Marie Albert

Tauopathies 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.

There is increasing evidence of association between particulate matter air pollution and cardiovascular mortality and morbidity. However, the association with the out-of-hospital cardiac arrest (OHCA) event is less clear. We investigated the effects of short-term particulate matter exposure on OHCA especially among specific subgroups. The study included OHCA that occurred in the Nord-Pas-de-Calais region, France, in 2015. A time-stratified casecrossover study design coupled with a conditional logistic regression was used to evaluate the association between OHCA and particle levels of 10 or 2.5 micrometers or less (PM10 or PM2.5 respectively) measured within the hour of the arrest up to 5 days before. Susceptible subgroups by sex, age, diabetes status among OHCA that occurred during non-holiday periods were investigated. In all, 1039 cases were included. Significant associations were found between OHCA during non-holiday periods and PM2.5 and PM10 exposure four days before the arrest and on the day of the arrest. The largest OR were found for the cumulative average twelve hours before the arrest of PM2.5 (OR = 1.17, p = 0.016) and PM10 (OR = 1.33, p < 0.001). With PM2.5, larger OR with smaller p-values were generally obtained within the subgroups of men, age 50 to 75 years old and cases with diabetes. The findings show a significant link between short-term exposure to particulate matter and OHCA during non-holiday periods, with susceptible subgroups to PM2.5 (men, age 50 to 75 years old and diabetics).

Background: Air pollution is increasingly associated with cardiovascular events. As for ozone (O3 ) pollution, results are inconsistent though O3 levels are associated with hospital admissions, global mortality, and respiratory, and cardiovascular mortality. Methods: In this time-stratified case-crossover study, the associations between short-term exposure to O3 (on an hourly and daily scale) and out-of-hospital cardiac arrests (OHCA) were investigated. Specific subgroups were explored by sex, age, diabetes status, for OHCA during non-holiday periods. Data were collected in the Nord-Pas-de-Calais region, France, in 2015. Data were statistically analyzed using conditional logistic regression (CLR). Results: The study included 1039 cases of OHCA. Significant negative associations were found between OHCA and O3 levels measured in 3 or 4 days before the arrest for all the people, and 1, 2 or 3 days before the arrest for men. As for OHCA during non-holiday periods, there was no significant negative associations but a positive association was revealed for women between OHCA and O3 levels measured in 5 days before the arrest (OR=1.53, P=0.008). Conclusion: According to the results, OHCA should be investigated during non-holiday periods to control potential confounders that would lead to negative associations. Women might be a susceptible subgroup to O3 pollution.

In tauopathies such as Alzheimer's disease (AD), Tau protein becomes pathologically hyperphosphorylated leading to its intracellular accumulation and aggregation which will progressively cause neuronal loss and cognitive decline. Anti-Tau immunotherapy is increasingly considered as a potential treatment to block progression of tauopathies. We report that anti-Tau antibody treatment reduces Tau seeding & spreading in two mouse models of tauopathy. Previously, we showed that an anti-Tau antibody (Ab) produced by UCB Pharma, is able to block Tau aggregation induced by AD patient-derived materials in vitro. Here, we used two in vivo transgenic mouse (tg) models of tauopathies: First, a seed model, based on the unilateral injection of AD brain lysate into the hippocampus of THYTau30 transgenic mice before the appearance of basal pathology due to transgene expression. Second, a model of Tau spreading, by injecting P301L-K18 tau preformed fibrils in P301L tg mice. Tau pathology induced by seed injection was quantified in the ipsi and contralateral hippocampus after weekly intraperitoneal injections of the anti-Tau Ab or negative control. Hyperphosphorylated abnormal Tau species were detected in brain sections using AT8 (pSer202, pThr205 Tau) or AT100 (pThr212, pSer214) Abs. Tau pathology was then quantitatively analyzed using Mercator (Explora Nova, La Rochelle, France). In the seed model, the anti-Tau Ab reduced the AT8 (p<0.001) and AT100 (p<0.01) immunoreactivity by 80% compared to negative control antibody. Significant reduction of Tau pathology was observed in both the ispi and contralateral hippocampus. In the P301L-K18 injection-based model, the anti-Tau Ab significantly reduced secreted Tau spreading in the contralateral hippocampus compared with the negative control (p<0.05). Our data show that the anti-Tau Ab reduces not only Tau pathology induced by intracranial injection of human seeds but also the transynaptic spreading of Tau pathology. Investigations are now under way to determine the mechanisms by which the anti-Tau Ab reduces Tau pathology mediated by extracellular pathological Tau species.

