Tobacco Smoke Exposure Impairs Brain Insulin/IGF Signaling: Potential Co-Factor Role in Neurodegeneration

Article type: Research Article

Authors: Deochand, Chetram^{a; b; d} | Tong, Ming^{a; b; d} | Agarwal, Amit R.^h | Cadenas, Enrique^h | de la Monte, Suzanne M.^{a; b; c; d; e; f; g; *}

Affiliations: [a] Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [b] Divisions of Gastroenterology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [c] Divisions of Neuropathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [d] Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [e] Department of Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [f] Department of Neurology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [g] Department of Neurosurgery, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [h] Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA

Correspondence: [*] Correspondence to: Dr. Suzanne M. de la Monte, MD, MPH, Pierre Galletti Research Building, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI 02903, USA.Tel.: +401 444 7364; Fax: +401 444 2939; E-mail: [email protected].

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. Conclusion: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.

Keywords: Alzheimer’s disease, cigarette smoke, insulin resistance, mouse model, neurodegeneration

DOI: 10.3233/JAD-150664

Journal: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 373-386, 2016