title: Tobacco Smoke-Induced Brain White Matter Myelin Dysfunction: Potential Co-Factor Role of Smoking in Neurodegeneration.
abstract: BACKGROUND
  Meta-analysis studies showed that smokers have increased risk for developing Alzheimer's disease (AD) compared with non-smokers, and neuroimaging studies revealed that smoking damages white matter structural integrity.
  
  
  OBJECTIVE
  The present study characterizes the effects of side-stream (second hand) cigarette smoke (CS) exposures on the expression of genes that regulate oligodendrocyte myelin-synthesis, maturation, and maintenance and neuroglial functions.
  
  
  METHODS
  Adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). The frontal lobes were used for histology and qRT-PCR analysis.
  
  
  RESULTS
  Luxol fast blue, Hematoxylin and Eosin stained histological sections revealed CS-associated reductions in myelin staining intensity and narrowing of the corpus callosum. CS exposures broadly decreased mRNA levels of immature and mature oligodendrocyte myelin-associated, neuroglial, and oligodendrocyte-related transcription factors. These effects were more prominent in the CS8 compared with CS4 group, suggesting that molecular abnormalities linked to white matter atrophy and myelin loss worsen with duration of CS exposure. Recovery normalized or upregulated less than 25% of the suppressed genes; in most cases, inhibition of gene expression was either sustained or exacerbated.
  
  
  CONCLUSIONS
  CS exposures broadly inhibit expression of genes needed for myelin synthesis and maintenance. These adverse effects often were not reversed by short-term CS withdrawal. The results support the hypothesis that smoking contributes to white matter degeneration, and therefore could be a key risk factor for a number of neurodegenerative diseases, including AD.
authors.affiliation: Liver Research Center, Divisions of Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Gastroenterology and Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Yu
authors.affiliation: Liver Research Center, Divisions of Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Gastroenterology and Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Molecular Pharmacology and Physiology Graduate Program at Brown University, Providence, RI, USA.
authors.forename: Chetram
authors.initials: C
authors.lastname: Deochand
authors.affiliation: Molecular Pharmacology and Physiology Graduate Program at Brown University, Providence, RI, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Krotow
authors.affiliation: Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Raiane
authors.initials: R
authors.lastname: Leão
authors.affiliation: Liver Research Center, Divisions of Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Gastroenterology and Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tong
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
authors.forename: Amit R
authors.initials: AR
authors.lastname: Agarwal
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
authors.forename: Enrique
authors.initials: E
authors.lastname: Cadenas
authors.affiliation: Liver Research Center, Divisions of Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Gastroenterology and Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Neuropathology, and Departments of Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Neurology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Neurosurgery, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000235:genetics / Q000378:metabolism; D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D005699:Galactosylceramides / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D056784:Leukoencephalopathies / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000209:etiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D012907:Smoking; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014026:Nicotiana
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D005699:Galactosylceramides; D006023:Glycoproteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D014157:Transcription Factors; C002454:galactocerebroside; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases
keywords: Alzheimer’s disease; cigarette smoke; mouse model; myelin genes; neurodegeneration; tobacco; white matter