Inhibition of Tau aggregation with BSc3094 reduces Tau and decreases cognitive deficits in rTg4510 mice.

Background One of the major hallmarks of Alzheimer's disease (AD)is the aberrant modification and aggregation of the microtubule-associated protein Tau . The extent of Tau pathology correlates with cognitive decline, strongly implicating Tau in the pathogenesis of the disease. Because the inhibition of Tau aggregation may be a promising therapeutic target, we tested the efficacy of BSc3094, an inhibitor of Tau aggregation, in reducing Tau pathology and ameliorating the disease symptoms in transgenic mice. Methods Mice expressing human Tau with the P301L mutation (line rTg4510) were infused with BSc3094 into the lateral ventricle using Alzet osmotic pumps connected to a cannula that was placed on the skull of the mice, thus bypassing the blood-brain barrier (BBB) . The drug treatment lasted for 2 months, and the effect of BSc3094 on cognition and on reversing hallmarks of Tau pathology was assessed. Results BSc3094 significantly reduced the levels of Tau phosphorylation and sarkosyl-insoluble Tau. In addition, the drug improved cognition in different behavioral tasks and reduced anxiety-like behavior in the transgenic mice used in the study. Conclusions Our in vivo investigations demonstrated that BSc3094 is capable of partially reducing the pathological hallmarks typically observed in Tau transgenic mice, highlighting BSc3094 as a promising compound for a future therapeutic approach for AD

Adenosine A1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau δK280

Accumulation of Tau is a characteristic hallmark of several neurodegenerative diseases but the mode of toxic action of Tau is poorly understood. Here, we show that the Tau protein is toxic due to its aggregation propensity, whereas phosphorylation and/or missorting is not sufficient to cause neuronal dysfunction. Aggregate-prone Tau accumulates, when expressed in vitro at near-endogenous levels, in axons as spindle-shaped grains. These axonal grains contain Tau that is folded in a pathological (MC-1) conformation. Proaggregant Tau induces a reduction of neuronal ATP, concomitant with loss of dendritic spines. Counterintuitively, axonal grains of Tau are not targeted for degradation and do not induce a molecular stress response. Proaggregant Tau causes neuronal and astrocytic hypoactivity and presynaptic dysfunction instead. Here, we show that the adenosine A1 receptor antagonist rolofylline (KW-3902) is alleviating the presynaptic dysfunction and restores neuronal activity as well as dendritic spine levels in vitro. Oral administration of rolofylline for 2-wk to 14-mo-old proaggregant Tau transgenic mice restores the spatial memory deficits and normalizes the basic synaptic transmission. These findings make rolofylline an interesting candidate to combat the hypometabolism and neuronal dysfunction associated with Tau-induced neurodegenerative diseases

Polí­tiques i experiències catalanes en dipòsits col·lectius

L'any 1999, el Centre de Supercomputació de Catalunya (CESCA) va crear, conjuntament amb el Consorci de Biblioteques Universitàries de Catalunya (CBUC), un dipòsit cooperatiu anomenat Tesis Doctorals en Xarxa o TDX per emmagatzemar, en format digital, el text complet de les tesis doctorals llegides a les universitats catalanes i difondre-les arreu del món, en accés obert, tot preservant els drets de propietat intel·lectual dels autors. Aquest servei va iniciar-se l'any 2001 i avui dia està plenament consolidat, no només entre les universitats catalanes sinó també entre algunes universitats espanyoles. Des d'aleshores, s'han creat quatre dipòsits cooperatius més: el Dipòsit de la Recerca de Catalunya o RECERCAT, per a la cerca de publicacions d’investigació; Revistes Catalanes amb Accés Obert o RACO, per a revistes científiques, culturals i erudites catalanes; Patrimoni Digital de Catalunya o PADICAT, per emmagatzemar pàgines web catalanes; i Memòria Digital de Catalunya o MDC, per a col·leccions digitals catalanes de pintures, mapes, pòsters i revistes antigues, entre d'altres. Tots cinc dipòsits cooperatius comparteixen algunes característiques: són d'accés obert, és a dir, s'hi pot accedir gratuïtament des de la Xarxa; la majoria fan servir el protocol d'interoperabilitat Open Archives Initiative Protocol, que facilita la difusió eficaç dels continguts; s'han creat de manera cooperativa per tal que sigui més senzill adoptar procediments comuns i poder compartir els costos de desenvolupament i gestió del dipòsit; permeten donar més visibilitat als documents indexats gràcies als motors de cerca; i afavoreixen les condicions per preservar la informació a llarg termini. En aquest document es presenta la política comuna establerta per als dipòsits cooperatius catalans, es descriuen breument els cinc dipòsits, i es comenten els resultats obtinguts dels sis anys d'experiència des que el primer dipòsit va omençar a funcionar

