SYSTEMIC ADMINISTRATION OF EPOTHYLONE-D RECUES MEMORY AND AMELIORATES ALZHEIMER’S DISEASE-LIKE PATHOLOGY IN APP/PS1 MICE

Aims Cognitive and memory decline in Alzheimer's disease (AD) patients is highly related to synaptic dysfunction and neuronal loss. Tau hyperphosphorylation destabilizes microtubules leading to axonal transport failure, 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 drug in the progression of the disease in an APP751SL/PS1M146L transgenic model. Method APP/PS1 mice (3 month-old) were weekly treated with 2 mg/kg intraperitoneal injections of Epothilone-D (Epo-D) for 3 months. Vehicle-injected animals were used as controls. For memory performance, animals were tested on the object-recognition tasks, Y-maze and Morris water maze. Levels of Abeta, ubiquitin, AT8 and synaptic markers were analyzed by Western-blot. Hippocampal plaque burden, dystrophic and synaptic loadings were quantified after immunostaining by image analysis. Results Epo-D treated mice showed a significant improvement in the performance of hippocampus-associated cognitive tests compared to controls. This memory recovery correlated with a significant reduction in the AD-like hippocampal pathology. Abeta, APP and ubiquitin levels were significantly reduced in treated animals, and a decrease in both the plaque loading and the axonal pathology was also found. Finally, synaptic levels were significantly preserved in treated animals in comparison with controls. Conclusion Epo-D treatment promotes synaptic and cognitive improvement, 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.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Supported by FIS-PI15/00796 (AG), FIS-PI15/00957(JV) and co-financed by FEDER funds from European Union

Dissecting the microglial response in transgenic models of amyloidogenesis and tauopathy

Amyloid-beta (Abeta) peptide deposits and hyperphosphorylated tau protein (phospho-tau) accumulate in Alzheimer’s disease (AD) brains. These abnormal protein aggregates leads to glial activation, synaptic dysfunction, neuronal loss and cognitive decline. While microglial response has mostly been analyzed in relation to Abeta accumulation, little is still known about inflammatory processes associated with tau pathology. Microglial reactivity and defective glial responses have been involved in these proteinopathies. Our aim is to clarify the effects of Abeta and tau separately, in order to improve the comprehension of their differential contribution to neuroinflammation and neurodegeneration. We compared the progression of these processes in an amyloidogenic AD model (APPSL/PS1M146L) and two different models of tauopathy (ThyTau22 and hP301S) from 2 to 18 months of age. Accumulation of aggregated proteins was assessed using specific anti- Abeta and phospho-tau antibodies. Inflammatory response was studied using a battery of microglial markers (Iba1, CD45, CD68, Trem2 and Gal-3). In the hippocampus of these models, Tau and Abeta pathologies initiated as early as 2 months of age and increased progressively with aging. Neuritic plaques induced a strong microglial activation associated to plaques in APP/PS1 mice. Interestingly, inflammatory markers and microglial reactivity were barely increased in the hippocampus of ThyTau mice in contrast to not only APP/PS1, but also to P301S mice, which displayed a prominent microglial response. Deciphering the specific effects of Abeta, tau and their different toxic species, would indeed enable the development of novel therapeutic strategies and drugs targeting neuroinflammatory pathways related to these proteinopathies.Universidad de Málaga. Campus de excelencia Andalucía-Tech. Supported by PI18/01557 (AG) and PI18/01556 (JV) grants from ISCiii of Spain co-financed by FEDER funds from European Union, and by grant PPIT.UMA.B1.2017/26 (RS-V)

Circularly polarised broadband planar lightweight reflectarray with eligible pattern for satellite communications in Ku-Band

This study presents a lightweight planar patch-array reflectarray at Ku-band for satellite communications. The reflectarray is composed of two separate planar structures: the radiating interface formed by a planar multi-layered broadband patch array, and a phase shifting device formed by 3 dB/90° couplers. The radiating element is a multi-layered patch structure, designed to provide circular polarisation (CP). Each array cell phase is controlled by open-ended shifting lines of variable length connected to the 3 dB/90° couplers. The use of this kind of couplers maintains the same CP received/transmitted: the design imposes that if a right-hand CP (RHCP) [or left-hand CP (LHCP)] is received coming from the feeder, the same RHCP (or LHCP) configuration is re-radiated by the reflectarray. Additionally, the feeding horn can be moved in the x or y axes, so that the feeder angular position let re-define the radiation pattern and its pointing direction. Finally, measurements of a lightweight portable planar reflectarray prototype are provided and very good agreement is observed when compared with theoretical result

A New Comorbidity in Periodontitis: Fusobacterium nucleatum and Colorectal Cancer

There is very recent and strong evidence relating Fusobacterium nucleatum to colorectal cancer. In this narrative review, we update the knowledge about gingival dysbiosis and the characteristics of Fusobacterium nucleatum as one of the main bacteria related to periodontitis. We provide data on microbiome, epidemiology, risk factors, prognosis, and treatment of colorectal cancer, one of the most frequent tumours diagnosed and whose incidence increases every year. We describe, from its recent origin, the relationship between this bacterium and this type of cancer and the knowledge and emerging mechanisms that scientific evidence reveals in an updated way. A diagram provided synthesizes the pathogenic mechanisms of this relationship in a comprehensive manner. Finally, the main questions and further research perspectives are presented

