title: Tobacco Smoke Exposure Impairs Brain Insulin/IGF Signaling: Potential Co-Factor Role in Neurodegeneration.
abstract: BACKGROUND
  Human studies suggest tobacco smoking is a risk factor for cognitive impairment and neurodegeneration, including Alzheimer's disease (AD). However, experimental data linking tobacco smoke exposures to underlying mediators of neurodegeneration, including impairments in brain insulin and insulin-like growth factor (IGF) signaling in AD are lacking.
  
  
  OBJECTIVE
  This study tests the hypothesis that cigarette smoke (CS) exposures can impair brain insulin/IGF signaling and alter expression of AD-associated proteins.
  
  
  METHODS
  Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 or 8 weeks (CS4, CS8), or CS8 followed by 2 weeks recovery (CS8+R). Gene expression was measured by qRT-PCR analysis and proteins were measured by multiplex bead-based or direct binding duplex ELISAs.
  
  
  RESULTS
  CS exposure effects on insulin/IGF and insulin receptor substrate (IRS) proteins and phosphorylated proteins were striking compared with the mRNA. The main consequences of CS4 or CS8 exposures were to significantly reduce insulin R, IGF-1R, IRS-1, and tyrosine phosphorylated insulin R and IGF-1R proteins. Paradoxically, these effects were even greater in the CS8+R group. In addition, relative levels of S312-IRS-1, which inhibits downstream signaling, were increased in the CS4, CS8, and CS8+R groups. Correspondingly, CS and CS8+R exposures inhibited expression of proteins and phosphoproteins required for signaling through Akt, PRAS40, and/or p70S6K, increased AβPP-Aβ, and reduced ASPH protein, which is a target of insulin/IGF-1 signaling.
  
  
  CONCLUSIONS
  Secondhand CS exposures caused molecular and biochemical abnormalities in brain that overlap with the findings in AD, and many of these effects were sustained or worsened despite short-term CS withdrawal.
authors.affiliation: Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Divisions of Gastroenterology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Chetram
authors.initials: C
authors.lastname: Deochand
authors.affiliation: Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Divisions of Gastroenterology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Department of 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, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Divisions of Gastroenterology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Divisions of Neuropathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Department of Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Department of Neurology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Department of 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: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013002:Somatomedins / Q000378:metabolism*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D007328:Insulin; D013002:Somatomedins; D014028:Tobacco Smoke Pollution; D017526:Receptor, IGF Type 1
keywords: Alzheimer’s disease; cigarette smoke; insulin resistance; mouse model; neurodegeneration