo de la biotecnología han creado interesantes perspectivas para la detección temprana de la EA a través de la evaluación de biomarcadores, que se considera un procedimiento más seguro y más eficiente. Las moléculas reconocidas como biomarcadores se pueden expresar en algunos fluidos corporales, incluidos el líquido cerebroespinal, la saliva y la sangre. La presencia del péptido beta amiloide (AB) y la proteína Tau (t-Tau) se puede confirmar en la saliva, que también es un material fácil y no invasivo de recolección con un costo accesible. El objetivo fue evaluar las concentraciones de la proteína t-Tau y el péptido Ab42 en la saliva de las personas de edad avanzada con y sin demencia del tipo de tipo EA. El estudio de casos y controles, se realizó en un total de 120 personas, para analizar si existe una correlación entre las variaciones en las concentraciones de los biomarcadores t-Tau y Ab42 en la saliva de pacientes con EA confirmada e individuos en el grupo de inclusión pero sin AD. Encontramos que la expresión de t-Tau en pacientes con EA es significativamente menor que en individuos sin EA, mientras que la concentración salival de Ab42 es mayor en pacientes con EA pero no significativamente diferente de la del grupo sin la enfermedad . Por lo tanto, se demuestra la viabilidad del uso de biomarcadores salivales como marcadores predictivos para el diagnóstico de la enfermedad de Alzheimer.
Subject(s)
Humans , Male , Female , Middle Aged , Aged , Amyloid beta-Peptides/metabolism , tau Proteins/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Saliva/metabolism , Saliva/chemistry , Biomarkers/analysis , Biomarkers/metabolism , Amyloid beta-Peptides/analysis , tau Proteins/analysisABSTRACT
In this work, the inhibitory activity of a wide range of polysaccharide extracts from two Iranian and French strains of Agaricus subrufescens were evaluated toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, two extracts S9 and S'7 obtained from Iranian and French strains under different extraction conditions showed selective AChE inhibitory activity with IC50 values of 154.63 and 145.43 µg/mL, respectively. It should be noted that all extracts from both strains demonstrated no BChE inhibitory activity. S9 and S'7 were also tested for their effect on amyloid beta (Aß) aggregation, antioxidant activity, and neuroprotectivity. Their activity against Aß aggregation was comparable to that of donepezil as the reference drug but they induced moderate antioxidant activity by DPPH radical scavenging activity and negligible neuroprotectivity against Aß-induced damage.
En este trabajo, se evaluó la actividad inhibitoria de acetilcolinesterasa (AChE) y butirilcolinesterasa (BChE) para varios extractos de polisacáridos de dos cepas iraníes y francesas de Agaricus subrufescens. Los extractos más potentes mostraron valores de IC50 de 154,63 y 145 µg/ml para las cepas iraní (S9) y francesa (S'7), respectivamente, las cuales se obtuvieron de diferentes condiciones de extracción; sin embargo, todos los extractos no mostraron actividad inhibitoria de BChE. Además, S9 y S'7 se probaron para determinar su efecto sobre la agregación de beta-amiloide (Aß), así como su actividad antioxidante y neuroprotectora. Su actividad inhibitoria de la agregación de Aß fue comparable con donepezil, fármaco de referencia, pero indujeron una actividad antioxidante moderada, medida mediante la captación de radicales DPPH, y una neuroprotectora insignificante contra el daño inducido por Aß.
Subject(s)
Agaricus/chemistry , Alzheimer Disease/drug therapy , Amyloid/drug effects , Antioxidants/pharmacology , Picrates , Biphenyl Compounds , Butyrylcholinesterase , Cholinesterase Inhibitors/pharmacology , Neuroprotective Agents , Alzheimer Disease/enzymology , Fungal Polysaccharides/pharmacologyABSTRACT
RESUMO Objetivo O artigo tem como objetivo determinar as famílias de receptores mais estudadas, envolvidas com a doença de Alzheimer, assim como determinar a região do sistema nervoso na qual mais tipos de receptores são expressos e quais funções dos receptores estão predominantemente associadas com a patologia em questão. O artigo busca mostrar os modelos e métodos mais utilizados nessas pesquisas, resumindo alguns achados e discutindo o impacto desses estudos no conhecimento científico. Métodos Esta revisão utilizou-se de uma metodologia sistemática (Prospero; ID 141957). Resultados Pode-se constatar que os receptores de transcrição nuclear foram os mais estudados. A maior parte desses receptores se expressa no córtex cerebral e hipocampo. Adicionalmente, a maioria das pesquisas avaliou os receptores relacionados com os efeitos benéficos na doença. A eliminação da proteína amiloide ou o bloqueio de vias relacionadas à síntese dessa proteína foram as principais funções desempenhadas por esses receptores. Por fim, as técnicas de imunoistoquímica e reação em cadeia de polimerase em tempo real (RT-PCR), respectivamente, foram as mais utilizadas, e os roedores consistiram no principal modelo de estudo. Conclusões Os receptores de transcrição nuclear, o córtex cerebral, o hipocampo, a micróglia e a proteína beta-amiloide mostraram importância na patogênese da doença de Alzheimer neste estudo.