Dans les tauopathies, telle la maladie d'Alzheimer, la protéine tau devient anormalement hyperphosphorylée ce qui conduit à son accumulation et à son agrégation intracellulaire. Ce processus aboutit progressivement à une perte neuronale et un déclin cognitif. L'immunothérapie anti-tau est de plus en plus considérée comme un traitement potentiel en vue de bloquer la progression des tauopathies.Récemment, l’entreprise UCB BioPharma a montré que l’anticorps D, anticorps ciblant la protéine tau en un épitope central (aa 235 à 250), était en mesure de bloquer, in vitro, l'agrégation intracellulaire de protéines tau, induite par des PHFs purifiés au départ de cerveaux Alzheimer. L’anticorps A, de même isotype, associé à des propriétés de liaison comparables mais reconnaissant la protéine tau en son extrémité N-terminale (aa 15 à 24), n’est pas en mesure de prévenir l’agrégation dans ce même modèle, ce qui souligne l’importance du choix de l’épitope en vue de neutraliser les amorces pathologiques issues de cerveaux Alzheimer.En vue d’étudier les propriétés de l’anticorps D in vivo, nous avons développé deux modèles murins de tauopathies. Premièrement, un modèle étudiant les phénomènes de recrutement et nucléation, basé sur l'injection unilatérale d’un homogénat de cerveau Alzheimer dans l'hippocampe de jeunes souris transgéniques (Tg30tau). Deuxièmement, un modèle permettant l’étude de la propagation intercellulaire de formes pathologiques de tau, par injection unilatérale de fibrilles P301L-K18 dans l’hippocampe de souris transgéniques (hTauP301L). Les tauopathies induites par ces injections intracérébrales ont été quantifiées dans l'hippocampe ipsi et controlatéral, en présence de traitements immunothérapeutiques utilisant les anticorps anti-tau A et D ou un anticorps témoin négatif de même isotype. La quantification des formes hyperphosphorylées et agrégées de tau a été réalisée par des approches immunohistochimique ou biochimique.Dans le modèle de nucléation, l’anticorps D est en mesure de prévenir significativement l’apparition des formes hyperphosphorylées et agrégées de tau à la fois dans l’hippocampe ipsilatéral (injecté avec l’homogénat Alzheimer) et contralatéral. A l’opposé, l’anticorps A n’est pas en mesure de prévenir l’apparition de la tauopathie dans ce modèle. Dans le modèle de propagation, basé sur l'injection unilatérale hippocampique de fibrilles P301L-K18, le traitement immunothérapeutique utilisant l’anticorps D réduit significativement la propagation d’espèces pathologiques de la protéine tau dans l'hippocampe controlatéral.De par l’utilisation de ces deux modèles murins de tauopathies, nous avons pu confirmer in vivo, la capacité de l’anticorps D à neutraliser les espèces pathologiques contenues dans un homogénat de cerveau Alzheimer et avons démontré sa capacité à s’opposer à la propagation intercellulaire de la tauopathie in vivo. Dans le modèle de nucléation, l’anticorps A n’a pas été en mesure de s’opposer à l’apparition de la tauopathie. Les résultats obtenus confirment ceux décrits par l’entreprise UCB BioPharma dans leur modèle d’agrégation in vitro et confirme l’importance considérable du choix de l’épitope en vue de prévenir efficacement le développement de tauopathies in vivo.