C/EBPβ/AEP Signaling Drives Alzheimer's Disease Pathogenesis / 神经科学通报·英文版

Alzheimer's disease (AD) is the most common type of dementia. Almost two-thirds of patients with AD are female. The reason for the higher susceptibility to AD onset in women is unclear. However, hormone changes during the menopausal transition are known to be associated with AD. Most recently, we reported that follicle-stimulating hormone (FSH) promotes AD pathology and enhances cognitive dysfunctions via activating the CCAAT-enhancer-binding protein (C/EBPβ)/asparagine endopeptidase (AEP) pathway. This review summarizes our current understanding of the crucial role of the C/EBPβ/AEP pathway in driving AD pathogenesis by cleaving multiple critical AD players, including APP and Tau, explaining the roles and the mechanisms of FSH in increasing the susceptibility to AD in postmenopausal females. The FSH-C/EBPβ/AEP pathway may serve as a novel therapeutic target for the treatment of AD.

Oxiracetam ameliorates cognitive deficits in vascular dementia rats by regulating the expression of neuronal apoptosis/autophagy-related genes associated with the activation of the Akt/mTOR signaling pathway

Oxiracetam (ORC) is a commonly used nootropic drug for improving cognition and memory impairments. The therapeutic effect and underlying mechanism of ORC in vascular dementia (VaD) treatment remain unknown. In this study, 3-month-old male Sprague-Dawley rats with permanent bilateral common carotid artery occlusion-induced VaD were treated orally with low (100 mg/kg) or high (200 mg/kg) dose ORC once a day for 4 weeks. The results of the Morris water maze test and Nissl staining showed that ORC treatment significantly alleviated learning and memory deficits and neuronal damage in rats with VaD. Mechanistically, the protein levels of a panel of genes associated with neuronal apoptosis (Bcl-2, Bax) and autophagy (microtubule-associated protein 1 chain 3, Beclin1, p62) were significantly altered by ORC treatment compared with VaD, suggesting a protective role of ORC against VaD-induced neuronal apoptosis and autophagy. Moreover, the Akt/mTOR pathway, which is known to be the upstream signaling governing apoptosis and autophagy, was found to be activated in ORC-treated rats, suggesting an involvement of Akt/mTOR activation in ORC-rendered protection in VaD rats. Taken together, this study demonstrated that ORC may alleviate learning and memory impairments and neuronal damage in VaD rats by altering the expression of apoptosis/autophagy-related genes and activation of the Akt/mTOR signaling pathway in neurons.

Effectiveness of individual and group interventions for people with type 2 diabetes / Efetividade das intervenções individual e em grupo junto a pessoas com diabetes tipo 2 / Efectividad de las intervenciones individual y en grupo en personas con diabetes tipo 2

OBJECTIVE: to compare the effectiveness of two educational interventions used by a healthcare provider in the monitoring of individuals with type 2 diabetes mellitus (T2DM), regarding knowledge of the disease, impact on quality of life and adoption of self-care actions. METHODS: comparative, longitudinal, prospective study performed with 150 subjects with type 2 diabetes, analyzed according to the type of participation in the program (individual and/or group). Participants of the individual intervention (II) received nursing consultations every six months and those of the group intervention (GI) took part in weekly meetings for three months. Data were collected through four questionnaires: Identification questionnaire, Problem Areas in Diabetes Questionnaire (PAID), Summary of Diabetes Self-Care Activities Questionnaire (SDSCA) and the Diabetes Knowledge Scale (DKN-A). Data were analyzed using the Friedman and Mann Whitney tests, considering a statistical significance of p ≤ 0.05. RESULTS: there was an increase in knowledge about the disease in the II (p<0.003) and GI (p<0.007), with reduction of the impact on the quality of life in the II (p<0.007) and improvement in self-care actions in the GI (p<0.001). CONCLUSION: in both intervention models improvements were observed in the indicators, over the six month monitoring period. .

OBJETIVO: comparar a efetividade de duas intervenções educativas, utilizadas por uma operadora de saúde, no acompanhamento ao indivíduo com diabetes mellitus Tipo 2 (DM2), quanto ao conhecimento sobre a doença, impacto na qualidade de vida e adoção de ações de autocuidado. MÉTODOS: estudo comparativo, longitudinal, prospectivo, realizado com 150 indivíduos com diabetes tipo 2, analisados conforme a modalidade de participação no programa (individual e/ou em grupo). Os participantes da intervenção individual (II) realizaram consultas de enfermagem a cada seis meses e os da intervenção em grupo (IG), reuniões semanais por três meses. Os dados foram coletados mediante quatro questionários: Questionário de identificação, Questionário de Impacto na Qualidade de Vida em Diabetes (PAID), Questionário de Autocuidado em Diabetes (QAD) e Questionário de Conhecimento do Diabetes (DKN-A). Os dados foram analisados utilizando-se o Teste de Friedman e o Teste de Mann Whitney, considerando significância estatística para p ≤ 0,05. RESULTADOS: verificou-se aumento do conhecimento sobre a doença na II (p<0,003) e na IG (p<0,007), redução do impacto na qualidade de vida na II (p<0,007) e melhora das ações de autocuidado na IG (p<0,001). CONCLUSÃO: em ambos os modelos de intervenção foram observadas melhoras dos indicadores, ao longo dos seis meses de acompanhamento. .

