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An enriched environment prevents cognitive impairment in an Alzheimer's disease model by enhancing the secretion of exosomal microRNA-146a from the choroid plexus.

ABSTRACT: Alzheimer's disease (AD) is characterized by the extensive deposition of amyloid-β plaques and neurofibrillary tangles. We previously found that preserved function of astrocytes is associated with cognitively normal subjects with AD pathology. Here we show that an enriched environment (EE) can prevent cognitive impairment in AD model mice by ameliorating astrocytic inflammation and increasing synaptic density in the subiculum area of the hippocampus. In AD model mice treated with an EE, increased levels of microRNA (miR)-146a and down-regulation of NF-κB were observed in the hippocampus. In addition, increased levels of interferon (IFN)-γ were seen in serum from mice exposed to an EE. In vitro, enhanced miR-146a expression was observed in exosomes derived from the choroid plexus (CP) after IFN-γ treatment. In further in vitro experiments, we transfected miR-146a into Aβ/lipopolysaccharide-induced inflammatory astrocytes and showed that miR-146a ameliorated astrocytic inflammation by down-regulating tumor necrosis factor receptor-associated factor 6 and NF-κB. The present study indicates that following an EE, exosomal miR-146a derived from the CP cells is a key factor in ameliorating astrocytic inflammation, leading to synaptogenesis and correction of cognitive impairment.

SUBMITTER: Nakano M

PROVIDER: S-EPMC8474441 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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An enriched environment prevents cognitive impairment in an Alzheimer's disease model by enhancing the secretion of exosomal microRNA-146a from the choroid plexus.

Nakano Masako M Kubota Kenta K Hashizume Shin S Kobayashi Eiji E Chikenji Takako S TS Saito Yuki Y Fujimiya Mineko M

Brain, behavior, & immunity - health 20200922

Alzheimer's disease (AD) is characterized by the extensive deposition of amyloid-β plaques and neurofibrillary tangles. We previously found that preserved function of astrocytes is associated with cognitively normal subjects with AD pathology. Here we show that an enriched environment (EE) can prevent cognitive impairment in AD model mice by ameliorating astrocytic inflammation and increasing synaptic density in the subiculum area of the hippocampus. In AD model mice treated with an EE, increase ...[more]

PMID: 34589894

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Project description:BackgroundAlthough fibroblast growth factor (Fgf) signalling plays crucial roles in several developing and mature tissues, little information is currently available on expression of Fgf2 during early choroid plexus development and whether Fgf2 directly affects the behaviour of the choroid plexus epithelium (CPe). The purpose of this study was to investigate expression of Fgf2 in rodent and human developing CPe and possible function of Fgf2, using in vitro models. The application of Fgf2 to brain in vivo can affect the whole tissue, making it difficult to assess specific responses of the CPe.MethodsExpression of Fgf2 was studied by immunohistochemistry in rodent and human embryonic choroid plexus. Effects of Fgf2 on growth, secretion, aggregation and gene expression was investigated using rodent CPe vesicles, a three-dimensional polarized culture model that closely mimics CPe properties in vivo, and rodent CPe monolayer cultures.ResultsFgf2 was present early in development of the choroid plexus both in mouse and human, suggesting the importance of this ligand in Fgf signalling in the developing choroid plexus. Parallel analysis of Fgf2 expression and cell proliferation during CP development suggests that Fgf2 is not involved in CPe proliferation in vivo. Consistent with this observation is the failure of Fgf2 to increase proliferation in the tri-dimensional vesicle culture model. The CPe however, can respond to Fgf2 treatment, as the diameter of CPe vesicles is significantly increased by treatment with this growth factor. We show that this is due to an increase in cell aggregation during vesicle formation rather than increased secretion into the vesicle lumen. Finally, Fgf2 regulates expression of the CPe-associated transcription factors, Foxj1 and E2f5, whereas transthyretin, a marker of secretory activity, is not affected by Fgf2 treatment.ConclusionFgf2 expression early in the development of both human and rodent choroid plexus, and its ability to modulate behaviour and gene expression in CPe, supports the view that Fgf signalling plays a role in the maintenance of integrity and function of this specialized epithelium, and that this role is conserved between rodents and humans.

Project description:BackgroundFemale sex is a known risk factor of brain disorders with raised intracranial pressure (ICP) and sex hormones have been suggested to alter cerebrospinal fluid (CSF) dynamics, thus impairing ICP regulation in CSF disorders such as idiopathic intracranial hypertension (IIH). The choroid plexus (CP) is the tissue producing CSF and it has been hypothesized that altered hormonal composition could affect the activity of transporters involved in CSF secretion, thus affecting ICP. Therefore, we aimed to investigate if expression of various transporters involved in CSF secretion at CP were different between males and females and between females in different estrous cycle states. Steroid levels in serum was also investigated.MethodsFemale and male rats were used to determine sex-differences in the genes encoding for the transporters Aqp1 and 4, NKCC1, NBCe2, NCBE; carbonic anhydrase enzymes II and III (CA), subunits of the Na+/K+-ATPase including Atp1a1, Atp1b1 and Fxyd1 at CP. The estrous cycle stage metestrus (MET) and estrous (ES) were determined before euthanasia. Serum and CP were collected and subjected to RT-qPCR analysis and western blots. Serum was used to measure steroid levels using liquid chromatography tandem mass spectrometry (LC-MS/MS).ResultsSignificant differences in gene expression and steroid levels between males and ES females were found, while no differences were found between male and MET females. During ES, expression of Aqp1 was lower (p < 0.01) and NKCC1 was higher in females compared to males. CAII was lower while CAIII was higher in ES females (p < 0.0001). Gene expression of Atp1a1 was lower in ES compared to male (p = 0.0008). Several of these choroidal genes were also significantly different in MET compared to females in ES. Differences in gene expression during the estrus cycle were correlated to serum level of steroid hormones. Protein expression of AQP1 (p = 0.008) and CAII (p = 0.035) was reduced in ES females compared to males.ConclusionsThis study demonstrates for the first time that expression at CP is sex-dependent and markedly affected by the estrous cycle in female rats. Further, expression was related to hormone levels in serum. This opens a completely new avenue for steroid regulation of the expression of CSF transporters and the close link to the understanding of CSF disorders such as IIH.

Dataset Information

An enriched environment prevents cognitive impairment in an Alzheimer's disease model by enhancing the secretion of exosomal microRNA-146a from the choroid plexus.

Publications

An enriched environment prevents cognitive impairment in an Alzheimer's disease model by enhancing the secretion of exosomal microRNA-146a from the choroid plexus.

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