15 research outputs found
Impact du diabÚte et de l'obésité sur la pathologie Tau dans la maladie d'Alzheimer
La maladie dâAlzheimer (MA) est la dĂ©mence la plus rĂ©pandue dans le monde. Les deux marqueurs histopathologiques de la MA sont les plaques amyloĂŻdes, formĂ©es d'agrĂ©gats du peptide bĂȘta-amyloĂŻde, et les enchevĂȘtrements neurofibrillaires, composĂ©s de la protĂ©ine Tau anormalement hyperphosphorylĂ©e. La pathologie Tau a un rĂŽle important dans la maladie puisque son Ă©tendue corrĂšle avec le degrĂ© du dĂ©ficit cognitif des patients. La majoritĂ© des cas de MA est dâorigine sporadique dont les causes demeurent encore mĂ©connues; elles semblent ĂȘtre multifactorielles, avec des facteurs externes, biologiques et/ou gĂ©nĂ©tiques qui accĂ©lĂšrent la manifestation de la maladie. Des Ă©tudes Ă©pidĂ©miologiques ont dĂ©montrĂ© que le statut mĂ©tabolique des individus au cours de leur vie influence le risque de MA. En effet, des altĂ©rations mĂ©taboliques comme un diabĂšte de type 2 (DT2) ou une obĂ©sitĂ© sont reconnus comme facteurs de risque de la MA. Or, le nombre de cas de DT2 et dâobĂ©sitĂ© est en pleine croissance Ă cause de la sĂ©dentarisation des populations, ce qui suggĂšre que lâincidence de la MA pourrait suivre cette inquiĂ©tante augmentation. Il est donc indispensable de mieux comprendre lâimpact de ces altĂ©rations mĂ©taboliques sur la MA afin dâespĂ©rer ralentir son Ă©volution. De nombreuses Ă©tudes ont Ă©valuĂ© lâimpact du DT2 et de lâobĂ©sitĂ© sur la pathologie amyloĂŻde in vivo, mais les Ă©tudes sur la pathogenĂšse de Tau sont plus rares et prĂ©sentent une importante divergence des rĂ©sultats. Dans ce contexte, notre hypothĂšse est que le diabĂšte et de lâobĂ©sitĂ© peuvent promouvoir la pathologie Tau in vivo. Notre 1e objectif Ă©tait donc dâexaminer la phosphorylation de la protĂ©ine Tau dans deux modĂšles murins qui dĂ©veloppent spontanĂ©ment une obĂ©sitĂ© et un DT2 : les souris ob/ob et db/db. Une hyperphosphorylation de Tau est observĂ©e dans le cerveau des deux modĂšles, principalement due Ă une hypothermie. En effet, ces souris sont hypothermiques et la normothermie restaure une phosphorylation de Tau semblable aux souris contrĂŽles. Comme la cafĂ©ine s'est rĂ©vĂ©lĂ©e bĂ©nĂ©fique pour le diabĂšte, l'obĂ©sitĂ© et la phosphorylation de Tau, nous l'avons utilisĂ© comme traitement thĂ©rapeutique chez les souris ob/ob. Cependant, la consommation de cafĂ©ine chronique a exacerbĂ© l'hyperphosphorylation de Tau en favorisant une hypothermie plus profonde. Notre 2e objectif Ă©tait dâĂ©valuer lâimpact du DT2 et de lâobĂ©sitĂ© sur pathogenĂšse de Tau dans des conditions plus proches de la pathologie humaine. Pour cela, nous avons nourri des souris hTau, exprimant la protĂ©ine Tau humaine, avec des rĂ©gimes riches en graisses, cholestĂ©rol et/ou sucre, reconnus pour induire lâobĂ©sitĂ© et le DT2 chez lâhumain. D'autre part, la restriction calorique et l'exercice physique ont Ă©tĂ© caractĂ©risĂ©s pour rĂ©duire l'incidence et lâĂ©volution des troubles mĂ©taboliques ainsi que la MA. Nous avons Ă©valuĂ© leur impact sur la pathologie Tau chez ces souris obĂšses comme stratĂ©gies thĂ©rapeutiques. Nous n'avons trouvĂ© aucun effet du gras, du sucre et du cholestĂ©rol, mĂȘme combinĂ©s, sur la phosphorylation, l'O-GlcNAcylation, l'Ă©pissage, le clivage et l'agrĂ©gation de Tau, suggĂ©rant que leur surconsommation nâaggrave pas la pathologie Tau chez ces souris. De plus, nous avons observĂ© un effet bĂ©nĂ©fique de l'exercice sur la phosphorylation Tau et un effet dĂ©lĂ©tĂšre de la restriction calorique sur l'agrĂ©gation de Tau chez les souris hTau obĂšses. Enfin, notre 3e objectif Ă©tait dâexplorer les effets dâune dĂ©ficience en insuline sur la pathologie Tau chez les souris hTau par injection de streptozotocine, une toxine qui dĂ©truit les cellules productrices d'insuline. Les souris hypoinsulinĂ©miques prĂ©sentent une hyperphosphorylation de Tau dans le cerveau sans