OBJETIVO: comparar la efectividad de dos intervenciones educativas, utilizadas por una operadora de planes de salud, en el acompañamiento al individuo con diabetes mellitus Tipo 2 (DM2), sobre al conocimiento de la enfermedad, impacto en la calidad de vida y adopción de acciones de autocuidado. MÉTODOS: estudio comparativo, longitudinal, prospectivo, realizado con 150 individuos con diabetes tipo 2, analizados conforme la modalidad de participación en el programa (individual y/o en grupo). Los participantes de la intervención individual (II) realizaron consultas de enfermería a cada seis meses y los de intervención en grupo (IG), reuniones semanales por tres meses. Los datos fueron recolectados mediante cuatro cuestionarios: Cuestionario de identificación, Cuestionario de Impacto en la Calidad de Vida en Diabetes (PAID), Cuestionario de Autocuidado en Diabetes (CAD) y Cuestionario de Conocimiento de la Diabetes (DKN-A). Los datos fueron analizados utilizando el test de Friedman y el test de Mann Whitney, considerando significación estadística para p ≤ 0,05. RESULTADOS: se verificó aumento del conocimiento sobre la enfermedad en la II (p<0,003) y en la IG (p<0,007), reducción del impacto en la calidad de vida en la II (p<0,007) y mejoría de las acciones de autocuidado en la IG (p<0,001). CONCLUSIÓN: en los dos modelos de intervención fueron observadas mejorías de los indicadores, a lo largo de los seis meses de acompañamiento. .

Alteraciones hipocampales y cambios cognitivos preceden al deposito de placas amiloides en un modelo murino de la enfermedad de Alzheimer

Existen múltiples evidencias de alteraciones neuronales y gliales en etapas avanzadas de la enfemedad de Alzheimer con abundantes depósitos cerebrales de beta amiloide, aunque hay pocos datos de cambios tempranos que podrían contribuir al desarrollo de la enfermedad. Evaluamos alteraciones morfológicas neuronales y gliales, y cambios cognitivos y emocionales tempranos en ratones transgénicos PDAPP-J20 (Tg), portadores del gen humano de APP (amyloid precursor protein) mutado, a los 5 meses de edad, aún sin depósitos amiloides en el hipocampo y con niveles bajos de péptidos amiloides cerebrales. Mediante inmunohistoquímica para NeuN, los Tg presentaron menor número de neuronas piramidales y granulares en el hipocampo, junto con un menor volumen de la estructura, en comparación con los controles no transgénicos. La neurogénesis se encontró afectada, evidenciada por reducido número de neuronas DCX+ en el giro dentado. En la región CA3, hubo una menor densidad de sinaptofisina sugiriendo alteraciones sinápticas entre neuronas granulares y piramidales, sin cambios en la densidad de espinas dendríticas en CA1. Utilizando microscopía confocal, observamos una disminución del número de astrocitos GFAP+ con una reducción de la complejidad celular, sugiriendo atrofia glial. Se detectó un déficit cognitivo (reconocimiento de localización novedosa de un objeto) y un aumento de la ansiedad (campo abierto) en los Tg, con aumento en los núcleos c-Fos+ en amígdala, evidenciando el papel de la emocionalidad en los inicios de la enfermedad. El estudio de las alteraciones iniciales en la enfermedad amiloide podría contribuir al desarrollo de métodos de diagnóstico temprano y de terapéutica preventiva.

Although there is strong evidence about neuronal and glial disturbances at advanced stages of Alzheimer’s disease, less attention has been directed to early, pre-amyloid changes that could contribute to the progression of the disease. We evaluated neuronal and glial morphological changes and behavioral disturbances in PDAPP-J20 transgenic (Tg) mice, carrying mutated human APP gene (amyloid precursor protein), at 5 months of age, before brain amyloid deposition occurs. Using NeuN immunohistochemistry we found decreased numbers of pyramidal and granular neurons in the hippocampus associated with a reduction of hippocampal volume in Tg mice compared with controls. Neurogenesis was impaired, evidenced by means of DCX immunohistochemistry in the dentate gyrus. In the CA3 region we found a decreased density of synaptophysin, suggesting synaptic disturbance, but no changes were found in CA1 synaptic spine density. Using confocal microscopy we observed decreased number and cell complexity of GFAP+ astrocytes, indicating potential glial atrophy. Cognitive impairment (novel location recognition test) and increased anxiety (open field) were detected in Tg mice, associated with more c-Fos+ nuclei in the amygdala, possibly indicating a role for emotionality in early stages of the disease. The study of early alterations in the course of amyloid pathology could contribute to the development of diagnostic and preventive strategies.