Catalan Policies and Experiences on Cooperative Repositories

The Centre de Supercomputació de Catalunya (CESCA) together with the Consorci de Biblioteques Universitàries de Catalunya (CBUC) started in 1999 a cooperative repository, named TDR, to file in digital format the full-text of the read thesis at the universities of our country to spread them worldwide in open access preserving the intellectual copyright of the authors. This became operational in 2001 and today it is a service fully consolidated not only among the Catalan universities, but also used by other Spanish universities. Since then, there are four additional cooperative repositories which have been created: RECERCAT, for research papers; RACO, for scientific, cultural and erudite Catalan magazines; PADICAT, for archiving Catalan web sites; and MDC, for Catalan digital collections of pictures, maps, posters, old magazines... These five repositories have some common characteristics: they are open access, that is, they are accessible on the internet for free; they mostly comply with the Open Archive Initiative interoperability protocol for facilitating the efficient dissemination of content; and they have been built in a cooperative manner so that it is easy to adopt common procedures and to share the repository developing and managing costs, it permits more visibility of the indexed documents throughout the search engines, and a better provision for long-term preservation can be made. In this paper we present the common policy established for the Catalan cooperative repositories, we describe the five of them briefly, and we comment on the results obtained of our 6-year experience since the first one became operational

Assessment of the in vivo relationship between cerebral hypometabolism, Tau deposition, TSPO expression, and synaptic density in a tauopathy mouse model: a multi-tracer PET study

Cerebral glucose hypometabolism is a typical hallmark of Alzheimer's disease (AD), usually associated with ongoing neurodegeneration and neuronal dysfunction. However, underlying pathological processes are not fully understood and reproducibility in animal models is not well established. The aim of the present study was to investigate the regional interrelation of glucose hypometabolism measured by [18F]FDG positron emission tomography (PET) with various molecular targets of AD pathophysiology using the PET tracers [18F]PI-2620 for tau deposition, [18F]DPA-714 for TSPO expression associated with neuroinflammation, and [18F]UCB-H for synaptic density in a transgenic tauopathy mouse model. Seven-month-old rTg4510 mice (n=8) and non-transgenic littermates (n=8) were examined in a small animal PET scanner with the tracers listed above. Hypometabolism was observed throughout the forebrain of rTg4510 mice. Tau pathology, increased TSPO expression, and synaptic loss were co-localized in the cortex and hippocampus and correlated with hypometabolism. In the thalamus, however, hypometabolism occurred in the absence of tau-related pathology. Thus, cerebral hypometabolism was associated with two regionally distinct forms of molecular pathology: (1) characteristic neuropathology of the Alzheimer-type including synaptic degeneration and neuroinflammation co-localized with tau deposition in the cerebral cortex, and (2) pathological changes in the thalamus in the absence of other markers of AD pathophysiology, possibly reflecting downstream or remote adaptive processes which may affect functional connectivity. Our study demonstrates the feasibility of a multitracer approach to explore complex interactions of distinct AD-pathomechanisms in vivo in a small animal model. The observations demonstrate that multiple, spatially heterogeneous pathomechanisms can contribute to hypometabolism observed in AD mouse models and they motivate future longitudinal studies as well as the investigation of possibly comparable pathomechanisms in human patients. © 2022. The Author(s)

7,8-dihydroxyflavone ameliorates cognitive and motor deficits in a Huntington's disease mouse model through specific activation of the PLC gamma 1 pathway

Huntington's disease (HD) is a fatal neurodegenerative disease with motor, cognitive and psychiatric impairment. Dysfunctions in HD models have been related to reduced levels of striatal brain-derived neurotrophic factor (BDNF) and imbalance between its receptors TrkB and p75(NTR). Thus, molecules with activity on the BDNF/TrkB/p75 system can have therapeutic potential. 7,8-Dihydroxyflavone (7,8-DHF) was described as a TrkB agonist in several models of neuro-degenerative diseases, however, its TrkB activation profile needs further investigation due to its pleiotropic properties and divergence from BDNF effect. To investigate this, we used in vitro and in vivo models of HD to dissect TrkB activation upon 7,8-DHF treatment. 7,8-DHF treatment in primary cultures showed phosphorylation of TrkB(Y816) but not TrkB(Y515) with activation of the PLC gamma 1 pathway leading to morphological and functional improvements. Chronic administration of 7,8-DHF delayed motor deficits in R6/1 mice and reversed deficits on the Novel Object Recognition Test (NORT) at 17 weeks. Morphological and biochemical analyses revealed improved striatal levels of enkephalin, and prevention of striatal volume loss. We found a TrkB(Y816) but not TrkB(Y515) phosphorylation recovery in striatum concordant with in vitro results. Additionally, 7,8-DHF normalized striatal levels of induced and neuronal nitric oxide synthase (iNOS and nNOS, respectively) and ameliorated the imbalance of p75/TrkB. Our results provide new insights into the mechanism of action of 7,8-DHF suggesting that its effect through the TrkB receptor in striatum is via selective phosphorylation of its Y816 residue and activation of PLC gamma 1 pathway, but pleiotropic effects of the drug also contribute to its therapeutic potential