agrĂ©gation, par inhibition de PP2A, la phosphatase majeur de Tau. Lâensemble de ces rĂ©sultats suggĂšre que i) les perturbations mĂ©taboliques peuvent induire l'hyperphosphorylation de Tau de maniĂšre indirecte, en perturbant la thermorĂ©gulation; ii) les rĂ©gimes hypercaloriques ne semblent pas modifier l'homĂ©ostasie de Tau en conditions strictement contrĂŽlĂ©es; iii) la dĂ©ficience en insuline peut induire l'hyperphosphorylation de Tau sans pour autant conduire Ă son agrĂ©gation. Nous rĂ©vĂ©lons Ă©galement que les stratĂ©gies utilisĂ©es pour rĂ©duire la MA doivent ĂȘtre adaptĂ© avec le statut mĂ©tabolique des patients pour Ă©viter l'exacerbation des diverses neuropathologies de la MA. Ces donnĂ©es se confrontent Ă certains travaux publiĂ©s et montrent que les relations entre le mĂ©tabolisme et la MA peuvent ĂȘtre moins directes que pensĂ©es. Ce travail pose des bases de rigueur et de mĂ©thodologie qui pourrait contribuer Ă Ă©viter certains biais pour les Ă©tudes futures.Alzheimer's disease (AD) is the leading form of dementia worldwide. The two histopathological markers of AD are senile plaques composed of amyloid- peptide, and neurofibrillary tangles of abnormally hyperphosphorylated Tau protein. Tau pathology is important since it correlates with the degree of cognitive impairment in AD patients. The majority of AD cases are of sporadic form whose causes are still unknown; it seems to be multifactorial, with external, biological and/or genetic, which accelerate the manifestation of the disease. Epidemiological studies have shown that metabolic status of individuals during their life strongly increases the risk of developing AD. Indeed, metabolic disorders such as type 2 diabetes (T2D) or obesity are described as risk factors for AD. New cases of T2D and obesity is increasing because of people sedentarization, suggesting that the incidence of AD cases could follow this worrying growth. Therefore, it is essential to better understand the impact of these metabolic disorders on AD. Many studies have evaluated the impact of T2D and obesity in vivo on amyloid pathology, but there are fewer studies on the pathogenesis of Tau and they exhibit some discrepencies between results. In this context, our hypothesis is that diabetes and obesity could promote Tau pathology in vivo. Our first aim was thus to evaluate the phosphorylation of Tau protein in two mouse models that spontaneously develop obesity and DT2: the ob/ob and db/db mice. Significant hyperphosphorylation of Tau was observed in the brain of these two models, mainly due to hypothermia. Indeed, ob/ob and db/db mice were hypothermic and normothermia restored Tau phosphorylation similar to control levels. As caffeine has been shown to be beneficial for diabetes, obesity and Tau phosphorylation, we used it as a therapeutic treatment in ob/ob mice. Unexpectedly, chronic caffeine consumption exacerbated Tau hyperphosphorylation in ob/ob mice by promoting deeper hypothermia. Then, our second aim was to assess the impact of T2D and obesity on Tau pathogenesis in conditions closer to human pathology. For this purpose, we fed hTau mice, expressing the human Tau protein, with high-fat, high-cholesterol and/or high-sugar diets, described to induce obesity and DT2 in humans. On the other hand, caloric restriction and physical activity have been characterized to reduce the incidence and outcome of metabolic disorders as well as AD. We evaluated their impact on Tau pathology in obese hTau mice as therapeutic strategies. Surprisingly, we found no effect of fat, sugar and cholesterol, even combined, on Tau phosphorylation, O-GlcNAcylation, splicing, cleavage and aggregation, suggesting that their overconsumption does not worsen Tau pathology in these mice. Moreover, we observed a beneficial effect of exercise on Tau phosphorylation and a deleterious effect of caloric restriction on Tau aggregation in obese hTau mice. Finally, our last aim