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. 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.

Cigarette Smoke-Induced Alterations in Frontal White Matter Lipid Profiles Demonstrated by MALDI-Imaging Mass Spectrometry: Relevance to Alzheimer’s Disease

“…The effects of CS worsened with duration of exposure, but were partly reversed by short-term withdrawal. Furthermore, the abnormalities correspond with recent findings of CS-associated impairments in insulin and IGF signaling and altered expression of myelin-associated genes in frontal lobes of the CS-exposed mice [36, 37]. The use of MALDI-IMS to detect biochemical indices of WM degeneration holds promise for future investigations, including studies of human brains with AD.…”

“…Although the vast majority of research on nitrosamine-induced diseases pertains to carcinogenesis, emerging evidence supports the concept that low-level nitrosamine exposures also threaten health by causing progressive degenerative diseases linked to tissue injury, inflammation, impairments in insulin/IGF signaling through cell survival and metabolic pathways, oxidative and nitrosative stress, and dysregulated lipid metabolism [42–44]. In this regard, we have shown that NNK and other nitrosamines cause neurodegeneration [31, 44] including in WM [45–47] with abnormalities similar to those described herein and in recent CS exposure related publications [36, 37]. …”

Progressive white matter atrophy with altered lipid profiles is partially reversed by short-term abstinence in an experimental model of alcohol-related neurodegeneration

“…M. de la Monte, 2012; S. M. de la Monte, Re, Longato, & Tong, 2012; Yu et al, 2016), including ARBD (S. de la Monte et al, 2012; S.…”

White matter pathways as both a target and mediator of health behaviors

“…77 Yet, mouse models of cigarette smoke exposure in adulthood suggest that it broadly reduces myelin synthesis and maintenance that could not be reversed by short-term withdrawal. 78 These largely mixed results on the direction of the link between smoking and white matter architecture suggest a more complex relationship compared to obesity or cardiorespiratory fitness; however, the emerging findings do make it clear that smoking does have a strong association with the integrity of the underlying white matter systems.…”