Tobacco Smoke-Induced Brain White Matter Myelin Dysfunction: Potential Co-Factor Role of Smoking in Neurodegeneration

Article type: Research Article

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

Affiliations: [a] Liver Research Center, Divisions of Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [b] Gastroenterology and Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [c] Neuropathology, and Departments of Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [d] Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [e] Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [f] Neurology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [g] Neurosurgery, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [h] Molecular Pharmacology and Physiology Graduate Program at Brown University, Providence, RI, USA | [i] Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil | [j] 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.: +1 401 444 7364; Fax: +1 401 444 2939; E-mail: [email protected].

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. Conclusion: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.

Keywords: Alzheimer’s disease, cigarette smoke, mouse model, myelin genes, neurodegeneration, tobacco, white matter

DOI: 10.3233/JAD-150751

Journal: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 133-148, 2016