ABSTRACT Objective The article aims to find the receptors family involved with Alzheimer's disease most studied as well as the tissue that most receptors are expressed. This study also aims to determine the functions predominantly associated with the pathology. In addition, the work seeks to show the models and techniques most used, as well as summarize the findings and discuss the impact of these studies on scientific knowledge. Methods This review addressed a systematic methodology (Prospero; ID 141957). Results It can be seen that nuclear transcription receptors were the most studied. Most of these receptors are expressed in the cerebral cortex and hippocampus. Additionally, a great number of studies evaluated the receptors related to beneficial effects in the disease. The depletion of amyloid protein or the blockade of pathways related to its synthesis were the main functions performed by these receptors. Finally, immunohistochemistry and RT-PCR techniques, respectively, were the most used and the rodents were the main study model. Conclusions Nuclear transcription receptors, cerebral cortex and hippocampus, microglia, and amyloid beta protein have shown significant importance in the pathogenesis of Alzheimer's disease in this study.
ABSTRACT
Abstract Alzheimer disease (AD) is the most prevalent form of dementia of adult-onset, characterized by progressive impairment in cognition and memory. There is no cure for the disease and the current treatments are only symptomatic. Drug discovery is an expensive and time-consuming process; in the last decade no new drugs have been found for AD despite the efforts of the scientific community and pharmaceutical companies. The Aβ immunotherapy is one of the most promising approaches to modify the course of AD. This therapeutic strategy uses synthetic peptides or monoclonal antibodies (mAb) to decrease the Aβ load in the brain and slow the progression of the disease. Therefore, this article will discuss the main aspects of AD neuropathogenesis, the classical pharmacologic treatment, as well as the active and passive immunization describing drug prototypes evaluated in different clinical trials.
Resumen La enfermedad de Alzheimer (EA) es la forma más frecuente de demencia de inicio en el adulto, caracterizada por un deterioro progresivo en la cognición y la memoria. No hay cura para la enfermedad y los tratamientos actuales son sólo sintomáticos. El descubrimiento de fármacos es un proceso costoso y que consume mucho tiempo; en la última década no se han encontrado nuevos fármacos para la EA a pesar de los esfuerzos de la comunidad científica y las compañías farmacéuticas. La inmunoterapia contra Aβ es uno de los enfoques más prometedores para modificar el curso de la EA. Esta estrategia terapéutica utiliza péptidos sintéticos o anticuerpos monoclonales (mAb) para disminuir la carga de Aβ en el cerebro y retardar la progresión de la enfermedad. Por lo tanto, este artículo discutirá los principales aspectos de la neuropatogénesis de la EA, el tratamiento farmacológico clásico, así como la inmunización activa y pasiva describiendo los prototipos de fármacos evaluados en diferentes ensayos clínicos.
