Consequences of a maternal high fat diet during lactation on offspring in a mouse model of tauopathy

De nombreuses études indiquent qu'une perturbation de l'environnement périnatal contribuerait au développement de maladies chez les descendants adultes. La perturbation la plus étudiée est la malnutrition qui touche plus de 2 milliards d'individus dans le monde. Des travaux ont associé la malnutrition maternelle et des altérations à court- et à long-terme chez les descendants, avec en particulier une augmentation de troubles métaboliques et cognitifs. Bien que la plupart des études se soient focalisées sur les conséquences au niveau périphérique, quelques travaux ont montré des effets sur le cerveau, lequel se développe principalement durant la lactation chez la souris et durant la fin de grossesse chez l'Homme. En effet, des travaux suggèrent qu'un régime riche en graisse (HF) durant la période périnatale provoque des altérations au niveau de l'hippocampe (structure essentielle dans les processus cognitifs). Par ailleurs, les altérations métaboliques étant un facteur de risque de la maladie d'Alzheimer (MA) et les troubles cognitifs étant une caractéristique de celle-ci, il semble possible que la malnutrition maternelle puisse participer au développement de la MA. A l'heure actuelle, peu de données sont disponibles et aucune étude a appliqué le régime uniquement durant la lactation. De plus, aucun travail a étudié la présence d'un éventuel dimorphisme sexuel alors que la MA touche davantage les femmes que les hommes. Ainsi, l'objectif principal de mes travaux de thèse était d'identifier les effets d'un régime maternel HF durant la lactation chez les descendants mâles et femelles adultes dans un modèle murin mimant le versant Tau de la MA (souris THY-Tau22). Pour atteindre cet objectif, nous avons croisé des femelles C57Bl6/J avec des mâles THY-Tau22 et soumis les femelles à un régime standard ou HF (58% de graisse) durant les 3 semaines de lactation. Au sevrage les descendants THY-Tau22 et leurs contrôles de portée ont reçu un régime standard jusqu'au sacrifice à l'âge de 4 (début de la lésion Tau) ou 7 mois (début du déclin cognitif). Les résultats indiquent que le régime maternel HF diminue la masse pondérale des mères durant la lactation et augmente celle des descendants au sevrage. A l'âge adulte, la régime maternel HF induit une intolérance au glucose chez les descendants mâles uniquement. De plus, le régime maternel HF provoque une altération de la mémoire spatiale chez les descendants mâles et femelles, quel que soit leur génotype. Ces troubles s'accompagnent, chez les descendants THY-Tau22, d'une augmentation de la phosphorylation de la protéine Tau hippocampique à l'âge de 4 mois chez les mâles et à 7 mois chez les femelles, mettant en évidence un décalage entre les deux sexes. Par ailleurs, ils s'accompagnent d'une altération de la neurogenèse hippocampique adulte, avec une augmentation de la prolifération chez les descendants C57Bl6/J mâles et de neurones matures chez les descendants THY-Tau22 femelles. De plus, les analyses révèlent que le régime maternel HF modifie les synapses avec une diminution de compartiments post-synaptiques chez les femelles C57BL6/J et des protéines NR2B et SNAP25 chez les mâles THY-Tau22. Enfin, par une approche multi-omiques, nous avons montré que le régime maternel HF modifie le transcriptome et le protéome hippocampiques, en affectant des voies biologiques associés à la mitochondrie, au métabolisme énergétique et à la traduction, que ce soit en condition physiologique ou pathologique. Toutefois, les gènes et protéines dérégulés par le régime maternel HF sont différents selon le sexe.Nos données suggèrent que la malnutrition maternelle accélère l'apparition des altérations liées au vieillissement et à la tauopathie chez les descendants et que ses effets sont dépendants du sexe. Nos résultats confirment l'importance de l'environnement périnatal qui constitue une période opportune d'intervention pour tenter d'enrayer l'expansion des maladies métaboliques et neurodégénératives.Numerous studies indicate that disruption of the perinatal environment contributes to the development of diseases in adult offspring. The most studied disturbance is malnutrition, which affects over 2 billion people worldwide. Studies have associated maternal malnutrition with short- and long-term alterations in offspring, particularly an increase in metabolic and cognitive disorders. Although most studies have focused on consequences at the peripheral level, a few have shown effects on the brain, which develops mainly during lactation in mice and late pregnancy in humans. Indeed, research suggests that a high-fat (HF) diet during the perinatal period causes alterations in the hippocampus (a structure essential to cognitive processes). Moreover, since metabolic alterations are a risk factor for Alzheimer's disease (AD), and cognitive impairment is a characteristic feature of the disease, it seems possible that maternal malnutrition may contribute to the development of AD. To date, few data are available, and no studies have applied the diet solely during lactation. Furthermore, no work has investigated the presence of a possible sexual dimorphism, despite the fact that AD affects women more than men. Thus, the main objective of my thesis work was to identify the effects of a maternal HF diet during lactation in adult male and female offspring in a mouse model mimicking the Tau pathology of AD (THY-Tau22 mice). To achieve this objective, C57Bl6/J females were crossed with THY-Tau22 males and subjected to a standard or HF (58% fat) diet during the 3-week lactation period. At weaning, THY-Tau22 offspring and their littermate were fed a standard diet until sacrifice at 4 (onset of Tau lesion) or 7 months of age (onset of cognitive decline). The results indicate that the HF maternal diet decreases maternal body weight during lactation and increases offspring body weight at weaning. In adulthood, the HF maternal diet induced glucose intolerance in male offspring only. The HF maternal diet also impaired spatial memory in male and female offspring, independently of genotype. In THY-Tau22 offspring, these disorders are accompanied by an increase in hippocampal Tau protein phosphorylation at 4 months of age in males and 7 months of age in females, highlighting a delay between the two sexes. Moreover, they are accompanied by an alteration in adult hippocampal neurogenesis, with increased proliferation in male C57Bl6/J offspring and mature neurons in female THY-Tau22 offspring. Furthermore, analyses reveal that the maternal HF diet modifies synapses, with a decrease in post-synaptic compartments in C57BL6/J females and in NR2B and SNAP25 proteins in THY-Tau22 males. Finally, using a multi-omics approach, we have shown that the maternal HF diet modifies the hippocampal transcriptome and proteome, affecting biological pathways associated with mitochondria, energy metabolism and translation, both in physiological and pathological conditions. However, the genes and proteins deregulated by maternal HF diet differ according to sex.Our data suggest that maternal malnutrition accelerates the onset of age-related alterations and tauopathy in offspring, and that its effects are sex-dependent. Our results confirm the importance of the perinatal environment as an opportune time for intervention in an attempt to stem the spread of metabolic and neurodegenerative diseases

