An imbalance of tau isoforms containing either three or four microtubule-binding repeats causes frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) in families with intronic mutations in the MAPT gene. Here we report equivalent imbalances at the mRNA and protein levels and increased total tau levels in the brains of subjects with Huntington's disease (HD) together with rod-like tau deposits along neuronal nuclei. These tau nuclear rods show an ordered filamentous ultrastructure and can be found filling the neuronal nuclear indentations previously reported in HD brains. Finally, alterations in serine/arginine-rich splicing factor-6 coincide with tau missplicing, and a role of tau in HD pathogenesis is evidenced by the attenuation of motor abnormalities of mutant HTT transgenic mice in tau knockout backgrounds.
Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1-4 (CPEB1-4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes. Together, these data identify CPEB4 as a regulator of ASD risk genes.
BackgroundNumerous neurological and psychiatric disorders show sex differences in incidence, age of onset, symptomatology or outcome. Astrocytes, one of the glial cell types of the brain, show sex differences in number, differentiation and function. Since astrocytes are involved in the response of neural tissue to injury and inflammation, these cells may participate in the generation of sex differences in the response of the brain to pathological insults. To explore this hypothesis, we have examined whether male and female astrocytes show a different response to an inflammatory challenge and whether perinatal testosterone influences this response.MethodsCortical astrocyte cultures were prepared from postnatal day 1 (one day after birth) male or female CD1 mice pups. In addition, cortical astrocyte cultures were also prepared from female pups that were injected at birth with 100 μg of testosterone propionate or vehicle. Cultures were treated for 5 hours with medium containing lipopolysaccharide (LPS) or with control medium. The mRNA levels of IL6, interferon-inducible protein 10 (IP10), TNFα, IL1β, Toll-like receptor 4 (TLR4), steroidogenic acute regulatory protein and translocator protein were assessed by quantitative real-time polymerase chain reaction. Statistical significance was assessed by unpaired t-test or by one-way analysis of variance followed by the Tukey post hoc test.ResultsThe mRNA levels of IL6, TNFα and IL1β after LPS treatment were significantly higher in astrocytes derived from male or androgenized females compared to astrocytes derived from control or vehicle-injected females. In contrast, IP10 mRNA levels after LPS treatment were higher in astrocytes derived from control or vehicle-injected females than in those obtained from males or androgenized females. The different response of male and female astrocytes to LPS was due neither to differences in the basal expression of the inflammatory molecules nor to differences in the expression of the LPS receptor TLR4. In contrast, the different inflammatory response was associated with increased mRNA levels of translocator protein, a key steroidogenic regulator, in female astrocytes that were treated with LPS.ConclusionsMale and female cortical astrocytes respond differentially to an inflammatory challenge and this may be predetermined by perinatal testosterone exposure.
After brain injury, astrocytes acquire a reactive phenotype characterized by a series of morphological and molecular modifications, including the expression of the cytoskeletal protein vimentin. Previous studies have shown that estradiol down-regulates reactive astrogliosis. In this study we assessed whether raloxifene and tamoxifen, two selective estrogen receptor modulators, have effects similar to estradiol in astrocytes. We also assessed whether aging and the timing of estrogenic therapy after ovariectomy influence the action of the estrogenic compounds. Four groups of animals were studied: 1) young rats, ovariectomized at 2 months of age; 2) middle-aged rats, ovariectomized at 8 months of age; 3) aged rats, ovariectomized at 18 months of age; and 4) aged rats, ovariectomized at 2 months and sham operated at 18 months of age. Fifteen days after ovariectomy or sham surgery, animals received a stab wound brain injury and the treatment with the estrogenic compounds. The number of vimentin-immunoreactive astrocytes after injury was significantly higher in the hippocampus of aged rats after a long-term ovariectomy compared with aged animals after a short-term ovariectomy and middle-aged rats. In addition, reactive astrocytes were more numerous in the two groups of aged animals than in young animals. Despite these differences, the estrogenic compounds reduced reactive astrogliosis in all animal groups. These findings indicate that estradiol, raloxifene, and tamoxifen are potential candidates for the control of astrogliosis in young and older individuals and after a prolonged depletion of ovarian hormones.
Selective estrogen receptor modulators (SERMs), used for the treatment of breast cancer, osteoporosis, and menopausal symptoms, affect the nervous system. Some SERMs trigger neuroprotective mechanisms and reduce neural damage in different experimental models of neural trauma, brain inflammation, neurodegenerative diseases, cognitive impairment, and affective disorders. New SERMs with specific actions on neurons and glial cells may represent promising therapeutic tools for the brain.
Neuroinflammation comprises a feature of many neurological disorders that is accompanied by the activation of glial cells and the release of pro‐inflammatory cytokines and chemokines. Such activation is a normal response oriented to protect neural tissue and it is mainly regulated by microglia and astroglia. However, excessive and chronic activation of glia may lead to neurotoxicity and may be harmful for neural tissue. The ovarian hormone oestradiol exerts protective actions in the central nervous system that, at least in part, are mediated by a reduction of reactive gliosis. Several selective oestrogen receptor modulators may also exert neuroprotective effects by controlling glial inflammatory responses. Thus, tamoxifen and raloxifene decrease the inflammatory response caused by lipopolysaccharide, a bacterial endotoxin, in mouse and rat microglia cells in vitro. Tamoxifen and raloxifene are also able to reduce microglia activation in the brain of male and female rats in vivo after the peripheral administration of lipopolysaccharide. In addition, tamoxifen decreases the microglia inflammatory response induced by irradiation. Furthermore, treatment with tamoxifen and raloxifene resulted in a significant reduction of the number of reactive astrocytes in the hippocampus of young, middle‐aged and older female rats after a stab wound injury. Tamoxifen, raloxifene and the new selective oestrogen receptor modulators ospemifene and bazedoxifene decrease the expression and release of interleukine‐6 and interferon‐γ inducible protein‐10 in cultured astrocytes exposed to lipopolysaccharide. Ospemifene and bazedoxifene exert anti‐inflammatory effects in astrocytes by a mechanism involving classical oestrogen receptors and the inhibition of nuclear factor‐kappa B p65 transactivation. These data suggest that oestrogenic compounds are candidates to counteract brain inflammation under neurodegenerative conditions by targeting the production and release of pro‐inflammatory molecules by glial cells.
Astrocyte-neuron cross-talk is an essential component of the mechanisms involved in the neuroendocrine and neuroprotective actions of estradiol. Astrocytes express estrogen receptors, show morphological and functional modifications in response to estradiol and participate in the hormonal regulation of synaptic plasticity and neuroendocrine events. In addition, estradiol interferes with the activation of astrocytes under pathological conditions, modulating the release of neurotrophic factors and inflammatory molecules by these cells. Furthermore, under neurodegenerative conditions, astrocytes synthesize estradiol, which acts as a local neuroprotectant. The actions of estradiol on astrocytes can be imitated by selective estrogen receptor modulators. Some of these molecules, which are free of the peripheral risks associated with estrogen therapy, exert estradiol-like anti-inflammatory actions on astrocytes and are potential therapeutic candidates for the control of reactive astrogliosis.
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