Suchergebnisse

Tauopathies are a class of neurodegenerative diseases associated with the microtubule-associated protein tau, with Alzheimer's disease (AD) being the most prevalent related disorder. Neurofibrillary tangles (NFTs) are one of the neuropathological hallmarks present in the brains of AD patients. Because NFTs are aberrant intracellular inclusions formed by hyperphosphorylated tau, it was initially proposed that phosphorylated and/or aggregated intracellular tau protein was causative of neuronal death. However, recent studies suggest a toxic role for non-phosphorylated and non-aggregated tau when it is located in the brain extracellular space. In this work, we will discuss the neurotoxic role of extracellular tau as well its involvement in the spreading of tau pathologies. ; This work was supported by funding from the Spanish Ministry of Science and Education BFU2012-31195 European Union project H2020-MSCA-ITN-2017 number 766124 to M.D.-H. and from Universidad Complutense of Madrid (UCM)-Santander Central Hispano Bank PR41/17-21014 to M.D.-H. Á.S.-S. was hired by BFU2012-31195 grant and L.d.D.-G. has an UCM pre-doctoral fellowship supervised by M.D.-H. ; Peer reviewed

It is well known that transgenic mice overexpressing human tau protein with P301S mutation driven by the mouse prion protein promoter show clasping and limb retraction, hunched back and paralysis, followed by inability to feed that results in death around 12 months of age. To understand these motor deficits, we have carried out rotarod tests on PS19 line and demonstrated how they worsened during aging. Then, we have analyzed if these phenotypic characteristics correlate with sciatic nerve degeneration. We first demonstrated by western blot and immunohistochemistry that the sciatic nerve expresses the transgenic tau protein; then, electron microscopy studies showed alterations in myelin, mainly a detachment of myelin lamellae at Schmidt-Lanterman clefts. Similar motor deficits and myelin alterations have been previously reported in tau knockout and overexpressing transgenic mice; taking into account that PS19 model is widely used to study tauopathies, we suggest that analyzing the expression of transgenic tau protein and myelin abnormalities in the sciatic nerve should be considered when studying some features as motor performance or survival. ; Spanish Ministry of Economy and Competitiveness (BFU2016-77885-P), Comunidad de Madrid cofinanced with the Structural Funds of the European Union (S2017/BMD-3700 (NEUROMETAB-CM)), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), and from an institutional grant from the Fundación R. Areces

© 2019 Martínez-Frailes, Di Lauro, Bianchi, de Diego-García, Sebastián-Serrano, Boscá and Díaz-Hernández. ; Alzheimer disease is a neurodegenerative disease characterized by the presence of senile plaques composed of amyloid-β (Aβ) peptide, neurofibrillary tangles, neuronal loss and neuroinflammation. Previous works have revealed that extracellular ATP, through its selective receptor P2X7 (P2X7R), is essential to neuroinflammation and neurotoxicity induced by Aβ. P2X7R is upregulated on microglial cells around the senile plaques. This upregulation progressively rises with age and is parallel with an accumulation of senile plaques and also correlates with the synaptic toxicity detected both in animal models reproducing AD and human patients of AD. Furthermore, the late onset of the first AD-associated symptoms suggests that aging associated-changes may be relevant to the disease progression. Thus, microglia motility and its capacity to respond to exogenous ATP stimulus decrease with aging. To evaluate whether the P2X7R age related-changes on microglia cells may be relevant to the AD progression, we generated a new transgenic mouse model crossing an Aβ peptide mouse model, J20 mice and the P2X7R reporter mice P2X7REGFP. Our results indicate that neuroinflammation induced by Aβ peptide causes changes in the P2X7R distribution pattern, increasing it s expression in microglial cells at advanced and late stages, when microgliosis occurs, but not in the early stages, in the absence of microgliosis. In addition, we found that P2X7R activation promotes microglial cells migration to senile plaques but decreases their phagocytic capacity. Moreover, we found a significant reduction of P2X7R transcription on neuronal cells at the early and advanced stages, but not at the late stages. Since previous studies have reported that either pharmacological inhibition or selective downregulation of P2X7R significantly improve behavioral alterations and reduce the incidence and size of senile plaques in the early and advanced stages of AD, the results presented here provide new evidence, indicating that this therapeutic approach could be also efficient in the late stages of the disease. ; This work was supported by funding from the Spanish Ministry of Science and Education BFU2012-31195 (to MD-H), SAF2017-82436R (to LB), European Union project H2020-MSCA-ITN-2017 number 766124 (to MD-H), and from Universidad Complutense of Madrid (UCM)-Santander Central Hispano Bank PR41/17-21014 (to MD-H). CM-F had an FPI pre-doctoral fellowship associated to BFU2012-31195. CDL and CB were hired by H2020-MSCA-ITN-2017 number 766124. AS-S was hired by BFU2012-31195 grant and LdD-G had an UCM pre-doctoral fellowship supervised by MD-H. This work was supported in part by FEDER.