Early-Life Environment Influence on Late-Onset Alzheimer’s Disease

International audienceWith the expand of the population’s average age, the incidence of neurodegenerative disorders has dramatically increased over the last decades. Alzheimer disease (AD) which is the most prevalent neurodegenerative disease is mostly sporadic and primarily characterized by cognitive deficits and neuropathological lesions such as amyloid -β (Aβ) plaques and neurofibrillary tangles composed of hyper- and/or abnormally phosphorylated Tau protein. AD is considered a complex disease that arises from the interaction between environmental and genetic factors, modulated by epigenetic mechanisms. Besides the well-described cognitive decline, AD patients also exhibit metabolic impairments. Metabolic and cognitive perturbations are indeed frequently observed in the Developmental Origin of Health and Diseases (DOHaD) field of research which proposes that environmental perturbations during the perinatal period determine the susceptibility to pathological conditions later in life. In this review, we explored the potential influence of early environmental exposure to risk factors (maternal stress, malnutrition, xenobiotics, chemical factors … ) and the involvement of epigenetic mechanisms on the programming of late-onset AD. Animal models indicate that offspring exposed to early-life stress during gestation and/or lactation increase both AD lesions, lead to defects in synaptic plasticity and finally to cognitive impairments. This long-lasting epigenetic programming could be modulated by factors such as nutriceuticals, epigenetic modifiers or psychosocial behaviour, offering thus future therapeutic opportunity to protect from AD development

P2X7-deficiency improves plasticity and cognitive abilities in a mouse model of Tauopathy

International audienceAlzheimer's disease is the most common form of dementia characterized by intracellular aggregates of hyperphosphorylated Tau protein and extracellular accumulation of amyloid β (Aβ) peptides. We previously demonstrated that the purinergic receptor P2X7 (P2X7) plays a major role in Aβ-mediated neurodegeneration but the relationship between P2X7 and Tau remained overlooked. Such a link was supported by cortical upregulation of P2X7 in patients with various type of frontotemporal lobar degeneration, including mutation in the Tau-coding gene, MAPT, as well as in the brain of a Tauopathy mouse model (THY-Tau22). Subsequent phenotype analysis of P2X7-deficient Tau mice revealed the instrumental impact of this purinergic receptor. Indeed, while P2X7-deficiency had a moderate effect on Tau pathology itself, we observed a significant reduction of microglia activation and of Tau-related inflammatory mediators, particularly CCL4. Importantly, P2X7 deletion ultimately rescued synaptic plasticity and memory impairments of Tau mice. Altogether, the present data support a contributory role of P2X7 dysregulation on processes governing Tau-induced brain anomalies. Due to the convergent role of P2X7 blockade in both Aβ and Tau background, P2X7 inhibitors might prove to be ideal candidate drugs to curb the devastating cognitive decline in Alzheimer's disease and Tauopathies

