Interleukin 1ß triggers synaptic and memory deficits in Herpes simplex virus type-1-infected mice by downregulating the expression of synaptic plasticity-related genes via the epigenetic MeCP2/HDAC4 complex.

Extensive research provides evidence that neuroinflammation underlies numerous brain disorders. However, the molecular mechanisms by which inflammatory mediators determine synaptic and cognitive dysfunction occurring in neurodegenerative diseases (e.g., Alzheimer's disease) are far from being fully understood. Here we investigated the role of interleukin 1ß (IL-1ß), and the molecular cascade downstream the activation of its receptor, to the synaptic dysfunction occurring in the mouse model of multiple Herpes simplex virus type-1 (HSV-1) reactivations within the brain. These mice are characterized by neuroinflammation and memory deficits associated with a progressive accumulation of neurodegenerative hallmarks (e.g., amyloid-ß protein and tau hyperphosphorylation). Here we show that mice undergone two HSV-1 reactivations in the brain exhibited increased levels of IL-1ß along with significant alterations of: (1) cognitive performances; (2) hippocampal long-term potentiation; (3) expression synaptic-related genes and pre- and post-synaptic proteins; (4) dendritic spine density and morphology. These effects correlated with activation of the epigenetic repressor MeCP2 that, in association with HDAC4, affected the expression of synaptic plasticity-related genes. Specifically, in response to HSV-1 infection, HDAC4 accumulated in the nucleus and promoted MeCP2 SUMOylation that is a post-translational modification critically affecting the repressive activity of MeCP2. The blockade of IL-1 receptors by the specific antagonist Anakinra prevented the MeCP2 increase and the consequent downregulation of gene expression along with rescuing structural and functional indices of neurodegeneration. Collectively, our findings provide novel mechanistic evidence on the role played by HSV-1-activated IL-1ß signaling pathways in synaptic deficits leading to cognitive impairment.

Intracellular accumulation of tau oligomers in astrocytes and their synaptotoxic action rely on Amyloid Precursor Protein Intracellular Domain-dependent expression of Glypican-4.

Several studies including ours reported the detrimental effects of extracellular tau oligomers (ex-oTau) on glutamatergic synaptic transmission and plasticity. Astrocytes greatly internalize ex-oTau whose intracellular accumulation alters neuro/gliotransmitter handling thereby negatively affecting synaptic function. Both amyloid precursor protein (APP) and heparan sulfate proteoglycans (HSPGs) are required for oTau internalization in astrocytes but the molecular mechanisms underlying this phenomenon have not been clearly identified yet. Here we found that a specific antibody anti-glypican 4 (GPC4), a receptor belonging to the HSPG family, significantly reduced oTau uploading from astrocytes and prevented oTau-induced alterations of Ca2+-dependent gliotransmitter release. As such, anti-GPC4 spared neurons co-cultured with astrocytes from the astrocyte-mediated synaptotoxic action of ex-oTau, thus preserving synaptic vesicular release, synaptic protein expression and hippocampal LTP at CA3-CA1 synapses. Of note, the expression of GPC4 depended on APP and, in particular, on its C-terminal domain, AICD, that we found to bind Gpc4 promoter. Accordingly, GPC4 expression was significantly reduced in mice in which either APP was knocked-out or it contained the non-phosphorylatable amino acid alanine replacing threonine 688, thus becoming unable to produce AICD. Collectively, our data indicate that GPC4 expression is APP/AICD-dependent, it mediates oTau accumulation in astrocytes and the resulting synaptotoxic effects.

Effects Mediated by Dimethyl Fumarate on In Vitro Oligodendrocytes: Implications in Multiple Sclerosis.

BACKGROUND: Dimethyl fumarate (DMF) is a drug currently in use in oral therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS) due to its immunomodulatory and neuroprotective effects. The mechanisms by which DMF exerts its therapeutic effects in MS and in particular its influence on the oligodendrocytes (OLs) survival or differentiation have not yet been fully understood. METHODS: Characterization of Oli neu cells was performed by immunocytochemistry and RT-PCR. The effect of DMF on cell proliferation and morphology was assessed by MTT assay, trypan blue staining, RT-PCR and Western blot analysis. The antioxidant and anti-inflammatory properties of DMF were analysed by ROS detection through DCFDA staining and lipid content analysis by Oil Red O staining and TLC. RESULTS: DMF has been observed to induce a slowdown of cell proliferation, favoring the oligodendrocyte lineage cells (OLCs) differentiation. DMF has an antioxidant effect and is able to modify the lipid content even after the LPS-mediated inflammatory stimulus in Oli neu cells. CONCLUSIONS: The results obtained confirm that DMF has anti-inflammatory and antioxidant effects also on Oli neu cells. Interestingly, it appears to promote the OLCs differentiation towards mature and potentially myelinating cells.

Extracellular tau oligomers affect extracellular glutamate handling by astrocytes through downregulation of GLT-1 expression and impairment of NKA1A2 function.

AIMS: Several studies reported that astrocytes support neuronal communication by the release of gliotransmitters, including ATP and glutamate. Astrocytes also play a fundamental role in buffering extracellular glutamate in the synaptic cleft, thus limiting the risk of excitotoxicity in neurons. We previously demonstrated that extracellular tau oligomers (ex-oTau), by specifically targeting astrocytes, affect glutamate-dependent synaptic transmission via a reduction in gliotransmitter release. The aim of this work was to determine if ex-oTau also impair the ability of astrocytes to uptake extracellular glutamate, thus further contributing to ex-oTau-dependent neuronal dysfunction. METHODS: Primary cultures of astrocytes and organotypic brain slices were exposed to ex-oTau (200 nM) for 1 h. Extracellular glutamate buffering by astrocytes was studied by: Na+ imaging; electrophysiological recordings; high-performance liquid chromatography; Western blot and immunofluorescence. Experimental paradigms avoiding ex-oTau internalisation (i.e. heparin pre-treatment and amyloid precursor protein knockout astrocytes) were used to dissect intracellular vs extracellular effects of oTau. RESULTS: Ex-oTau uploading in astrocytes significantly affected glutamate-transporter-1 expression and function, thus impinging on glutamate buffering activity. Ex-oTau also reduced Na-K-ATPase activity because of pump mislocalisation on the plasma membrane, with no significant changes in expression. This effect was independent of oTau internalisation and it caused Na+ overload and membrane depolarisation in ex-oTau-targeted astrocytes. CONCLUSIONS: Ex-oTau exerted a complex action on astrocytes, at both intracellular and extracellular levels. The net effect was dysregulated glutamate signalling in terms of both release and uptake that relied on reduced expression of glutamate-transporter-1, altered function and localisation of NKA1A1, and NKA1A2. Consequently, Na+ gradients and all Na+ -dependent transports were affected.