Subject(s)
Humans , Amyloid beta-Peptides/immunology , Alzheimer Disease/therapy , Immunotherapy/methods , Peptides/therapeutic use , Peptides/pharmacology , Disease Progression , Alzheimer Disease/physiopathology , Alzheimer Disease/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/pharmacologyABSTRACT
El Alzheimer es una enfermedad neurodegenerativa que se manifiesta como deterioro cognitivo y trastornos conductuales. En Cuba, junto a la demencia, ocupa el lugar número 6 en el cuadro de principales causas de muerte. No hay tratamiento eficaz para detener la progresión del Alzheimer. Sin embargo, algunas terapias detienen o ralentizan temporalmente el deterioro cognitivo, funcional y conductual de la enfermedad. En el trabajo se presenta una revisión actualizada a partir de la base de datos MEDLINE (2008-2013) sobre los mecanismos patológicos y los medicamentos usados en el tratamiento de los pacientes con la referida afección(AU)
Alzheimer disease is a neurodegenerative illness that manifests as cognitive deterioration and behavioral disorders. It holds the 6th place, like dementia, in the list of main causes of death in Cuba. There is no effective treatment to stop progression of Alzheimer's disease. However, some therapies manage to halt or to slow at least temporarily the cognitive, functional and behavioral deterioration of the disease. This paper presented an updated review on the pathological mechanisms and the drugs used in the treatment of Alzheimer patients, using MEDLINE database(AU)
Subject(s)
Humans , Alzheimer Disease/drug therapy , Alzheimer Disease/therapyABSTRACT
A doença de Alzheimer (DA) é a forma de demência degenerativa esporádica mais comum. Caracteristicamente ocorre expressiva perda neuronal progressiva em locais específicos nas pessoas atingidas. O distúrbio degenerativo progressivo se caracteriza pela perda de sinapses, de neurônios cerebrais e por depósitos de fibrilas de peptídeos de beta-amilóide extraneuronais, constituindo as placas senis e a presença de agregados intraneuronais da proteína tau, formando os emaranhados neurofibrilares. Fatores genéticos, metabólicos, neuroinflamação, alterações mitocondriais, distúrbios vasculares e processos oxidativos estão envolvidos no desencadear e manutenção de várias doenças neurodegenerativas, incluindo a DA. Todas essas alterações participam no processo fisiopatológico da doença. O objetivo desta revisão é mostrar a associação das várias causas subjacentes ao processo fisiopatológico da DA, com vistas ao desenvolvimento de marcadores biológicos e estratégias terapêuticas.
Alzheimer's disease (AD) is the most common form of sporadic degenerative dementia. Characteristically there is an expressive neuronal loss in specific sites in the affected persons. The progressive degenerative disorder is characterized by synaptic loss, of brain neurons, and by extraneuronal deposition of beta-amyloid fibrils, constituting the senile plaques, and the presence of intraneuronal aggregates of tau protein, forming the neurofibrillary tangles. Genetic factors, metabolic, neuroinflammation, mitochondrial disturbances, vascular disorders and oxidative processes are involved in the onset and maintenance of several neurodegenerative disorders, including AD. All these disturbances participate in the pathophysiological process of the disease. The aim of this review is to show the association of the varied causes underlying the pathophysiological process of AD, having in view the development of biological markers and therapeutic strategies.
Subject(s)
Humans , Aged , Cognition Disorders , Alzheimer Disease/etiology , Alzheimer Disease/physiopathology , Synapses , Amyloid beta-Peptides , Oxidative Stress , Alzheimer Disease/genetics , Mitochondria , Nerve DegenerationABSTRACT
La enfermedad de Alzheimer (EA) es la forma de demencia más común en la edad adulta. Se manifiesta con la pérdida progresiva de la memoria a medida que las neuronas en la corteza cerebral y el hipocampo mueren. En todas las formas de EA se evidencia aumento de la expresión de diferentes proteínas, así como la presencia de agregados insolubles de péptido-β-amiloide (PBA). La glutamina sintetasa (GS) es una enzima clave en el metabolismo del glutamato y en la detoxificación de amonio (NH4+). Previamente se ha reportado una posible interacción GS-PBA que puede estar asociada con EA. En este trabajo se realizó la purificación de la enzima cerebral de rata a partir de un extracto sometido a precipitación fraccionada con (NH4)2SO4 del 20-60 % de saturación y posteriormente a través de cromatografías sucesivas de filtración en gel, intercambio iónico y afinidad. El peso molecular del complejo fue calculado en 137 kDa por el orden de elución en la columna de filtración. Se identificó interacción de la enzima con PBA 1-40, lográndose la purificación de una sola banda de 45 kDa, correspondiente a la forma monomérica de la GS. En este trabajo se presenta un nuevo método de purificación de la enzima y se demuestra la interacción de GS con el PBA. Se propone que esta interacción GS-PBA puede ser uno de los procesos que se presentan en la enfermedad al explicar la reducción de la actividad de la enzima en paciente con EA, ya que podría alterar el ciclo glutamato-glutamina y generar cambios en el entorno celular que favorecen excitotoxicidad por glutamato típica de los procesos de neurodegeneración.
