RESUMEN
Hippocampus is the most widely studied brain area coupled with impairment of memory in a variety of neurological diseases and Alzheimer's disease (AD). The limbic structures within the Papez circuit have been linked to various aspects of cognition. Unfortunately, the brain regions that include this memory circuit are often ignored in terms of understanding cognitive decline in these diseases. To properly comprehend where cognition problems originate, it is crucial to clarify any aberrant contributions from all components of a specific circuit -on both a local and a global level. The pharmacological treatments currently available are not long lasting. Deep Brain Stimulation (DBS) emerged as a new powerful therapeutic approach for alleviation of the cognitive dysfunctions. Metabolic, functional, electrophysiological, and imaging studies helped to find out the crucial nodes that can be accessible for DBS. Targeting these nodes within the memory circuit produced significant improvement in learning and memory by disrupting abnormal circuit activity and restoring the physiological network. Here, we provide an overview of the neuroanatomy of the circuit of Papez along with the mechanisms and various deep brain stimulation targets of the circuit structures which could be significant for improving cognitive dysfunctions in AD.
RESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an impairment of cognition and memory. Current research on connectomics have now related changes in the network organization in AD to the patterns of accumulation and spread of amyloid and tau, providing insights into the neurobiological mechanisms of the disease. In addition, network analysis and modeling focus on particular use of graphs to provide intuition into key organizational principles of brain structure, that stipulate how neural activity propagates along structural connections. The utility of connectome-based computational models aids in early predicting, tracking the progression of biomarker-directed AD neuropathology. In this article, we present a short review of tau trajectory, the connectome changes in tau pathology, and the dependent recent connectome-based computational modelling approaches for tau spreading, reproducing pragmatic findings, and developing significant novel tau targeted therapies.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Conectoma , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Proteínas tau/metabolismo , Imagen por Resonancia Magnética , Encéfalo/metabolismo , Simulación por Computador , Péptidos beta-Amiloides/metabolismo , Tomografía de Emisión de Positrones , Disfunción Cognitiva/patologíaRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised pathologically by the presence of extracellular amyloid plaques and the intracellular neurofibrillary tangles, along with inflammation, and a compromised antioxidant system. Significant insights into the neurobiology to better understand the pathophysiology of AD and to evaluate the possibility of cutting-edge therapy strategies, can be obtained through the selection of a well-designed experimental animal model. From the transgenic to chemical/drug-induced models, none of them represents the complete picture of Alzheimer pathology and incidence of cognitive dysfunction. Researchers did not explain why one model was preferred over another, did not consider how the pathological phenomena were formed (spontaneously, experimentally, or by genetic manipulation), and did not address the traits of the species that affect the results. There is a lack of concordance between preclinical models and clinical trials that could be due to variety of reasons such as incomplete models, choice of animal species, lack of variability, and the validity of the models. To provide greater translation of preclinical AD studies to clinical trials proper designing of the model is essential. This review provides a brief recap ranging from animal doses to their induction mechanism and common limitations of the chemical-induced AD models. ⢠Animal models may fail to replicate the exact pathology of the disease ⢠Validity of the model is essential for proper translation of pathology from animal models to human disease ⢠Appropriate induction doses need to be administered.
RESUMEN
Mechanistic/mammalian target of rapamycin (mTOR) belongs to the phosphatidylinositol kinase-related kinase (PIKK) family. mTOR signaling is required for the commencement of essential cell functions including autophagy. mTOR primarily governs cell growth in response to favourable nutrients and other growth stimuli. However, it also influences aging and other aspects of nutrient-related physiology such as protein synthesis, ribosome biogenesis, and cell proliferation in adults with very limited growth. The major processes for survival such as synaptic plasticity, memory storage and neuronal recovery involve a significant mTOR activity. mTOR dysregulation is becoming a prevalent motif in a variety of human diseases, including cancer, neurological disorders, and other metabolic syndromes. The use of rapamycin to prolong life in different animal models may be attributable to the multiple roles played by mTOR signaling in various processes involved in ageing, protein translation, autophagy, stem cell pool turnover, inflammation, and cellular senescence. mTOR activity was found to be altered in AD brains and rodent models, supporting the notion that aberrant mTOR activity is one of the key events contributing to the onset and progression of AD hallmarks This review assesses the molecular association between the mTOR signaling pathway and pathogenesis of Alzheimer's disease. The research data supporting this theme are also reviewed.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/metabolismo , Animales , Autofagia , Humanos , Mamíferos/metabolismo , Transducción de Señal , Sirolimus , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Alzheimer's disease (AD) isaprogressive neurodegenerative disorder characterized by chronic inflammation due to the presence of neurotoxic Aß and tau proteins. Increased microglial activation and inflated immune response are the other factors to be considered in AD pathology. Microglial cells own biochemical machinery that synthesizes and release endocannabinoids. The exploitation of therapeutic actions of endocannabinoid system has newly emerged in the field of Alzheimer's disease. The activation of cannabinoid receptors/ cannabinoid system modulates inflammatory responses. This review assesses the association between the microglial endocannabinoid system and neuroinflammation in AD. The data supporting the anti-inflammatory role of pharmacological agents modulating cannabinoid system are also reviewed.