Impaired Glucose Homeostasis in a Tau Knock-In Mouse Model

International audienceAlzheimer’s disease (AD) is the leading cause of dementia. While impaired glucose homeostasis has been shown to increase AD risk and pathological loss of tau function, the latter has been suggested to contribute to the emergence of the glucose homeostasis alterations observed in AD patients. However, the links between tau impairments and glucose homeostasis, remain unclear. In this context, the present study aimed at investigating the metabolic phenotype of a new tau knock-in (KI) mouse model, expressing, at a physiological level, a human tau protein bearing the P301L mutation under the control of the endogenous mouse Mapt promoter. Metabolic investigations revealed that, while under chow diet tau KI mice do not exhibit significant metabolic impairments, male but not female tau KI animals under High-Fat Diet (HFD) exhibited higher insulinemia as well as glucose intolerance as compared to control littermates. Using immunofluorescence, tau protein was found colocalized with insulin in the β cells of pancreatic islets in both mouse (WT, KI) and human pancreas. Isolated islets from tau KI and tau knock-out mice exhibited impaired glucose-stimulated insulin secretion (GSIS), an effect recapitulated in the mouse pancreatic β-cell line (MIN6) following tau knock-down. Altogether, our data indicate that loss of tau function in tau KI mice and, particularly, dysfunction of pancreatic β cells might promote glucose homeostasis impairments and contribute to metabolic changes observed in AD

Mechanical Thrombectomy for Acute Ischemic Stroke Amid the COVID-19 Outbreak

International audienceBackground and Purpose: The efficiency of prehospital care chain response and the adequacy of hospital resources are challenged amid the coronavirus disease 2019 (COVID-19) outbreak, with suspected consequences for patients with ischemic stroke eligible for mechanical thrombectomy (MT). Methods: We conducted a prospective national-level data collection of patients treated with MT, ranging 45 days across epidemic containment measures instatement, and of patients treated during the same calendar period in 2019. The primary end point was the variation of patients receiving MT during the epidemic period. Secondary end points included care delays between onset, imaging, and groin puncture. To analyze the primary end point, we used a Poisson regression model. We then analyzed the correlation between the number of MTs and the number of COVID-19 cases hospitalizations, using the Pearson correlation coefficient (compared with the null value). Results: A total of 1513 patients were included at 32 centers, in all French administrative regions. There was a 21% significant decrease (0.79; [95%CI, 0.76–0.82]; P <0.001) in MT case volumes during the epidemic period, and a significant increase in delays between imaging and groin puncture, overall (mean 144.9±SD 86.8 minutes versus 126.2±70.9; P <0.001 in 2019) and in transferred patients (mean 182.6±SD 82.0 minutes versus 153.25±67; P <0.001). After the instatement of strict epidemic mitigation measures, there was a significant negative correlation between the number of hospitalizations for COVID and the number of MT cases ( R 2 −0.51; P =0.04). Patients treated during the COVID outbreak were less likely to receive intravenous thrombolysis and to have unwitnessed strokes (both P <0.05). Conclusions: Our study showed a significant decrease in patients treated with MTs during the first stages of the COVID epidemic in France and alarming indicators of lengthened care delays. These findings prompt immediate consideration of local and regional stroke networks preparedness in the varying contexts of COVID-19 pandemic evolution

Successful Thrombectomy Improves Functional Outcome in Tandem Occlusions with a Large Ischemic Core

International audienceBackground: Emergent stenting in tandem occlusions and mechanical thrombectomy (MT) of acute ischemic stroke related to large vessel occlusion (LVO-AIS) with a large core are tested independently. We aim to assess the impact of reperfusion with MT in patients with LVO-AIS with a large core and a tandem occlusion and to compare the safety of reperfusion between large core with tandem and nontandem occlusions in current practice. Methods: We analyzed data of all consecutive patients included in the prospective Endovascular Treatment in Ischemic Stroke Registry in France between January 2015 and March 2023 who presented with a pretreatment ASPECTS (Alberta Stroke Program Early CT Score) of 0–5 and angiographically proven tandem occlusion. The primary end point was a favorable outcome defined by a modified Rankin Scale (mRS) score of 0–3 at 90 days. Results: Among 262 included patients with a tandem occlusion and ASPECTS 0–5, 203 patients (77.5%) had a successful reperfusion (modified Thrombolysis in Cerebral Infarction grade 2b-3). Reperfused patients had a favorable shift in the overall mRS score distribution (adjusted odds ratio [aOR], 1.57 [1.22–2.03]; P < 0.001), higher rates of mRS score 0–3 (aOR, 7.03 [2.60–19.01]; P < 0.001) and mRS score 0–2 at 90 days (aOR, 3.85 [1.39–10.68]; P = 0.009) compared with nonreperfused. There was a trend between the occurrence of successful reperfusion and a decreased rate of symptomatic intracranial hemorrhage (aOR, 0.5 [0.22–1.13]; P = 0.096). Similar safety outcomes were observed after large core reperfusion in tandem and nontandem occlusions. Conclusions: Successful reperfusion was associated with a higher rate of favorable outcome in large core LVO-AIS with a tandem occlusion, with a safety profile similar to nontandem occlusion