The role of immune responses in the cognitive impairments associated with tauopathy is unclear. Laurent et al. identify a CD8+ T-cell infiltration in the hippocampus of THY-Tau22 transgenic mice. T-cell depletion reverses spatial memory deficits in these animals, supporting a role for hippocampal T-cell infiltration in tau-driven cognitive impairments.

Physiological functions of tau remain ill defined. In the present study, Marciniak et al. uncover a novel function of tau in its ability to regulate brain insulin signaling and discuss the pathophysiological implications of these findings for Alzheimer’s disease and tauopathies.

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The τ pathology found in Alzheimer disease (AD) is crucial in cognitive decline. Midlife development of obesity, a major risk factor of insulin resistance and type 2 diabetes, increases the risk of dementia and AD later in life. The impact of obesity on AD risk has been suggested to be related to central insulin resistance, secondary to peripheral insulin resistance. The effects of diet-induced obesity (DIO) on τ pathology remain unknown. In this study, we evaluated effects of a high-fat diet, given at an early pathological stage, in the THY-Tau22 transgenic mouse model of progressive AD-like τ pathology. We found that early and progressive obesity potentiated spatial learning deficits as well as hippocampal τ pathology at a later stage. Surprisingly, THY-Tau22 mice did not exhibit peripheral insulin resistance. Further, pathological worsening occurred while hippocampal insulin signaling was upregulated. Together, our data demonstrate that DIO worsens τ phosphorylation and learning abilities in τ transgenic mice independently from peripheral/central insulin resistance.

SummaryWhile the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampusdependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptordependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N-methyl-D-Aspartate receptors (NMDAR). Using THY-Tau22 transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA-induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY-Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies.

Objectives The Fragile X Mental Retardation Protein (FMRP) is a widely expressed RNA-binding protein involved in translation regulation. Since the absence of FMRP leads to Fragile X Syndrome (FXS) and autism, FMRP has been extensively studied in brain. The functions of FMRP in peripheral organs and on metabolic homeostasis remain elusive; therefore, we sought to investigate the systemic consequences of its absence. Methods Using metabolomics, in vivo metabolic phenotyping of the Fmr1- KO FXS mouse model and in vitro approaches, we show that the absence of FMRP induced a metabolic shift towards enhanced glucose tolerance and insulin sensitivity, reduced adiposity, and increased β-adrenergic-driven lipolysis and lipid utilization. Results Combining proteomics and cellular assays, we highlight that FMRP loss increased hepatic protein synthesis and impacted pathways notably linked to lipid metabolism. Mapping metabolomic and proteomic phenotypes onto a signaling and metabolic network, we predicted that the coordinated metabolic response to FMRP loss was mediated by dysregulation in the abundances of specific hepatic proteins. We experimentally validated these predictions, demonstrating that the translational regulator FMRP associates with a subset of mRNAs involved in lipid metabolism. Finally, we highlight that FXS patients mirror metabolic variations observed in Fmr1- KO mice with reduced circulating glucose and insulin and increased free fatty acids. Conclusions Loss of FMRP results in a widespread coordinated systemic response that notably involves upregulation of protein translation in the liver, increased utilization of lipids, and significant changes in metabolic homeostasis. Our study unravels metabolic phenotypes in FXS and further supports the importance of translational regulation in the homeostatic control of systemic metabolism.

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability, hyperactivity, and autism. FXS is due to the silencing of the X-linked FMR1 gene. Murine models of FXS, knock-out (KO) for the murine homolog Fmr1, have been generated, exhibiting CNS-related behavioral, and neuronal anomalies reminiscent of the human phenotypes. As a reflection of the almost ubiquitous expression of the FMR1 gene, FXS is also accompanied by physical abnormalities. This suggests that the FMR1-deficiency could impact skeletal ontogenesis. In the present study, we highlight that Fmr1-KO mice display changes in body composition with an increase in body weight, likely due to both increase of skeleton length and muscular mass along with reduced visceral adiposity. We also show that, while Fmr1-deficiency has no overt impact on cortical bone mineral density (BMD), cortical thickness was increased, and cortical eccentricity was decreased in the femurs from Fmr1-KO mice as compared to controls. Also, trabecular pore volume was reduced and trabecular thickness distribution was shifted toward higher ranges in Fmr1-KO femurs. Finally, we show that Fmr1-KO mice display increased physical activity. Although the precise molecular signaling mechanism that produces these skeletal and bone microstructure changes remains to be determined, our study warrants further investigation on the impact of FMR1-deficiency on whole-body composition, as well as skeletal and bone architecture.