Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). The RTT missense MECP2 R306C mutation prevents MeCP2 from interacting with the NCoR/histone deacetylase 3 (HDAC3) complex; however, the neuronal function of HDAC3 is incompletely understood. We found that neuronal deletion of Hdac3 in mice elicited abnormal locomotor coordination, sociability and cognition. Transcriptional and chromatin profiling revealed that HDAC3 positively regulated a subset of genes and was recruited to active gene promoters via MeCP2. HDAC3-associated promoters were enriched for the FOXO transcription factors, and FOXO acetylation was elevated in Hdac3 knockout (KO) and Mecp2 KO neurons. Human RTT-patient-derived MECP2 R306C neural progenitor cells had deficits in HDAC3 and FOXO recruitment and gene expression. Gene editing of MECP2 R306C cells to generate isogenic controls rescued HDAC3-FOXO-mediated impairments in gene expression. Our data suggest that HDAC3 interaction with MeCP2 positively regulates a subset of neuronal genes through FOXO deacetylation, and disruption of HDAC3 contributes to cognitive and social impairment.National Institutes of Health (U.S.) (Grant NS78839

Mitochondrial dysfunction mediated through dynamin-related protein 1 (Drp1) propagates impairment in blood brain barrier in septic encephalopathy

Abstract Background Out of the myriad of complications associated with septic shock, septic-associated encephalopathy (SAE) carries a significant risk of morbidity and mortality. Blood-brain-barrier (BBB) impairment, which subsequently leads to increased vascular permeability, has been associated with neuronal injury in sepsis. Thus, preventing BBB damage is an attractive therapeutic target. Mitochondrial dysfunction is an important contributor of sepsis-induced multi-organ system failure. More recently, mitochondrial dysfunction in endothelial cells has been implicated in mediating BBB failure in stroke, multiple sclerosis and in other neuroinflammatory disorders. Here, we focused on Drp1-mediated mitochondrial dysfunction in endothelial cells as a potential target to prevent BBB failure in sepsis. Methods We used lipopolysaccharide (LPS) to induce inflammation and BBB disruption in a cell culture as well as in murine model of sepsis. BBB disruption was assessed by measuring levels of key tight-junction proteins. Brain cytokines levels, oxidative stress markers, and activity of mitochondrial complexes were measured using biochemical assays. Astrocyte and microglial activation were measured using immunoblotting and qPCR. Transwell cultures of brain microvascular endothelial cells co-cultured with astrocytes were used to assess the effect of LPS on expression of tight-junction proteins, mitochondrial function, and permeability to fluorescein isothiocyanate (FITC) dextran. Finally, primary neuronal cultures exposed to LPS were assessed for mitochondrial dysfunction. Results LPS induced a strong brain inflammatory response and oxidative stress in mice which was associated with increased Drp1 activation and mitochondrial localization. Particularly, Drp1-(Fission 1) Fis1-mediated oxidative stress also led to an increase in expression of vascular permeability regulators in the septic mice. Similarly, mitochondrial defects mediated via Drp1-Fis1 interaction in primary microvascular endothelial cells were associated with increased BBB permeability and loss of tight-junctions after acute LPS injury. P110, an inhibitor of Drp1-Fis1 interaction, abrogated these defects, thus indicating a critical role for this interaction in mediating sepsis-induced brain dysfunction. Finally, LPS mediated a direct toxic effect on primary cortical neurons, which was abolished by P110 treatment. Conclusions LPS-induced impairment of BBB appears to be dependent on Drp1-Fis1-mediated mitochondrial dysfunction. Inhibition of mitochondrial dysfunction with P110 may have potential therapeutic significance in septic encephalopathy. </jats:sec

Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer’s disease related pathology

AbstractAldehyde dehydrogenase 2 deficiency (ALDH2*2) causes facial flushing in response to alcohol consumption in approximately 560 million East Asians. Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer’s Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD. In the present study, we show that fibroblasts of an AD patient that also has an ALDH2*2 mutation or overexpression of ALDH2*2 in fibroblasts derived from AD patients harboring ApoE ε4 allele exhibited increased aldehydic load, oxidative stress, and increased mitochondrial dysfunction relative to healthy subjects and exposure to ethanol exacerbated these dysfunctions. In an in vivo model, daily exposure of WT mice to ethanol for 11 weeks resulted in mitochondrial dysfunction, oxidative stress and increased aldehyde levels in their brains and these pathologies were greater in ALDH2*2/*2 (homozygous) mice. Following chronic ethanol exposure, the levels of the AD-associated protein, amyloid-β, and neuroinflammation were higher in the brains of the ALDH2*2/*2 mice relative to WT. Cultured primary cortical neurons of ALDH2*2/*2 mice showed increased sensitivity to ethanol and there was a greater activation of their primary astrocytes relative to the responses of neurons or astrocytes from the WT mice. Importantly, an activator of ALDH2 and ALDH2*2, Alda-1, blunted the ethanol-induced increases in Aβ, and the neuroinflammation in vitro and in vivo. These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.</jats:p

Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity

Stroke is a multiphasic process in which initial cerebral ischemia is followed by secondary injury from immune responses to ischemic brain components. Here we demonstrate that peripheral CD11b+CD45+ myeloid cells magnify stroke injury via activation of triggering receptor expressed on myeloid cells 1 (TREM1), an amplifier of proinflammatory innate immune responses. TREM1 was induced within hours after stroke peripherally in CD11b+CD45+ cells trafficking to ischemic brain. TREM1 inhibition genetically or pharmacologically improved outcome via protective antioxidant and anti-inflammatory mechanisms. Positron electron tomography imaging using radiolabeled antibody recognizing TREM1 revealed elevated TREM1 expression in spleen and, unexpectedly, in intestine. In the lamina propria, noradrenergic-dependent increases in gut permeability induced TREM1 on inflammatory Ly6C+MHCII+ macrophages, further increasing epithelial permeability and facilitating bacterial translocation across the gut barrier. Thus, following stroke, peripheral TREM1 induction amplifies proinflammatory responses to both brain-derived and intestinal-derived immunogenic components. Critically, targeting this specific innate immune pathway reduces cerebral injury

Soluble TREM2 is elevated in Parkinson’s disease subgroups with increased CSF tau

Abstract Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease and affects 1% of the population above 60 years old. Although Parkinson’s disease commonly manifests with motor symptoms, a majority of patients with Parkinson’s disease subsequently develop cognitive impairment, which often progresses to dementia, a major cause of morbidity and disability. Parkinson’s disease is characterized by α-synuclein accumulation that frequently associates with amyloid-β and tau fibrils, the hallmarks of Alzheimer’s disease neuropathological changes; this co-occurrence suggests that onset of cognitive decline in Parkinson’s disease may be associated with appearance of pathological amyloid-β and/or tau. Recent studies have highlighted the appearance of the soluble form of the triggering receptor expressed on myeloid cells 2 (sTREM2) receptor in CSF during development of Alzheimer’s disease. Given the known association of microglial activation with advancing Parkinson’s disease, we investigated whether CSF and/or plasma sTREM2 differed between CSF biomarker-defined Parkinson’s disease participant subgroups. In this cross-sectional study, we examined 165 participants consisting of 17 cognitively normal elderly subjects, 45 patients with Parkinson’s disease with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF amyloid-β and tau levels revealed that CSF sTREM2 concentrations were elevated in Parkinson’s disease subgroups with a positive tau CSF biomarker signature, but not in Parkinson’s disease subgroups with a positive CSF amyloid-β biomarker signature. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in Parkinson’s disease.</jats:p

CSF sTREM2 correlates with CSF tau in advancing Parkinson’s disease

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD) and affects 1% of the population above 60 years old. Although PD commonly manifests with motor symptoms, a majority of patients with PD subsequently develop cognitive impairment which often progresses to dementia, a major cause of morbidity and disability. PD is characterized by α-synuclein accumulation that frequently associates with amyloid beta (Aβ) and tau fibrils, the hallmarks of AD neuropathologic changes; this co-occurrence suggests that onset of cognitive decline in PD may be associated with appearance of pathologic Aβ and/or tau. Recent studies have highlighted the appearance of the soluble form of the Triggering Receptor Expressed on Myeloid cells 2 (sTREM2) receptor in CSF during development of AD. Given the known association of microglial activation with advancing PD, we investigated whether CSF and/or plasma sTREM2 increased with progression to PD dementia. We examined 165 participants consisting of 17 cognitively normal elderly, 45 PD patients with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF Aβ and tau levels revealed that CSF sTREM2 concentrations were elevated in PD subgroups with abnormal tau, but not Aβ, CSF concentration. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in PD that is associated with cognitive decline.One sentence summaryCSF sTREM2 correlates with CSF tau in PD</jats:sec