Nonalcoholic fatty liver disease (NAFLD), characterized by an excess accumulation of hepatic triglycerides, is a growing health epidemic. While ER stress in the liver has been implicated in the development of NAFLD, the role of brain ER stress — which is emerging as a key contributor to a number of chronic diseases including obesity — in NAFLD remains unclear. These studies reveal that chemical induction of ER stress in the brain caused hepatomegaly and hepatic steatosis in mice. Conversely, pharmacological reductions in brain ER stress in diet-induced obese mice rescued NAFLD independent of body weight, food intake, and adiposity. Evaluation of brain regions involved revealed robust activation of ER stress biomarkers and ER ultrastructural abnormalities in the circumventricular subfornical organ (SFO), a nucleus situated outside of the blood-brain-barrier, in response to high-fat diet. Targeted reductions in SFO-ER stress in obese mice via SFO-specific supplementation of the ER chaperone 78-kDa glucose–regulated protein ameliorated hepatomegaly and hepatic steatosis without altering body weight, food intake, adiposity, or obesity-induced hypertension. Overall, these findings indicate a novel role for brain ER stress, notably within the SFO, in the pathogenesis of NAFLD.
Julie A. Horwath, Chansol Hurr, Scott D. Butler, Mallikarjun Guruju, Martin D. Cassell, Allyn L. Mark, Robin L. Davisson, Colin N. Young
We lack a mechanistic explanation for the stereotyped pattern of white matter loss seen in Huntington’s disease (HD). While the earliest white matter changes are seen around the striatum, within the corpus callosum, and in the posterior white matter tracts, the order in which these changes occur and why these white matter connections are specifically vulnerable is unclear. Here, we use diffusion tractography in a longitudinal cohort of individuals yet to develop clinical symptoms of HD to identify a hierarchy of vulnerability, where the topological length of white matter connections between a brain area and its neighbors predicts the rate of atrophy over 24 months. This demonstrates a new principle underlying neurodegeneration in HD, whereby brain connections with the greatest topological length are the first to suffer damage that can account for the stereotyped pattern of white matter loss observed in premanifest HD.
Peter McColgan, Kiran K. Seunarine, Sarah Gregory, Adeel Razi, Marina Papoutsi, Jeffrey D. Long, James A. Mills, Eileanoir Johnson, Alexandra Durr, Raymund A.C. Roos, Blair R. Leavitt, Julie C. Stout, Rachael I. Scahill, Chris A. Clark, Geraint Rees, Sarah J. Tabrizi, the Track-On HD Investigators
Shadab A. Rahman, Melissa A. St. Hilaire, Anne-Marie Chang, Nayantara Santhi, Jeanne F. Duffy, Richard E. Kronauer, Charles A. Czeisler, Steven W. Lockley, Elizabeth B. Klerman
Martin Niethammer, Chris C. Tang, Peter A. LeWitt, Ali R. Rezai, Maureen A. Leehey, Steven G. Ojemann, Alice W. Flaherty, Emad N. Eskandar, Sandra K. Kostyk, Atom Sarkar, Mustafa S. Siddiqui, Stephen B. Tatter, Jason M. Schwalb, Kathleen L. Poston, Jaimie M. Henderson, Roger M. Kurlan, Irene H. Richard, Christine V. Sapan, David Eidelberg, Matthew J. During, Michael G. Kaplitt, Andrew Feigin
Intracerebral hemorrhage (ICH) causes high mortality and morbidity, but our knowledge of post-ICH neuronal death and related mechanisms is limited. In this study, we first demonstrated that ferroptosis, a newly identified form of cell death, occurs in the collagenase-induced ICH model in mice. We found that administration of ferrostatin-1, a specific inhibitor of ferroptosis, prevented neuronal death and reduced iron deposition induced by hemoglobin in organotypic hippocampal slice cultures (OHSCs). Mice treated with ferrostatin-1 after ICH exhibited marked brain protection and improved neurologic function. Additionally, we found that ferrostatin-1 reduced lipid reactive oxygen species production and attenuated the increased expression level of
Qian Li, Xiaoning Han, Xi Lan, Yufeng Gao, Jieru Wan, Frederick Durham, Tian Cheng, Jie Yang, Zhongyu Wang, Chao Jiang, Mingyao Ying, Raymond C. Koehler, Brent R. Stockwell, Jian Wang
Surgery can induce cognitive decline, a risk that increases with advancing age. In rodents, postoperative cognitive decline (POCD) is associated with the inflammatory activation of hippocampal microglia. To examine the role of microglia in POCD, we inhibited the colony-stimulating factor 1 receptor (CSF1R) in adult mice, effectively depleting CNS microglia. Surgical trauma (tibial fracture) reduced the ability of mice to remember a conditioned response learned preoperatively, a deficit more pronounced and persistent in mice with diet-induced obesity (DIO). Whereas microglial depletion by itself did not affect learning or memory, perioperative microglial depletion remarkably protected mice, including those with DIO, from POCD. This protection was associated with reduced hippocampal levels of inflammatory mediators, abrogation of hippocampal recruitment of CCR2+ leukocytes, and higher levels of circulating inflammation-resolving factors. Targeting microglia may thus be a viable strategy to mitigate the development of POCD, particularly in those with increased vulnerability.