Alzheimer's disease (AD) is the most common form of dementia in adulthood; it is manifested by the progressive loss of memory since neurons in both cerebral cortex and hippocampus die. In all the forms of AD is observed the increased expression of different proteins, as well as the presence of insoluble aggregates of β-amyloid peptide (BAP). Glutamine synthetase (GS) is a key enzyme in the metabolism of glutamate and in the detoxification of ammonium (NH4+). A possible interaction GS-PBA has been previously reported and it can be associated with AD. In this work we performed the purification of the enzyme from rat brain extract subjected to fractional precipitation 20-60 % saturation with (NH4)2SO4, and thereafter through successive chromatographies of gel filtration, ion exchange and affinity. The molecular weight of the complex was calculated at 137 kDa by the order of elution in the column filtration. The interaction of the enzyme with 1-40 PBA was identified, achieving the purification of a single band of 45 kDa corresponding to the monomeric form of the GS. In this paper we present a new method of the enzyme purification and we demonstrated the interaction of GS with the PBA. We propose this interaction GS-PBA can be one of the processes that occur in the disease and it could explain the reduction in enzyme activity in patients with AD, since it might alter the glutamate-glutamine cycle and generate changes in the cellular environment which favor glutamate excitotoxicity typical of neurodegeneration processes.
A doença do Alzhéimer (DA) é a forma mais comum de demência na idade adulta, que se manifesta pela perda progressiva da memória, já que os neurónios em córtex cerebral e hipocampo morrem. Em todas as formas de AD é observado o aumento da expressão de proteínas diferentes, bem como a presença de agregados insolúveis de β-amilóide péptido (BAP). Glutamina sintetase (GS) é uma enzima chave no metabolismo do glutamato e na desintoxicação de amónio (NH4+). Uma possível interacção GS-PBA foi relatada anteriormente e pode ser associada com o AD. Neste trabalho, foi realizada a purificação da enzima a partir do extrato do cérebro de rato e foi submetido a precipitação fraccionada com (NH4)2SO4 de 20- 60 % de saturação e, subsequentemente, através de cromatografias sucessivas de filtração em em gel, permuta iónica e de afinidade. O peso molecular do complexo foi calculado em 137 kDa por ordem de eluição na filtração de coluna. A interacção da enzima com 1-40 PBA foi identificada, alcançando a purificação de uma única banda de 45 kDa correspondente à forma monomérica do GS. Neste artigo, apresentamos um novo método de purificação da enzima e demonstramos a interação da GS com o PBA. Propomos que esta interacção GS-PBA pode ser um dos processos que ocorrem na doença e pode explicar a redução na actividade da enzima nos pacientes com o AD, uma vez que poderia alterar o ciclo de glutamatoglutamina e gerar alterações no ambiente celular que favorecem a excitotoxicidade típica do glutamato nos processos de neurodegeneração.
ABSTRACT
Unas 25 millones de personas padecen enfermedad de Alzheimer en el mundo, y probablemente en los práximos 20 años, se registrarán unos 70 millones de nuevos casos. Caracterizaada por una pérdida progresiva de la memoria, el déficit de la capacidad cognitiva es proporcional a la densidad de placas seniles, a la acumulación de la proteína beta amiloide, degeneraciones neuríticas y ovillos neurofibrilares, particularmente en el hipocampo y en la corteza cerebral. Este cuadro histopatológico se asocia a otro neuroquímico, caracterizado por una disminución de las enzimas colina acetiltransferasa y acetilcolinesterasa, y una menor densidad de los receptores colinérgicos muscarínicos y nicotínicos. Ello ha generado la teoría colinérgica del Alzheimer, que ha dado lugar a una aproximación racional al tratamiento de la enfermedad. Hoy disponemos de 3 anticolinesterásicos, galantamina, donepecilo y rivastigmina aprobados por FDA, que se recomiendan en EA leves y moderadas y de un antagonista no competitovo de los receptores NMDA memantina EA. El beneficio es modesto en relación a lo cogitivo y conductual. Se incluyen estudios sobre recomendaciones, farmacología, farmacognética, eficacia, tolerancia, características de los pacientes respondedores a los diferentes anticolinesterásicos, sus reemplazos el uso de comprimidos, parches, beneficiios, efectos adversos y de las nuevas terapéuticas que están en desarrollo como estanercept, NP12, resveratrol PBT2 y vacuna nasal, entre otras...