Tau pathology and astroglial reactivity: a comparative study of two mouse models of tauopathy

Objectives: Astrocytes are becoming crucial players in the context of neurodegenerative proteinopathies, such as Alzheimer’s disease (AD). Astroglial response has been mainly analyzed in amyloidogenic scenarios, but less is known about their involvement in tauopathies. Here, we aimed to analyze astroglial reactivity to hyperphosphorylated-tau (ptau) in the hippocampus of two transgenic mouse models of tauopathy, ThyTau22 and P301S (2- to 12/18-months). Methods: Proteinopathy was assessed by western-blotting and immunohistochemistry (AT8). Neuroinflammation was analyzed by qPCR and bright-field immunohistochemistry, glial-ptau relationship by confocal and transmission electron microscopy. Results: P301S mice exhibited an intense reactive astrogliosis, increasing progressively with aging accordingly to a strong ptau accumulation, whereas ThyTau22 model showed slighter astrocytosis related to lesser proteinopathy. P301S astrogliosis correlated with an acute DAM-like microglial activation, not observed in ThyTau22 hippocampus. In both models, reactive astrocytes contained ptau, especially around vessels. Conclusions: Our results support that astrocytes respond to ptau in the absence of Abeta. This reactivity correlates with tau pathology and depends on microglial DAM-like activation. In addition, reactive astrocytes may play a role in the elimination/spreading of ptau species through the brain. Deciphering the mechanisms underlying these processes might allow the development of strategies to slow down the progression of AD and other tauopathies.Supported by Instituto de Salud Carlos III of Spain, co-financed by FEDER funds from European Union, through grants PI18/01557 (to AG),PI18/01556 (to JV), and Junta de Andalucia through Consejería de Economía y Conocimiento grants UMA18-FEDERJA-211 (AG), P18-RT-2233 (AG) and US-1262734 (JV) co-financed by Programa Operativo FEDER 2014-2020. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Electronically reconfigurable phase shifter for reflectarray applications at microwave bands

This contribution provides the design of a microwave phase shifter for active steerable reflectarray devices at microwave frequencies. The device is based on a 3dB hybrid coupler with three of its ports connected to reflective circuits. This reflective circuit is responsible of the phase variation by means of the use of an electrically controllable microwave varactor. More than 360° phase shifting is obtained with this device as the signal is conducted through the device towards the reflective circuits in three different stages. The input port of the device is also the output one, providing the desired phase shifting and the reflective effect. This device is of great interest in reflectarray applications in order to provide controllable phase shifting at each array element. The document includes the design of the different parts of the shifter along with the device design. Results, considerations and discussion are also provided in this work

Comparing astroglial reactivity in two transgenic mouse models of tauopathy

Astrocytes are becoming crucial players in the pathology of neurodegenerative disorders, such as Alzheimer’s disease (AD). Astrocyte responses have been mainly analyzed in the context of amyloid-beta (Abeta) pathology, highlighting their role in the development/progression of amyloidosis and their relationship with the microglial response. Regarding tau pathology, some studies have reported that astrocytes respond to hyperphosphorylated tau (phospho-tau) and suggested their implication on tau transmission/elimination. Here, we aimed to analyze the astroglial reactivity to tau pathology in the hippocampus of two transgenic mouse models of tauopathy, ThyTau22 and P301S. Proteinopathy was assessed by western-blotting and immunohistochemistry using phospho-tau antibodies (AT8). Inflammatory markers (GFAP, Iba-1, CD45, TREM2) were analyzed by qPCR and immunohistochemistry for bright-field microscopy; glial-phospho-tau relationship was analyzed under confocal and transmission electron microscopy. P301S mice exhibited an intense reactive astrogliosis, increasing with aging in parallel to a strong phospho-tau pathology. ThyTau22 model showed a slighter astrocyte reactivity accompanied by a lesser accumulation of phospho-tau. Astrogliosis in P301S mice closely correlated with an acute DAM-like microglial activation, not observed in ThyTau22 hippocampus. Confocal and ultrastructural studies revealed that, in both models, astrocytic processes contained phospho-tau, especially those surrounding blood vessels. Our results support that astrocytes respond to tau pathology in the absence of Abeta. This reactivity highly correlates with phospho-tau pathology and markedly depends on microglial activation. Moreover, astrocytes may play a role in the elimination/spreading of phospho-tau species through the brain. Deciphering the mechanisms underlying these processes might help to develop therapies to slow down the progression of AD.Supported by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union through grants PI18/01557 (to AG), PI18/01556 (to JV), and by Junta de Andalucia through Consejería de Economía y Conocimiento grants UMA18-FEDERJA-211 (AG), P18-RT-2233 (AG) and US-1262734 (JV) co-financed by Programa Operativo FEDER2014-2020. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Analyzing hippocampal synaptic damage and glial response in a mouse model of tauopathy

