ABSTRACT
BACKGROUND: Primary angiitis of the central nervous system (PACNS) is a rare but serious condition. A fraction of patients suffering from PACNS concurrently exhibit pronounced cerebral amyloid angiopathy (CAA) which is characterized by deposits of amyloid-ß (Aß) in and around the walls of small and medium-sized arteries of the brain. PACNS with CAA has been identified as a distinct disease entity, termed Aß-related angiitis (ABRA). Evidence points to an immune reaction to vessel wall Aß as the trigger of vasculitis. OBJECTIVE: To investigate whether the inflammatory response to Aß has (1) any effect on the status of immune activation in the brain parenchyma and (2) leads to clearance of Aß from brain parenchyma. METHODS: We studied immune activation and Aß load by quantitative immunohistochemical analysis in brain parenchyma adjacent to affected vessels in 11 ABRA patients and 10 matched CAA controls. RESULTS: ABRA patients showed significantly increased immune activation and decreased Aß loads in the brain parenchyma adjacent to affected vessels. CONCLUSION: Our results are in line with the hypothesis of ABRA being the result of an excessive immune response to Aß and show that this can lead to enhanced clearance of Aß from the brain parenchyma by immune-mediated mechanisms.
Subject(s)
Amyloid beta-Peptides/immunology , Brain/immunology , Brain/pathology , Vasculitis, Central Nervous System/immunology , Vasculitis, Central Nervous System/pathology , Aged , Amyloid beta-Peptides/analysis , Case-Control Studies , Cerebral Amyloid Angiopathy/immunology , Cerebral Amyloid Angiopathy/pathology , Female , Humans , Immunohistochemistry , Macrophage Activation , Macrophages/immunology , Male , Middle Aged , Plaque, Amyloid/immunology , Plaque, Amyloid/pathologyABSTRACT
AIM: To review the basic molecular mechanisms that are triggered by neuroactive steroids related to protection and plasticity, and their possible therapeutic application in cases of cerebral ischaemia. DEVELOPMENT: The term 'neuroprotection' embraces a series of strategies and effects that are aimed at preventing, impeding or delaying anomalies in the functioning of the central nervous system. The neuroactive steroids, and particularly estradiol, have been widely reported owing to their neuroprotective action because they give rise to a wide range of cell signals and generate effects in genes by means of canonical pathways or through non-conventional mechanisms that are involved in neuronal survival, dendritogenesis and synapse remodelling. Thus, neuroactive steroids become an important long-term protective therapeutic alternative due to the fact that such effects converge on neuronal plasticity. CONCLUSIONS: Further work needs to be carried out to study the mechanisms of action of neuroactive steroids, especially the non-conventional ones, which involve proteins such as GSK-3beta and beta-catenin. These proteins are involved in the functions of synaptic plasticity and survival, and play a crucial role in maintaining and recovering the functional integrity of the brain after the appearance of the lesions caused by cerebral ischaemia.
Subject(s)
Brain Diseases/prevention & control , Brain Ischemia/complications , Estradiol/therapeutic use , Neuronal Plasticity/drug effects , Neuroprotective Agents/therapeutic use , Repressor Proteins/physiology , Synapses/drug effects , Animals , Brain Ischemia/physiopathology , Humans , Neuronal Plasticity/physiology , Synapses/physiologyABSTRACT
Revisar los mecanismos moleculares básicos desencadenados por esteroides neuroactivos relacionadoscon la protección y la plasticidad, y su posible aplicación terapéutica en la isquemia cerebral. Desarrollo. El término neuroprotecciónabarca una serie de estrategias y efectos encaminados a prevenir, impedir o retrasar anomalías en el funcionamiento del sistema nervioso central. Los esteroides neuroactivos, en particular el estradiol, se han referenciado ampliamente por su acción neuroprotectora porque originan una gran diversidad de señales celulares y producen efectos génicos por mediode rutas canónicas o a través de mecanismos no convencionales, involucrados en la supervivencia neuronal, la dendritogénesis y la remodelación sináptica, lo que convierte a los esteroides neuroactivos en una importante alternativa terapéuticade protección a largo plazo por su convergencia con dichos efectos en plasticidad neuronal. Conclusión. Es necesario profundizar en el estudio de los mecanismos de acción de los esteroides neuroactivos, en especial sobre los no convencionales, que involucran proteínas tales como la GSK-3beta y la beta-catenina, en las cuales convergen funciones de supervivencia y plasticidadsináptica y que pueden desempeñar un papel crucial en el mantenimiento y la recuperación de la integridad funcional del cerebro frente a las lesiones propias de la isquemia cerebral
To review the basic molecular mechanisms that are triggered by neuroactive steroids related to protection and plasticity, and their possible therapeutic application in cases of cerebral ischaemia. Development. The term neuroprotection embraces a series of strategies and effects that are aimed at preventing, impeding or delaying anomalies in the functioning ofthe central nervous system. The neuroactive steroids, and particularly estradiol, have been widely reported owing to their neuroprotective action because they give rise to a wide range of cell signals and generate effects in genes by means ofcanonical pathways or through non-conventional mechanisms that are involved in neuronal survival, dendritogenesis and synapse remodelling. Thus, neuroactive steroids become an important long-term protective therapeutic alternative due to thefact that such effects converge on neuronal plasticity. Conclusions. Further work needs to be carried out to study the mechanisms of action of neuroactive steroids, especially the non-conventional ones, which involve proteins such as GSK-3beta and beta-catenin. These proteins are involved in the functions of synaptic plasticity and survival, and play a crucial role inmaintaining and recovering the functional integrity of the brain after the appearance of the lesions caused by cerebral ischaemia