was to examin the effects of insulin deficiency on Tau pathology in hTau mice using streptozotocin injection, a toxin that destroys insulin producing cells. Hypoinsulinemic mice exhibited Tau hyperphosphorylation in the brain without aggregation through inhibition of PP2A, the main Tau phosphatase. All these results suggest that i) metabolic alterations can induce Tau hyperphosphorylation indirectly, by disrupting thermoregulation; ii) hypercaloric diets do not appear to modify Tau homeostasis under strictly controlled conditions; iii) insulin deficiency may induce Tau hyperphosphorylation without, however, leading to its aggregation. We also revealed that the strategies used to reduce AD have to be adapted to the meatbolic status of patients to avoid the exacerbation of some neuropathologies of AD. These data object to some published research and show that the relationship between metabolism and AD may be less direct than thought. This work establishes a basis of rigor and methodology, which could help to avoid some biases for future studies
Impact of TREM2R47H variant on tau pathology-induced gliosis and neurodegeneration
Alzheimer\u27s disease (AD) is characterized by plaques containing amyloid-ÎČ (AÎČ) and neurofibrillary tangles composed of aggregated, hyperphosphorylated tau. Beyond tau and AÎČ, evidence suggests that microglia play an important role in AD pathogenesis. Rare variants in the microglia-expressed triggering receptor expressed on myeloid cells 2 (TREM2) gene increase AD risk 2- to 4-fold. It is likely that these TREM2 variants increase AD risk by decreasing the response of microglia to AÎČ and its local toxicity. However, neocortical AÎČ pathology occurs many years before neocortical tau pathology in AD. Thus, it will be important to understand the role of TREM2 in the context of tauopathy. We investigated the impact of the AD-associated TREM2 variant (R47H) on tau-mediated neuropathology in the PS19 mouse model of tauopathy. We assessed PS19 mice expressing human TREM2CV (common variant) or human TREM2R47H. PS19-TREM2R47H mice had significantly attenuated brain atrophy and synapse loss versus PS19-TREM2CV mice. Gene expression analyses and CD68 immunostaining revealed attenuated microglial reactivity in PS19-TREM2R47H versus PS19-TREM2CV mice. There was also a decrease in phagocytosis of postsynaptic elements by microglia expressing TREM2R47H in the PS19 mice and in human AD brains. These findings suggest that impaired TREM2 signaling reduces microglia-mediated neurodegeneration in the setting of tauopathy
New insights into the role of TREM2 in Alzheimerâs disease
Abstract Alzheimerâs disease (AD) is the leading cause of dementia. The two histopathological markers of AD are amyloid plaques composed of the amyloid-ÎČ (AÎČ) peptide, and neurofibrillary tangles of aggregated, abnormally hyperphosphorylated tau protein. The majority of AD cases are late-onset, after the age of 65, where a clear cause is still unknown. However, there are likely different multifactorial contributors including age, enviornment, biology and genetics which can increase risk for the disease. Genetic predisposition is considerable, with heritability estimates of 60â80%. Genetic factors such as rare variants of TREM2 (triggering receptor expressed on myeloid cells-2) strongly increase the risk of developing AD, confirming the role of microglia in AD pathogenesis. In the last 5 years, several studies have dissected the mechanisms by which TREM2, as well as its rare variants affect amyloid and tau pathologies and their consequences in both animal models and in human studies. In this review, we summarize increases in our understanding of the involvement of TREM2 and microglia in AD development that may open new therapeutic strategies targeting the immune system to influence AD pathogenesis
Mutual relationship between Tau and central insulin signalling: consequences for AD and Tauopathies ?
