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Alzheimer&rsquo, s disease (AD) is the most common type of dementia and is the leading cause of disability in elderly people worldwide. Current pharmacological therapies do not cure the disease, and for this reason, some pharmacotherapy studies have investigated preventive treatments focused on modifiable nutritional factors such as diet. Quercetin (Qc) is a flavonoid found in fruits and vegetables that has several biological properties. In this study, we evaluated the effect of chronic oral quercetin administration (100 mg/kg) on neurodegeneration markers and cognitive and emotional deficits in a triple transgenic Alzheimer&rsquo, s disease (3xTg-AD) mouse model using histological and behavioral analyses. Our results suggest that long-term (12 months) oral preventive treatment with quercetin has significant effects on &beta, amyloidosis reduction and tends to decrease tauopathy in the hippocampus and amygdala. These decreases positively affected the cognitive functional recovery (without modifying the emotional skills) of 3xTg-AD mice. These findings suggest that preventive and chronic administration of Qc might help to delay the development of histopathological hallmarks and cognitive function deficits in AD.

Introduction: Alzheimer’s disease is the most common form of dementia. It is characterized by histopathological hallmarks such as senile plaques and neurofibrillary tangles, as well as a concomitant activation of microglial cells and astrocytes that release pro-inflammatory mediators such as IL-1β, iNOS, and COX-2, leading to neuronal dysfunction and death. Objective: To evaluate the effect of quercetin on the inflammatory response in the CA1 area of the hippocampus in a 3xTg-AD male and female mice model. Materials and methods: Animals were injected intraperitoneally with quercetin every 48 hours during three months, and we conducted histological and biochemical studies. Results: We found that in quercetin-treated 3xTg-AD mice, reactive microglia and fluorescence intensity of Aβ aggregates significantly decreased. GFAP, iNOS, and COX-2 immunoreactivity also decreased and we observed a clear tendency in the reduction of IL-1β in hippocampal lysates. Conclusion: Our work suggests an anti-inflammatory effect of quercetin in the CA1 hippocampal region of aged triple transgenic Alzheimer’s disease mice. Resumen Introducción. La enfermedad de Alzheimer es la forma más común de demencia; se caracteriza por la presencia de marcadores histopatológicos, como las placas seniles y los ovillos neurofibrilares, así como por una activación concomitante de células microgliales y astrocitos que liberan mediadores proinflamatorios, como IL-1β, iNOS y COX-2, lo cual conduce a la disfunción y la muerte neuronal. Objetivo. Evaluar el efecto de la quercetina sobre la reacción inflamatoria en el área CA1 del hipocampo en un modelo de ratones 3xTg-AD. Materiales y métodos. Los animales se inyectaron intraperitonealmente con quercetina cada 48 horas durante tres meses, y se hicieron estudios histológicos y bioquímicos. Resultados. Se encontró que en los animales 3xTg-AD tratados con quercetina, la microglía reactiva y la intensidad de fluorescencia de los agregados Aβ disminuyeron significativamente, y que hubo una menor reacción de GFAP, iNOS y COX-2, así como una clara tendencia a la reducción de la IL-1 β en lisados de hipocampo. Conclusión. Los resultados del estudio sugieren un efecto antiinflamatorio de la quercetina en la región CA1 del hipocampo en un modelo en ratón triple trasgénico para la enfermedad de Alzheimer.

Resumen Las enfermedades cerebrovasculares se han convertido en un problema de salud mundial debido a su alta tasa de mortalidad y discapacidad. En Colombia constituyen la tercera causa de riesgo de muerte y en el mundo son la primera causa de discapacidad física y mental. Se han evaluado muchas estrategias terapéuticas en modelos experimentales y en ensayos clínicos sin buenos resultados. Algunas de las falencias de los estudios sobre tales estrategias terapéuticas son el reducido tiempo de intervención (menos de cuatro horas y media), así como el poco tiempo de protección y la falta de seguimiento de la terapia, lo cual genera secuelas a largo plazo en los pacientes. La terapia génica ha demostrado ser una herramienta de gran utilidad para el tratamiento de las enfermedades neurodegenerativas; sin embargo, en el caso específico de la isquemia cerebral hay pocos estudios experimentales. En nuestras investigaciones hemos constatado el potencial de la terapia génica basada en el ARN de interferencia para prevenir y revertir la neurodegeneración y el deterioro cognitivo después de un infarto cerebral, aunque todavía deben sortearse algunas dificultades terapéuticas inherentes al sistema nervioso cerebral, así como concertar los intereses de los diversos sectores involucrados: el Gobierno, las empresas y el sector científico y académico, con el fin de incentivar la inversión y facilitar la aplicación en otras partes del país de las terapias promisorias propuestas en nuestra región para disminuir las secuelas de enfermedades crónicas no transmisibles, entre ellas la incapacidad física y mental después de un infarto cerebral. © 2017. Acad. Colomb. Cienc. Ex. Fis. Nat. Abstract Cerebrovascular disease has become a worldwide health problem due to its high mortality and disability rate. It is the third leading cause of death risk in our country and the first cause of physical and mental disability in the world. Many therapeutic strategies have been evaluated both in experimental models and in clinical trials without success. One of the major shortcomings of these therapeutic studies is the limitation in the intervention time (less than four and a half hours) and the short time of protection or follow-up of the therapy, which generates long-term sequelae in the patients. Gene therapy has been shown to be a very useful tool for the treatment of neurodegenerative diseases; however, experimental studies are few, specifically in cerebral ischemia. Our research has demonstrated the potential benefit of RNA interference based gene therapy to prevent and reverse neurodegenerative effects and cognitive impairment following a stroke. However, therapeutic difficulties inherent to the cerebral nervous system should be overcome, and the interests of government, business and scientific and academic sectors should be coordinated to procure investment and to facilitate the translation of promising therapies proposed from our region aimed at reducing the sequelae of chronic non-communicable diseases, including physical and mental disability after a stroke. © 2017. Acad. Colomb. Cienc. Ex. Fis. Nat.

Excitotoxicity is the main event during neurological disorders producing drastic morphological and functional changes. Rac-GTPase is involved in cytoskeletal remodeling and survival. However, the role of Rac1 after cerebral ischemia has not been completely understood yet. In this study, we evaluated the activity of Rac1 and its immunoreactivity associated to neuropathological hallmarks and behavioral task analyses after global cerebral ischemia in an acute and long-term post-ischemia period. Our findings showed that during the acute phase (24h) after global cerebral ischemia, a decrease of the active state of Rac1 was detected in the hippocampus, together with a down-regulation of survival signaling. In this same post-ischemia time, Rac1 immunoreactivity was redistributed to cytoplasm and to aberrant neurites, accompanied by dendritic and actin cytoskeletal retraction both in vivo and in vitro in neuronal primary cultures treated with glutamate. Neurons transfected with the constitutively active mutant of Rac1 were recovered from the glutamate-induced affection in vitro. However, in the in vivo model an inactive state of Rac1, and its cellular localization remained one month after ischemia, with still decreased survival signaling, significant tauopathy, and learning and memory alterations. These neuropathological hallmarks were reversed two months post-ischemia, related with a Rac1 activity state similar to control, as well as a "normalization" of the learning and memory tasks in the ischemic rats. In summary, our data suggests that changes in Rac1 activity are involved in the neurodegenerative processes after cerebral ischemia, and also in its long-term recovery.