Xiaomei Feng, Martin Valdearcos, Yosuke Uchida, David Lutrin, Mervyn Maze, Suneil K. Koliwad
Molecular mechanisms underlying learning and memory remain imprecisely understood, and restorative interventions are lacking. We report that intranasal administration of siRNAs can be used to identify targets important in cognitive processes and to improve genetically impaired learning and memory. In mice modeling the intellectual deficiency of Fragile X syndrome, intranasally administered siRNA targeting glycogen synthase kinase-3β (GSK3β), histone deacetylase-1 (HDAC1), HDAC2, or HDAC3 diminished cognitive impairments. In WT mice, intranasally administered brain-derived neurotrophic factor (BDNF) siRNA or HDAC4 siRNA impaired learning and memory, which was partially due to reduced insulin-like growth factor-2 (IGF2) levels because the BDNF siRNA– or HDAC4 siRNA–induced cognitive impairments were ameliorated by intranasal IGF2 administration. In
Marta Pardo, Yuyan Cheng, Dmitry Velmeshev, Marco Magistri, Hagit Eldar-Finkelman, Ana Martinez, Mohammad A. Faghihi, Richard S. Jope, Eleonore Beurel
Spinal muscular atrophy (SMA) is a leading genetic cause of infantile death and is caused by the loss of survival motor neuron-1 (
Kevin A. Kaifer, Eric Villalón, Erkan Y. Osman, Jacqueline J. Glascock, Laura L. Arnold, D.D.W. Cornelison, Christian L. Lorson
Neuroinflammation is a pathological hallmark of ALS in both transgenic rodent models and patients, and is characterized by proinflammatory T lymphocytes and activated macrophages/microglia. In ALS mouse models, decreased regulatory T lymphocytes (Tregs) exacerbate the neuroinflammatory process, leading to accelerated motoneuron death and shortened survival; passive transfer of Tregs suppresses the neuroinflammation and prolongs survival. Treg numbers and FOXP3 expression are also decreased in rapidly progressing ALS patients. A key question is whether the marked neuroinflammation in ALS can be attributed to the impaired suppressive function of ALS Tregs in addition to their decreased numbers. To address this question, T lymphocyte proliferation assays were performed. Compared with control Tregs, ALS Tregs were less effective in suppressing responder T lymphocyte proliferation. Although both slowly and rapidly progressing ALS patients had dysfunctional Tregs, the greater the clinically assessed disease burden or the more rapidly progressing the patient, the greater the Treg dysfunction. Epigenetically, the percentage methylation of the Treg-specific demethylated region was greater in ALS Tregs. After in vitro expansion, ALS Tregs regained suppressive abilities to the levels of control Tregs, suggesting that autologous passive transfer of expanded Tregs might offer a novel cellular therapy to slow disease progression.
David R. Beers, Weihua Zhao, Jinghong Wang, Xiujun Zhang, Shixiang Wen, Dan Neal, Jason R. Thonhoff, Abdullah S. Alsuliman, Elizabeth J. Shpall, Katy Rezvani, Stanley H. Appel
Decreased noradrenergic excitation of hypoglossal motoneurons during sleep causing hypotonia of pharyngeal dilator muscles is a major contributor to the pathogenesis of obstructive sleep apnea (OSA), a widespread disease for which treatment options are limited. Previous OSA drug candidates targeting various excitatory/inhibitory receptors on hypoglossal motoneurons have proved unviable in reactivating these neurons, particularly during rapid-eye-movement (REM) sleep. To identify a viable drug target, we show that the repurposed α2-adrenergic antagonist yohimbine potently reversed the depressant effect of REM sleep on baseline hypoglossal motoneuron activity (a first-line motor defense against OSA) in rats. Remarkably, yohimbine also restored the obstructive apnea–induced long-term facilitation of hypoglossal motoneuron activity (hLTF), a much-neglected form of noradrenergic-dependent neuroplasticity that could provide a second-line motor defense against OSA but was also depressed during REM sleep. Corroborating immunohistologic, optogenetic, and pharmacologic evidence confirmed that yohimbine’s beneficial effects on baseline hypoglossal motoneuron activity and hLTF were mediated mainly through activation of pontine A7 and A5 noradrenergic neurons. Our results suggest a 2-tier (impaired first- and second-line motor defense) mechanism of noradrenergic-dependent pathogenesis of OSA and a promising pharmacotherapy for rescuing both these intrinsic defenses against OSA through disinhibition of A7 and A5 neurons by α2-adrenergic blockade.
Gang Song, Chi-Sang Poon
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