About 25 millions of individuals in the world suffer from Alzheimer's disease. The next 20 years shall probably register 70 millions of new cases. Characterized by a progressive loss of memory, cognitive deficit is proportional to the density of senile plaques, accumulation of beta amyloid, neuritic degeneration and neurofibrillary tangles, particularly in the hippocampus and cerebral cortex. This histopathological condition is associated with another neurochemical, chracterized by a decrease in choline acetyltransferase and acetylcholinesterase enzymes, and a lower density of muscrinic and nicotinic cholinergic receptors. This results in the cholinergic theory of Alzheimer's, which has led to a rational approach to treatment of disease. Today we have 3 anticholinesterase Galantamine, Donepzil and Rivastigmine approved by FDA recommended in mild to moderate AD and an uncompetitive antagonist of NMDA receptors Memantine is recommended in mild Alzheimer's disease for people who can not take ACE inhibitors, and severe AD The benefit is modest in realtion to the cognitive and behavioral. Studies are included on therapeutic recommendations, pharmacology, pharmacogenetic, efficiency, tolerance, characteristics of responders to different anticholinesterases, their relacements, the use of pills, patches, benefits, side effects and new therapeutic under development as Etanercept, NP12, PBT 2, Resveratrol, Nasal Vaccine, among others...
Subject(s)
Humans , Acetylcholinesterase/adverse effects , Acetylcholinesterase/pharmacokinetics , Acetylcholinesterase/pharmacology , Acetylcholinesterase/therapeutic use , Cognition , Alzheimer Disease/therapy , Cholinesterase Inhibitors/therapeutic use , Memory Disorders/pathologyABSTRACT
A Doença de Alzheimer (DA), caracterizada pela perda da memória e de pelo menos outra função cognitiva, se tornou foco de atenção por parte dos pesquisadores, tendo em vista o aumento de sua prevalência na população mundial. A presença das placas neuríticas, formadas pelo acúmulo do peptídeo beta-amilóide e dos emaranhados neurofibrilares são as principais alterações neuropatológicas características da DA. Estas alterações são responsáveis pelo processo de neurodegeneração e pelo desenvolvimento progressivo da demência. Estudos demonstram menor prevalência e risco para a DA em usuários crônicos de estatinas, fármacos hipocolesterolêmicos. O objetivo desta revisão foi reunir parte dos estudos da literatura que previlegiasse a relação entre as estatinas e a DA. Há indícios de que tais fármacos podem desacelerar o declínio cognitivo e reduzir o ritmo evolutivo da doença, através de seus efeitos pleiotrópicos, das atuações na função endotelial, da inibição da síntese ?-amilóide e da redução do impacto do emaranhado neurofibrilar. Acredita-se que há uma ligação significativa entre os elevados níveis de colesterol nas células neuronais, o uso de estatinas e o prognóstico de pacientes com a DA.
Alzheimers Disease (AD), which is characterized by memory loss and at least another cognitive dysfunction, became focused by researchers due to its increasing prevalence in worlds population. Neuritic plaques, structured by the accumulation of the peptide beta-amyloid; and the neurofibrillary tangles are the main neuropathlogical alterations found in AD. Neurodegeneration and the progressive development of dementia are a consequence of these alterations. Studies observed that statins (hypocholesterolemic drugs) chronic users have a lower prevalence and a decreased risk for AD. The literature was revised targeting the relation between statins and AD. There is evidence that these drugs can deaccelerate the cognitive decline and reduce the diseases evolutive rhythm through: pleiotropic effects, performance concerning endothelial function, inhibition of beta-amyloids synthesis and reduction of neurofibrillary tangles impact. Thus, there is a noteworthy connection regarding high cholesterol levels in the neurons, statin use and the prognosis of patients with AD.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Alzheimer Disease , Amyloid beta-Peptides , Dementia , Alzheimer Disease/drug therapyABSTRACT
Abstract: Alzheimers disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, including memory loss, behavioral and psychological symptoms and personality changes. The neuropathological hallmarks of AD are the presence of neuritic (senile) plaques (NP) and neurofibrillary tangles (NFT), along with neuronal loss, dystrophic neurites, and gliosis. Neuritic plaques are extracellular lesions and their main constituent is the amyloid-beta42 peptide (A- beta42). Neurofibrillary tangles are intracellular lesions that are mainly composed of hyperphosphorylated ta u protein. In this article, we review the major hypotheses concerning the physiopathology of AD, focusing on the beta-amyloid cascade as primary events (supported by the "beta-aptists") and cytoskeletal abnormalities secondary to the hyperphosphorylation of protein Tau (as advocated by the "Tauists"). We further provide an integrative view of the physiopathology of AD.
