Epothilone-d rescues cognition and attenuates alzheimer’s disease-like pathology in APP/PS1 mice

AIMS: Cognitive decline in Alzheimer's disease (AD) patients has been linked to synaptic damage and neuronal loss. Hyperphosphorylation of tau protein destabilizes microtubules leading to the accumulation of autophagy/vesicular material and the generation of dystrophic neurites, thus contributing to axonal/synaptic dysfunction. In this study, we analyzed the effect of a microtubule-stabilizing compound in the progression of the disease in the hippocampus of APP751SL/PS1M146L transgenic model. METHODS: APP/PS1 mice (3 month-old) were treated with a weekly intraperitoneal injection of 2 mg/kg epothilone-D (Epo-D) for 3 months. Vehicle-injected animals were used as controls. Mice were tested on the Morris water maze, Y-maze and object-recognition tasks for memory performance. Abeta, AT8, ubiquitin and synaptic markers levels were analyzed by Western-blots. Hippocampal plaque, synaptic and dystrophic loadings were quantified by image analysis after immunohistochemical stainings. RESULTS: Epo-D treated mice exhibited a significant improvement in the memory tests compared to controls. The rescue of cognitive deficits was associated to a significant reduction in the AD-like hippocampal pathology. Levels of Abeta, APP and ubiquitin were significantly reduced in treated animals. This was paralleled by a decrease in the amyloid burden, and more importantly, in the plaque-associated axonal dystrophy pathology. Finally, synaptic levels were significantly restored in treated animals compared to controls. CONCLUSION: Epo-D treatment promotes synaptic and spatial memory recovery, reduces the accumulation of extracellular Abeta and the associated neuritic pathology in the hippocampus of APP/PS1 model. Therefore, microtubule stabilizing drugs could be considered therapeutical candidates to slow down AD progression. Supported by FIS-PI12/01431 and PI15/00796 (AG),FIS-PI12/01439 and PI15/00957(JV)Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Microglial response differences between amyloidogenic transgenic models and Alzheimer’s disease patients

Aims: The continuing failure to develop an effective treatment for Alzheimer’s disease (AD) reveals the complexity for AD pathology. Increasing evidence indicates that neuroinflammation involving particularly microglial cells contributes to disease pathogenesis. Here we analyze the differences in the microglial response between APP/PS1 model and human brains. Methods: RT-PCR, western blots, and immunostaining were performed in the hippocampus of human post mortem samples (from Braak II to Braak V-VI) and APP751SL/PS1M146L mice. In vitro studies to check the effect of S1 fractions on microglial cells were assayed. Results: In APP based models the high Abeta accumulation triggers a prominent microglial response. On the contrary, the microglial response detected in human samples is, at least, partial or really mild. This patent difference could simple reflect the lower and probably slower Abeta production observed in human hippocampal samples, in comparison with models or could reflect the consequence of a chronic long-standing microglial activation. However, beside this differential response, we also observed a prominent microglial degenerative process in Braak V-VI samples that, indeed, could compromise their normal role of surveying the brain environment and respond to the damage. This microglial degeneration, particularly relevant at the dentate gyrus of the hippocampal formation, might be mediated by the accumulation of toxic soluble phospho-tau species. Conclusions: These differences need to be considered when delineating animal models that better integrate the complexity of AD pathology and, therefore, guarantee clinical translation. Correcting dysregulated brain inflammatory responses might be a promising avenue to restore cognitive function. Supported by grants FIS PI15/00796 and FIS PI15/00957 co-financed by FEDER funds from European Union, and by Junta de Andalucia Proyecto de Excelencia CTS385 2035.Financiado por FIS PI15/00796 y FIS PI15/0095, cofinanciado por los fondos FEDER de la Unión Europea, y por Junta de Andalucia Proyecto de Excelencia CTS385 2035. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Microglial responses in the human Alzheimer’s disease frontal cortex

