RESUMO
Alzheimer's disease (AD) is a neurodegenerative, progressive, and fatal disorder characterized by marked atrophy of the cerebral cortex and loss of basal forebrain cholinergic neurons. The main pathological features of AD are related to neuronal degeneration and include extracellular deposition of amyloid beta plaques (Aß plaques), intracellular formation of neurofibrillary tangles (NFTs), and neuroinflammation. So far, drugs used to treat AD have symptomatic and palliative pharmacological effects, disappearing with continued use due to neuron degeneration and death. Therefore, there are still problems with an effective drug for treating AD. Few approaches evaluate the action of natural products other than alkaloids on the molecular targets of ß-amyloid protein (Aß protein) and/or tau protein, which are important targets for developing neuroprotective drugs that will effectively contribute to finding a prophylactic drug for AD. This review gathers and categorizes classes of natural products, excluding alkaloids, which in silico analysis (molecular docking) and in vitro and/or in vivo assays can inhibit the BACE1 and GSK-3ß enzymes involved in AD.
Assuntos
Doença de Alzheimer , Produtos Biológicos , Humanos , Peptídeos beta-Amiloides/metabolismo , Glicogênio Sintase Quinase 3 beta , Simulação de Acoplamento Molecular , Secretases da Proteína Precursora do Amiloide/metabolismo , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Ácido Aspártico Endopeptidases/uso terapêutico , Doença de Alzheimer/metabolismo , Proteínas tau/metabolismo , Proteínas tau/uso terapêuticoRESUMO
Alzheimer's disease is a neurodegenerative disorder whose etiology continues to be discussed, to the point that there are different hypotheses that seek to clarify it, in addition to the fact that, given its multifactorial nature, there are different risk factors associated with its development. As regards diagnosis, advances in molecule detection techniques at femtomolar scales have allowed to distinguish between healthy and diseased subjects at relatively early stages, although there is still much to be done. Aducanumab is a monoclonal antibody targeted against Aß, whose marketing approval by the Food and Drug Administration has been questioned by the international medical community, given the controversial results in clinical trials. Approval of this antibody as a disease-modifying treatment for Alzheimer's disease opens the door to continue using this type of treatments, but with different therapeutic targets, such as, for example, tau protein. Finally, given the population tendency towards longevity, conditions such as Alzheimer's disease are gaining epidemiological importance, which is why it is imperative to analyze and link what is being done in the social, familiar, clinical and research fields and, most importantly, to find those areas of opportunity for the benefit of the patient.
La enfermedad de Alzheimer es un desorden neurodegenerativo cuya etiología aún se discute, al punto de que existen diferentes hipótesis que pretenden esclarecerla; además, dada su naturaleza multifactorial, existen diferentes factores de riesgo asociados a su desarrollo. Respecto al diagnóstico, los avances en las técnicas de detección de moléculas a escalas femtomolares han permitido discernir entre sujetos sanos y enfermos en estadios relativamente tempranos, aunque todavía hay mucho por hacer. Aducanumab es un anticuerpo monoclonal dirigido contra Aß, cuya aprobación por parte de la Food and Drug Administration para comercializarse ha sido cuestionada por la comunidad médica internacional, dados los resultados controversiales en los ensayos clínicos. La aprobación de este anticuerpo como tratamiento modificador de la enfermedad de Alzheimer abre la puerta para seguir utilizando este tipo de tratamientos, pero con blancos terapéuticos diferentes, como, por ejemplo, la proteína tau. Finalmente, dada la tendencia de la población hacia la longevidad, padecimientos como la enfermedad de Alzheimer están tomando importancia epidemiológica, por lo que resulta imperativo analizar y vincular lo que se está haciendo en los ámbitos social, familiar, clínico y de investigación y, sobre todo, encontrar esas áreas de oportunidad en beneficio del paciente.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/etiologia , Proteínas tau/uso terapêutico , México/epidemiologia , Biomarcadores/metabolismo , Anticorpos Monoclonais/uso terapêutico , Fatores de RiscoRESUMO
Ubiquitin, an intracellular marker of non-lysosomal protein degradation was immunocytochemically and biochemically detected in paired helical filaments (PHF) of aged and Alzheimer's disease brains. Seven micron thick paraffin serial sections of the hippocampus were stained with PHF, or UBIQUITIN, or TAU antibodies using an indirect immunoperoxidase technique. The neuroplasm, axons, dendrites, neurophil threads of degenerating neurons from the stratum pyramidale and surrounding neuroparenchyma were intensely stained by the above types of antibodies. The cell bodies of these neurons had a specific shape, implicating the accumulation of intracellular cytoskeletal components. Using gel electrophoresis, Western blot and immunoblot techniques, ubiquitin epitopes were detected in PHF, where they were linked to tau protein. These results suggest that ubiquitin may be involved in the regulation of cellular events or degradation of the cytoskeletal protein tau,incorporated into PHF. Deposition of PHF in the perikarya of susceptible neurons may lead to their metabolic changes, reorganization of cytoskeletal components, impaired neuronal function, cell degeneration and death. (AU)