Resumo: A doença de Alzheimer (DA) é uma desordem neurodegenerativa progressiva que cursa comprometimento da memória e outras funções cognitivas, alterações comportamentais, psíquicas e da personalidade. Os achados neuropatológicos característicos da DA são as placas neuríticas (senis) e os emaranhados neurofibrilares, também ocorrendo distrofia de neuritos, gliose e perda neuronal. As placas neuríticas são lesões extracelulares que têm no peptídeo beta-amilóide (A beta42) seu principal constituinte. Os emaranhados neurofibrilares são lesões intraneuronais compostas por agregados de proteína TAU em estado hiperfosforilado. Neste artigo de revisão, apresentamos as principais hipóteses relacionadas à fisiopatologia da DA, com foco na cascata do amilóide como evento inicial (hipótese preconizada pelos "beta-aptistas") e nas alterações do citoesqueleto neuronal, decorrentes da fosforilação anormal da TAU (conforme proposto pelos "beta-tauístas"). Os achados são discutidos numa leitura integrada desses dois mecanismos fisiopatológicos.
Subject(s)
Humans , Amyloid beta-Peptides , tau Proteins , Amyloid Precursor Protein Secretases , Alzheimer DiseaseABSTRACT
La enfermedad de Alzheimer es la causa más común de demencia en la población de edad avanzada. Una de las características histopatológicas de esta enfermedad es la formación de placas seniles, cuyo componente proteínico es el péptido β-amiloide (Aβ) en su forma insoluble. Este péptido se produce normalmente en forma monomérica soluble y circula en concentraciones bajas en el líquido cefalorraquídeo y sangre. En concentraciones fisiológicas actúa como factor neurotrófico y neuroprotector, sin embargo con el envejecimiento y sobre todo en la enfermedad de Alzheimer se acumula, forma fibrillas insolubles y causa neurotoxicidad. La toxicidad del Aβ se ha asociado a la generación de radicales libres que causan peroxidación de lípidos y oxidación de proteínas entre otros daños. Se ha planteado que el Aβ pueda reconocer a receptores específicos que median a su vez neurotoxicidad. Entre estos se encuentra el receptor scavenger o pepenador que se expresa en la microglia y es capaz de internalizar agregados de este péptido. Independientemente de la vía de entrada del péptido a la célula, éste genera un estado de estrés oxidativo que eventualmente desencadena la muerte celular. Estudios recientes desarrollados en nuestro laboratorio muestran que el proceso de traducción de proteínas que intervienen en el proceso de endocitosis mediada por un receptor puede ser afectado por una condición de estrés oxidativo. Este es el caso de la β-adaptina, proteína clave en la formación del pozo cubierto.
Alzheimer's disease, the leading cause of dementia in the elderly is characterized by the presence in the brain of senile plaques formed of insoluble fibrillar deposits of beta-amyloid peptide. This peptide is normally produced in a monomeric soluble form and it is present in low concentrations in the blood and spinal fluid. At physiological concentrations, this peptide is a neurotrophic and neuroprotector factor; nevertheless, with aging and particularly in Alzheimer's disease this peptide accumulates, favors the formation of insoluble fibrils and causes neurotoxicity. beta-Amyloid peptide toxicity has been associated with the generation of free radicals that in turn promote lipid peroxidation and protein oxidation. Through the recognition of specific receptors such as the scavenger receptor, the beta-amyloid peptide becomes internalized in the form of aggregates. Independently of the way the peptide enters the cell, it generates oxidative stress that eventually triggers a state of neurotoxicity and cell death. Recent studies in our laboratory have shown the effect caused by an extracellular oxidative stress upon the internalization of the scavenger receptor. We have also demonstrated that the process of protein translation of molecules implicated in the mechanism of endocytosis through the scavenger receptor, such as the case of beta-adaptin, is arrested in microglial cells treated with beta-amyloid.