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Relation mutuelle entre Tau et signalisation centrale de lâinsuline
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Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy
International audienceAlzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-ÎČ (AÎČ) accumulation in the brain, although AÎČ deposits mostly in the brain parenchyma in AD and in the cerebrovasculature in CAA. The presence of CAA can exacerbate clinical outcomes of AD patients by promoting spontaneous intracerebral hemorrhage and ischemia leading to CAA-associated cognitive decline. Genetically, AD and CAA share the Δ4 allele of the apolipoprotein E (APOE) gene as the strongest genetic risk factor. Although tremendous efforts have focused on uncovering the role of APOE4 on parenchymal plaque pathogenesis in AD, mechanistic studies investigating the role of APOE4 on CAA are still lacking. Here, we addressed whether abolishing APOE4 generated by astrocytes, the major producers of APOE, is sufficient to ameliorate CAA and CAA-associated vessel damage. Methods We generated transgenic mice that deposited both CAA and plaques in which APOE4 expression can be selectively suppressed in astrocytes. At 2-months-of-age, a timepoint preceding CAA and plaque formation, APOE4 was removed from astrocytes of 5XFAD APOE4 knock-in mice. Mice were assessed at 10-months-of-age for AÎČ plaque and CAA pathology, gliosis, and vascular integrity. Results Reducing the levels of APOE4 in astrocytes shifted the deposition of fibrillar AÎČ from the brain parenchyma to the cerebrovasculature. However, despite increased CAA, astrocytic APOE4 removal reduced overall AÎČ-mediated gliosis and also led to increased cerebrovascular integrity and function in vessels containing CAA. Conclusion In a mouse model of CAA, the reduction of APOE4 derived specifically from astrocytes, despite increased fibrillar AÎČ deposition in the vasculature, is sufficient to reduce AÎČ-mediated gliosis and cerebrovascular dysfunction. </jats:sec
Parenchymal border macrophages regulate tau pathology and tau-mediated neurodegeneration
International audienceParenchymal border macrophages (PBMs) reside close to the central nervous system parenchyma and regulate CSF flow dynamics. We recently demonstrated that PBMs provide a clearance pathway for amyloid-ÎČ peptide, which accumulates in the brain in Alzheimerâs disease (AD). Given the emerging role for PBMs in AD, we explored how tau pathology affects the CSF flow and the PBM populations in the PS19 mouse model of tau pathology. We demonstrated a reduction of CSF flow, and an increase in an MHCII + PBM subpopulation in PS19 mice compared with WT littermates. Consequently, we asked whether PBM dysfunction could exacerbate tau pathology and tau-mediated neurodegeneration. Pharmacological depletion of PBMs in PS19 mice led to an increase in tau pathology and tau-dependent neurodegeneration, which was independent of gliosis or aquaporin-4 depolarization, essential for the CSF-ISF exchange. Together, our results identify PBMs as novel cellular regulators of tau pathology and tau-mediated neurodegeneration
Characterization of l -Theanine Excitatory Actions on Hippocampal Neurons: Toward the Generation of Novel N -Methyl- d -aspartate Receptor Modulators Based on Its Backbone
International audienceL-Theanine (or L-Îł-N-ethyl-glutamine) is the major amino acid found in Camellia sinensis. It has received much attention because of its pleiotropic physiological and pharmacological activities leading to health benefits in humans, especially. We describe here a new, easy, efficient, and environmentally friendly chemical synthesis of L-theanine and L-Îł-N-propyl-Gln and their corresponding D-isomers. L-Theanine, and its derivatives obtained so far, exhibited partial coagonistic action at N-methyl-D-aspartate (NMDA) receptors, with no detectable agonist effect at other glutamate receptors, on cultured hippocampal neurons. This activity was retained on NMDA receptors expressed in Xenopus oocytes. In addition, both GluN2A and GluN2B containing NMDA receptors were equally modulated by L-theanine. The stereochemical change from L-theanine to D-theanine along with the substitution of the ethyl for a propyl moiety in the Îł-N position of Land D-theanine significantly enhanced the biological efficacy, as measured on cultured hippocampal neurons. L-Theanine structure thus represents an interesting backbone to develop novel NMDA receptor modulators