The continuing failure to develop an effective treatment for Alzheimer’s disease (AD) reveals the complexity for this pathology. Increasing evidence indicates that neuroinflammation involving particularly microglial cells contributes to AD pathogenesis. The actual view, based on the findings in APP based models, gives a cytotoxic/proinflammatory role to activated microglia. However, we have previously reported a limited activation and microglial degeneration in the hippocampus of AD patients in contrast with that observed in amyloidogenic models. Here, we evaluated the microglial response in a different region of AD brains, the frontal cortex. Post mortem tissue from controls (Braak 0-II) and AD patients (Braak V-VI) including familial cases, were obtained from Spain Neurological Tissue Banks. Cellular (immunohistochemistry and image analysis) and molecular (qPCR and western blots) approaches were performed. Frontal cortex of AD patients (Braak V-VI) showed strong microglial activation similar to that observed in amyloidogenic mice. These strongly activated microglial cells, predominantly located surrounding amyloid plaques, could drive the AD pathology and, in consequence, could be implicated in the pathology progression. Furthermore, different microglial responses were observed between sporadic and familial AD cases. These findings in the frontal cortex were highly in contrast to the attenuated activation and degenerative morphology displayed by microglial cells in the hippocampus of AD patients. Regional differences in the microglial response suggest different functional states of microglial cells in a region-specific manner. All together, these data provide a better understanding of the immunological mechanisms underlying AD progression and uncover new potential therapeutic targets to fight this devastating neurodegenerative disease.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Supported by PI18/01557 (AG) and PI18/01556 (JV) grants from ISCiii of Spain co-financed by FEDER funds from European Unio

Dual-Drive Directional Couplers for Programmable Integrated Photonics

A novel class of photonic integrated circuits employs large-scale integration of combined beam splitters and waveguides loaded with phase actuators to provide complex linear processing functionalities that can be reconfigured dynamically. Here, we propose and experimentally demonstrate a thermally-actuated Dual-Drive Directional Coupler (DD-DC) design, integrated in a silicon nitride platform, functioning both as a standalone optical component providing arbitrary optical beam splitting and common phase as well as for its use in waveguide mesh arrangements. We analyze the experimental demonstration of the first integration of a triangular waveguide mesh arrangement, and the first DD-DC based arrangement along with an extended analysis of its performance and scalability

AGRICULTURE FINANCING AND ECONOMIC GROWTH IN NIGERIA

The importance of agricultural surplus for the structural transformation accompanying economic growth is often stressed by development economists. This lead to the question: Does agriculture financing matters in the growth process? To this end, the need to investigate the impact of agriculture financing on economic growth appears more imperative for Nigeria. This paper employed secondary data and some econometric techniques such as Ordinary Least Square (OLS); Augmented Dickey-Fuller (ADF) unit root test; Granger Causality test. The results of the various models used suggest that there is bidirectional causality between economic growth and agriculture financing; and there is bidirectional causality between economic growth and agricultural growth. It further suggests that productivity of investment will be more appropriately financed with foreign direct private loan, share capital, foreign direct investment and development stocks. And also capital-output ratio will be more appropriate financed with multilateral loan, domestic savings, Treasury bill, official development assistant, foreign direct investment and development stock. It is recommended that maintenance of credible macroeconomic policies that is pro-investment; and debt-equity swap option are necessary for a agricultural-led economic growth

Decoding damage-associated microglia in post mortem hippocampus of Alzheimer’s disease patients

The relationship between Alzheimer’s disease (AD) and neuroinflammation has become stronger since the identification of several genetic risk factors related to microglial function. Though the role of microglial cells in the development/progression of AD is still unknown, a dysfunctional response has recently gained support. In this sense, we have reported an attenuated microglial activation associated to amyloid plaques in the hippocampus of AD patients, including a prominent degenerative process of the microglial population in the dentate gyrus, which was in contrast to the exacerbated microglial response in amyloidogenic models. This microglial degeneration could compromise their normal role of surveying the brain environment and respond to the damage. Here, we have further analyzed the phenotypic profile displayed by the damage-associated microglial cells by immunostaining and qPCR in the hippocampus of postmortem samples of AD patients (Braak V-VI) and control cases (Braak 0-II). Damage-associated microglial cells of Braak V-VI individuals were clustered around amyloid plaques and expressed Iba1, CD68, Trem2, TMEM119 and CD45high. A subset of these cells also expressed ferritin. On the contrary, these microglia down-regulated homeostatic markers, such as Cx3cr1 and P2ry12. The homeostatic and ramified microglial cells of non-demented Braak II cases were characterized by Iba1, CX3CR1, P2ry12, TMEM119 and CD45low expression. The dynamic of the microglial molecular phenotypes associated to AD pathology needs to be considered for better understand the disease complexity and, therefore, guarantee clinical success. Correcting dysregulated brain inflammatory responses might be a promising avenue to prevent/slow cognitive decline.Universidad de Málaga. Campus de excelencia Internacional-Andalucía Tech. Supported by PI18/01557 (AG) and PI18/01556 (JV) grants from ISCiii of Spain co-financed by FEDER funds from European Union