Alzheimer'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.

With 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.

Alzheimer’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.

Early-life exposure to high-fat diets (HF) can program metabolic and cognitive alterations in adult offspring. Although the hippocampus plays a crucial role in memory and metabolic homeostasis, few studies have reported the impact of maternal HF on this structure. We assessed the effects of maternal HF during lactation on physiological, metabolic, and cognitive parameters in young adult offspring mice. To identify early-programming mechanisms in the hippocampus, we developed a multi-omics strategy in male and female offspring. Maternal HF induced a transient increased body weight at weaning, and a mild glucose intolerance only in 3-month-old male mice with no change in plasma metabolic parameters in adult male and female offspring. Behavioral alterations revealed by a Barnes maze test were observed both in 6-month-old male and female mice. The multi-omics strategy unveiled sex-specific transcriptomic and proteomic modifications in the hippocampus of adult offspring. These studies that were confirmed by regulon analysis show that, although genes whose expression was modified by maternal HF were different between sexes, the main pathways affected were similar with mitochondria and synapses as main hippocampal targets of maternal HF. The effects of maternal HF reported here may help to better characterize sex-dependent molecular pathways involved in cognitive disorders and neurodegenerative diseases.

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.

Early-life exposure to high-fat diet (HF) can program metabolic and cognitive alterations in adult offspring. Although the hippocampus plays a crucial role in memory and metabolic homeostasis, few studies reported the impact of maternal HF on this structure. We assessed the effects of maternal HF during lactation on physiological, metabolic and cognitive parameters in young adult offspring mice. To identify early-programming mechanisms in hippocampus, we developed a multi-omics strategy in male and female offspring. Maternal HF induced a transient increased body weight at weaning, a mild glucose intolerance only in 3-month-old male mice with no change in plasma metabolic parameters in adult male and female offspring. Behavioral alterations revealed by Barnes maze test were observed both in 6-month-old male and female mice. Multi-omics strategy unveiled sex-specific transcriptomic and proteomic modifications in the hippocampus of adult offspring. These studies that were confirmed by regulon analysis, showing that, although genes whose expression was modified by maternal HF were different between sexes, the main pathways affected were similar with mitochondria and synapses as main hippocampal targets of maternal HF. The effects of maternal HF reported here may help to better characterize sex-dependent molecular pathways involved in cognitive disorders and neurodegenerative diseases.