Anciennes et nouvelles classes moyennes turques : émergence, identification, caractérisation et politiques publiques

En Turquie, de nombreux ménages ont connu une amélioration sensible de leurs revenus et une modification conséquente de leur style de vie depuis la série de réformes libérales engagée dans les années 80. Il ne fait aucun doute que la classe moyenne émergente turque constitue un ensemble disparate dont les contours et les différents groupes constitutifs méritent d’être explorés. Notre objectif consiste ici à identifier et à caractériser de la manière la plus précise possible la diversité des groupes constitutifs de la classe moyenne turque et à envisager la façon dont ceux-ci influencent ou sont influencés par les politiques publiques. Nous identifions quatre groupes très distincts au sein de la classe moyenne de revenu turque : (i) la classe moyenne des retraités et inactifs (39 %) ; (ii) la classe moyenne supérieure des employeurs et cadres (17 %) ; (iii) la classe moyenne des travailleurs du secondaire et du tertiaire formel et des « petits patrons » (31 %) ; (iv) la classe moyenne des exploitants agricoles (13 %). Les quatre classes moyennes ainsi identifiées et caractérisées permettent de formaliser de façon multidimensionnelle la diversité et les « fractures » existant au sein de la classe moyenne de revenu en Turquie. Ainsi, il apparaît assez clairement que les deux premières classes s’apparentent, au moins en grande partie, aux « anciennes classes moyennes laïques », plutôt en perte de vitesse et que les deux autres classess’identifient assez nettement aux « nouvelles classes moyennes conservatrices » émergeant depuis le début des années 2000 en milieu urbain (travailleurs du secondaire et du tertiaire formel, « petits patrons ») comme en milieu rural (exploitants agricoles)

Single Domain Antibody Fragments as New Tools for the Detection of Neuronal Tau Protein in Cells and in Mice Studies

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Gradient reconstitution of membrane proteins for solid-state NMR studies

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Inhibition of Tau seeding by targeting Tau nucleation core within neurons with a single domain antibody fragment

Tau proteins aggregate into filaments in brain cells in Alzheimer’s disease and related disorders referred to as tauopathies. Here, we used fragments of camelid heavy-chain-only antibodies (VHHs or single domain antibody fragments) targeting Tau as immuno-modulators of its pathologic seeding. A VHH issued from the screen against Tau of a synthetic phage-display library of humanized VHHs was selected for its capacity to bind Tau microtubule-binding domain, composing the core of Tau fibrils. This lead VHH was optimized to improve its biochemical properties and to act in the intracellular compartment, resulting in VHH Z70. VHH Z70 was more efficient than the lead to inhibit in vitro Tau aggregation in heparin-induced assays. Expression of VHH Z70 in a cellular model of Tau seeding also decreased the fluorescence-reported aggregation. Finally, intracellular expression of VHH Z70 in the brain of an established tauopathy mouse seeding model demonstrated its capacity to mitigate accumulation of pathological Tau. VHH Z70, by targeting Tau inside brain neurons, where most of the pathological Tau resides, provides a new tool to explore the optimal strategies of immunotherapy in tauopathies

Extracellular vesicles: major actors of heterogeneity in tau spreading among human tauopathies

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Prévention des mécanismes de nucléation et propagation de tau par immunothérapie anti-tau ciblant un épitope central

Marie Albert, Georges Mairet-Coello, Luc Buée and Morvane Colin : these author contributed equally to this work.International audienceTauopathies are neurodegenerative diseases characterized by the intraneuronal accumulation of aggregated tau. The staging of this neurodegenerative process is well established for Alzheimer's disease as well as for other tauopathies. The stereotypical pattern of tau pathology in these diseases is consistent with the hypothesis that the tau protein can spread in a 'prion-like' manner. It proposes that extracellular pathological tau species can transmit pathology from cell to cell. Accordingly, by targeting these spreading species with therapeutic antibodies one should be able to slow or halt the progression of tau pathology. To be effective, antibodies should neutralize the pathological species present in Alzheimer's disease brains and block their cell-to-cell spread. To evaluate both aspects, tau antibody D, which recognizes an epitope in the central region of tau, and was selected for its outstanding ability to block tau seeding in cell based assays, was used in this study. Here, we addressed two fundamental questions: (i) can this anti-tau antibody neutralize the pathological species present in Alzheimer's disease brains; and (ii) can it block the cell-to-cell spread of tau seeds in vivo? First, antibody D effectively prevented the induction of tau pathology in the brains of transgenic mice that had been injected with human Alzheimer's disease brain extracts, showing that it could effectively neutralize the pathological species present in these extracts. Second, by using K18 P301L tau fibrils to induce pathology, we further demonstrated that antibody D was also capable of blocking the progression of tau pathology to distal brain regions. In contrast, an amino-terminal tau antibody, which was less effective at blocking tau seeding in vitro showed less efficacy in reducing Alzheimer's disease patient tau driven pathology in the transgenic mouse model. We did not address whether the same is true for a spectrum of other amino-terminal antibodies that were tested in vitro. These data highlight important differences between tau antibodies and, when taken together with other recently published data, suggest that epitope may be important for function

Aggregate-selective removal of pathological tau by clustering-activated degraders.

Selective degradation of pathological protein aggregates while sparing monomeric forms is of major therapeutic interest. The E3 ligase tripartite motif-containing protein 21 (TRIM21) degrades antibody-bound proteins in an assembly state-specific manner due to the requirement of TRIM21 RING domain clustering for activation, yet effective targeting of intracellular assemblies remains challenging. Here, we fused the RING domain of TRIM21 to a target-specific nanobody to create intracellularly expressed constructs capable of selectively degrading assembled proteins. We evaluated this approach against green fluorescent protein-tagged histone 2B (H2B-GFP) and tau, a protein that undergoes pathological aggregation in Alzheimer's and other neurodegenerative diseases. RING-nanobody degraders prevented or reversed tau aggregation in culture and in vivo, with minimal impact on monomeric tau. This approach may have therapeutic potential for the many disorders driven by intracellular protein aggregation

Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor

International audienceAccumulating data support the role of tau pathology in cognitive decline in ageing and Alzheimer's disease, but underlying mechanisms remain ill-defined. Interestingly, ageing and Alzheimer's disease have been associated with an abnormal upregulation of adenosine A2A receptor (A2AR), a fine tuner of synaptic plasticity. However, the link between A2AR signalling and tau pathology has remained largely unexplored. In the present study, we report for the first time a significant upregulation of A2AR in patients suffering from frontotemporal lobar degeneration with the MAPT P301L mutation. To model these alterations, we induced neuronal A2AR upregulation in a tauopathy mouse model (THY-Tau22) using a new conditional strain allowing forebrain overexpression of the receptor. We found that neuronal A2AR upregulation increases tau hyperphosphorylation, potentiating the onset of tau-induced memory deficits. This detrimental effect was linked to a singular microglial signature as revealed by RNA sequencing analysis. In particular, we found that A2AR overexpression in THY-Tau22 mice led to the hippocampal upregulation of C1q complement protein-also observed in patients with frontotemporal lobar degeneration-and correlated with the loss of glutamatergic synapses, likely underlying the observed memory deficits. These data reveal a key impact of overactive neuronal A2AR in the onset of synaptic loss in tauopathies, paving the way for new therapeutic approaches