Tau pathology is highly related to synaptic and neuronal loss, leading to cognitive decline and dementia in Alzheimer’s disease (AD) and other tauopathies. Tau transgenic mice are widely used to investigate the specific contribution of this protein to AD since they reproduce the synaptic and cognitive dysfunction in parallel to an age-dependent accumulation of hyperphosphorylated forms of tau (phospho-tau). The aim of this study was to investigate the progression of tau aggregation and analyze its relationship with microglial activation and synaptic damage within the hippocampus of a transgenic tau model. 2, 6, 9, 12 and 18 month-old THY-Tau22 transgenic and WT mice were analyzed. Tau pathology was assessed by western blotting and immunohistochemistry (AT8, AT100). Confocal microscopy was used to study microglial/phospho-tau relationship, and Thioflavin-S staining to evidence fibrillar aggregates. Levels of general (Synaptophysin) and subtype-specific (ChAT, VGAT, VGLUT-1) synaptic proteins were determined by WB and immunohistochemistry. Inflammatory markers were assessed by quantitative PCR (CD45, CD68, TREM2), immunohistochemistry (Iba-1) and image analysis. Tau pathology was detectable in the hippocampus from 2 months of age and increased progressively during aging. Presynaptic protein levels were significantly decreased from 9-12 months compared to age-matched WT mice. Even though some inflammatory markers were slightly increased in the hippocampus, microglial reactivity was found to be generally attenuated and some cells even exhibited reduction in their prolongations and a clear degenerative phenotype at advanced ages similar to that seen in the hippocampus of AD patients. Finally, this model could be a relevant tool to further understand the specific role of tau in both microglial response and synaptic pathology in AD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Microtubule stabilization protects cognitive function and slows down the course of Alzheimer's like pathology in an amyloidogenic mouse model

Cognitive decline in Alzheimer's disease (AD) is highly related to synaptic dysfunction and neuronal loss. In AD, the hyperphosphorylation of tau compromises axonal transport and leads to the generation of dystrophic neurites, contributing to synaptic impairment. In addition to phospho-tau, AD brains accumulate amyloid-beta. This study evaluated the effect of the brain-penetrant microtubule-stabilizing agent, Epothilone D (EpoD) in the progression of the disease in a double transgenic mouse model of amyloidosis. Young APP/PS1 mice were weekly treated with intraperitoneal injections of EpoD (2 mg/kg) or vehicle solution for 3 months. Memory performance was tested using object-recognition tasks, Y-maze and Morris water maze. EpoD-treated mice improved their performance of cognitive tests, while hippocampal phospho-tau and Aβ levels, especially soluble oligomers, decreased significantly. β/γ-secretase activities were not affected by EpoD in vitro. A significant amelioration of synaptic/neuritic pathology was found. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. In conclusion, EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Abeta accumulation, and promoting neuronal and cognitive protection. These results underline the crosstalk between cytoskeleton pathology and proteinopathy. Therefore, microtubule-stabilizing drugs could be candidates for slowing AD progression at both tau and Aβ pathologies.Supported by PI18/01557 (to AG) and PI18/01556 (to JV) grants from ISCiii of Spain, co-financed by FEDER funds from European Union, CIBERNED collaborative grant (to AG and JV), and by PPIT.UMA.B1.2017/26 grant (to RSV). Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Disentangling the contribution of tau and abeta pathologies in transgenic models of Alzheimer's disease

AIMS: Amyloid-beta (Abeta) deposits and intraneuronal hyperphosphorylated tau are major pathological hallmarks of Alzheimer’s disease (AD). The coexistence of these aggregates in AD brains leads to synaptic dysfunction, neuronal loss and cognitive decline. Failures in protein homeostasis, along with defective glial responses, have been identified as pathological mechanisms linked to this disorder. Thus, our main objective is to better understand the differential impact of Abeta- and tau-aggregates to these processes in the hippocampus of AD models. METHODS: We analyzed APP- (APPSL/PS1M146L) and Tau- (ThyTau22 and hP301S) based models from 2 to 18 months of age. Tau and Abeta pathologies were assessed by western blotting and immunohistochemistry. Confocal microscopy was used to study microglia/aggregates relationship. Levels of synaptic proteins, autophagy and inflammatory markers were determined by quantitative PCR, WB and immunohistochemistry. RESULTS: Tau and Abeta pathologies initiated as early as 2 months of age and increased progressively with aging. Even though only APP/PS1 hippocampus showed dystrophic neurites positive to proteostatic and presynaptic markers, their protein levels were altered in both types of models from 6-9 months compared to age-matched WT mice. Inflammatory markers and microglial reactivity were barely increased in the hippocampus of ThyTau mice in contrast to P301S and APP/PS1 mice which displayed a prominent microglial response. CONCLUSIONS: Clarifying the effects of Abeta and tau separately would indeed enable the development of novel therapeutic strategies and drugs targeting pathways related to these proteinopathies. Supported by grants FIS PI15/00796 and PI15/00957 co-financed by FEDER funds from European Union, by Junta de Andalucia Proyecto de Excelencia CTS385 2035 and by grant PPIT.UMA.B1/2017.26Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec