While chronic smoking triggers cardiovascular disease, controversy remains regarding its effects on the brain and cognition. We investigated the effects of long-term cigarette smoke (CS) exposure (CSE) on cerebrovascular function, neuronal injury, and cognition in a novel mouse exposure model. Longitudinal studies were performed in CS or air-exposed mice, 2 hours/day, for up to 60 weeks. Hypertension and carotid vascular endothelial dysfunction (VED) occurred by 16 weeks of CSE, followed by reduced carotid artery blood flow, with oxidative stress detected in the carotid artery, and subsequently in the brain of CS-exposed mice with generation of reactive oxygen species (ROS) and secondary protein and DNA oxidation, microglial activation and astrocytosis. Brain small vessels exhibited decreased levels of endothelial NO synthase (eNOS), enlarged perivascular spaces with blood brain barrier (BBB) leak and decreased levels of tight-junction proteins. In the brain, amyloid-β deposition and phosphorylated-tau were detected with increases out to 60 weeks, at which time mice exhibited impaired spatial learning and memory. Thus, long-term CSE initiates a cascade of ROS generation and oxidative damage, eNOS dysfunction with cerebral hypoperfusion, as well as cerebrovascular and BBB damage with intracerebral inflammation, and neuronal degeneration, followed by the onset of impaired cognition and memory.
DurazzoTCMattssonNWeinerMW. and Alzheimer’s Disease Neuroimaging I.
Smoking and increased Alzheimer’s disease risk: a review of potential mechanisms. Alzheimers Dement2014;
10: S122–S145.
2.
BarnesDEYaffeK.The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol2011;
10: 819–828.
3.
LiuYLiHWangJ, et al.
Association of cigarette smoking with cerebrospinal fluid biomarkers of neurodegeneration, neuroinflammation, and oxidation. JAMA Netw Open2020;
3: e2018777.
4.
CaldirolaDDaccòSGrassiM, et al.
Effects of cigarette smoking on neuropsychological performance in mood disorders: a comparison between smoking and nonsmoking inpatients. J Clin Psychiatry2013;
74: e130–e136.
5.
CervillaJAPrinceMMannA.Smoking, drinking, and incident cognitive impairment: a cohort community based study included in the gospel oak project. J Neurol Neurosurg Psychiatry2000;
68: 622–626.
6.
HerbertLEScherrPABeckettLA, et al.
Relation of smoking and low-to-moderate alcohol consumption to change in cognitive function: a longitudinal study in a defined community of older persons. Am J Epidemiol1993;
137: 881–891.
7.
FordABMefroucheZFriedlandRP, et al.
Smoking and cognitive impairment: a population-based study. J Am Geriatr Soc1996;
44: 905–909.
8.
WangHXFratiglioniLFrisoniGB, et al.
Smoking and the occurrence of Alzheimer’s disease: cross-sectional and longitudinal data in a population-based study. Am J Epidemiol1999;
149: 640–644.
9.
McDonaldWM.Overview of neurocognitive disorders. Focus (Am Psychiatr Publ)2017;
15: 4–12.
10.
SousaRMFerriCPAcostaD, et al.
Contribution of chronic diseases to disability in elderly people in countries with low and Middle incomes: a 10/66 dementia research group population-based survey. Lancet2009;
374: 1821–1830.
11.
KimHAMillerAADrummondGR, et al.
Vascular cognitive impairment and Alzheimer’s disease: role of cerebral hypoperfusion and oxidative stress. Naunyn Schmiedebergs Arch Pharmacol2012;
385: 953–959.
12.
LiuHZhangJ.Cerebral hypoperfusion and cognitive impairment: the pathogenic role of vascular oxidative stress. Int J Neurosci2012;
122: 494–499.
13.
PanzaFSolfrizziVColaciccoAM, et al.
Cerebrovascular disease in the elderly: lipoprotein metabolism and cognitive decline. Aging Clin Exp Res2006;
18: 144–148.
14.
DeCarliCMillerBLSwanGE, et al.
Cerebrovascular and brain morphologic correlates of mild cognitive impairment in the national heart, lung, and blood institute twin study. Arch Neurol2001;
58: 643–647.
ChenCADe PascaliFBasyeA, et al.
Redox modulation of endothelial nitric oxide synthase by glutaredoxin-1 through reversible oxidative post-translational modification. Biochemistry2013;
52: 6712–6723.
17.
ChenC-AWangT-YVaradharajS, et al.
S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature2010;
468: 1115–1118.
18.
CrowJPBeckmanJS.Reactions between nitric oxide, superoxide, and peroxynitrite: footprints of peroxynitrite in vivo. In: IgnarroLMuradF (eds) Advances in pharmacology.
Amsterdam:
Academic Press, 1995, pp. 17–43.
19.
WardlawJMSmithCDichgansM.Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol2013;
12: 483–497.
20.
ZlokovicBV.The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron2008;
57: 178–201.
21.
Starke RobertMThompson JohnWAli MuhammadS, et al.
Cigarette smoke initiates oxidative Stress-Induced cellular phenotypic modulation leading to cerebral aneurysm pathogenesis. Arterioscler Thromb Vasc Biol2018;
38: 610–621.
22.
El-MahdyMAAbdelghanyTMHemannC, et al.
Chronic cigarette smoke exposure triggers a vicious cycle of leukocyte and endothelial-mediated oxidant stress that results in vascular dysfunction. Am J Physiol Heart Circ Physiol2020;
319: H51–H65.
23.
Moreno-GonzalezIEstradaLDSanchez-MejiasE, et al.
Smoking exacerbates amyloid pathology in a mouse model of Alzheimer’s disease. Nat Commun2013;
4: 1495.
24.
TalukderMAJohnsonWMVaradharajS, et al.
Chronic cigarette smoking causes hypertension, increased oxidative stress, impaired NO bioavailability, endothelial dysfunction, and cardiac remodeling in mice. Am J Physiol Heart Circ Physiol2011;
300: H388–96.
25.
ChurchDFPryorWA.Free-radical chemistry of cigarette smoke and its toxicological implications. Environ Health Perspect1985;
64: 111–126.
26.
CaiaGLEfimovaOVVelayuthamM, et al.
Organ specific mapping of in vivo redox state in control and cigarette smoke-exposed mice using EPR/NMR co-imaging. J Magn Reson2012;
216: 21–27.
27.
CafèCTorriCGazzanigaL, et al.
Oxygen radicals in central nervous system injury. Minerva Anestesiol1994;
60: 517–521.
28.
FloydRAHensleyK.Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol Aging2002;
23: 795–807.
29.
Percie Du SertNHurstVAhluwaliaA, et al.
The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. J Cereb Blood Flow Metab2020;
40: 1769–1777.
30.
El-MahdyMAMahgoupEMEweesMG, et al.
Long-term electronic cigarette exposure induces cardiovascular dysfunction similar to tobacco cigarettes: role of nicotine and exposure duration. Am J Physiol Heart Circ Physiol2021;
320: H2112–H2129.
31.
YamazakiHHoriuchiKTakanoR, et al.
Human blood concentrations of cotinine, a biomonitoring marker for tobacco smoke, extrapolated from nicotine metabolism in rats and humans and physiologically based pharmacokinetic modeling. Int J Environ Res Public Health2010;
7: 3406–3421.
32.
ZweierJLShalaanMTSamouilovA, et al.
Whole body electronic cigarette exposure system for efficient evaluation of diverse inhalation conditions and products. Inhal Toxicol2020;
32: 477–486.
33.
El-MahdyMAEweesMGEidMS, et al.
Electronic cigarette exposure causes vascular endothelial dysfunction due to NADPH oxidase activation and eNOS uncoupling. Am J Physiol Heart Circ Physiol2022;
322: H549–H567.
34.
GaoSHoDVatnerDE, et al.
Echocardiography in mice. Curr Protoc Mouse Biol2011;
1: 71–83.
35.
JeongJWParkOKParkYK, et al.
Changes of the carotid artery doppler flow velocity pattern after sublingual nitroglycerin in patients with hypertension. Korean J Intern Med1998;
13: 22–26.
36.
Santa-MaríaIPérezMHernándezF, et al.
Characteristics of the binding of thioflavin S to tau paired helical filaments. J Alzheimers Dis2006;
9: 279–285.
37.
GroenningM.Binding mode of thioflavin T and other molecular probes in the context of amyloid fibrils – current status. J Chem Biol2010;
3: 1–18.
38.
KalariaRNKennyRABallardCG, et al.
Towards defining the neuropathological substrates of vascular dementia. J Neurol Sci2004;
226: 75–80.
39.
RosenfeldCSFergusonSA.Barnes maze testing strategies with small and large rodent models. J Vis Exp2014; e51194.
40.
ShojiHTakaoKHattoriS, et al.
Contextual and cued fear conditioning test using a video analyzing system in mice. J Vis Exp2014; 50871.
41.
ZhaoHKalivendiSZhangH, et al.
Superoxide reacts with hydroethidine but forms a fluorescent product that is distinctly different from ethidium: potential implications in intracellular fluorescence detection of superoxide. Free Radic Biol Med2003;
34: 1359–1368.
42.
DuarteAICandeiasEAlvesIN, et al.
Liraglutide protects against brain amyloid-β(1-42) accumulation in female mice with early Alzheimer’s disease-like pathology by partially rescuing oxidative/nitrosative stress and inflammation. Int J Mol Sci2020;
21: 1746.
43.
TiwariSSMizunoKGhoshA, et al.
Alzheimer-related decrease in CYFIP2 links amyloid production to tau hyperphosphorylation and memory loss. Brain2016;
139: 2751–2765.
44.
GravesABvan DuijnCMChandraV, et al.
Alcohol and tobacco consumption as risk factors for Alzheimer’s disease: a collaborative re-analysis of case-control studies. EURODEM risk factors research group. Int J Epidemiol1991;
20 Suppl 2: S48–57.
45.
UlrichJJohannson-LocherGSeilerWO, et al.
Does smoking protect from Alzheimer’s disease? Alzheimer-type changes in 301 unselected brains from patients with known smoking history. Acta Neuropathol1997;
94: 450–454.
46.
Hellström-LindahlEMousaviMRavidR, et al.
Reduced levels of abeta 40 and abeta 42 in brains of smoking controls and Alzheimer’s patients. Neurobiol Dis2004;
15: 351–360.
47.
TyasSLWhiteLRPetrovitchH, et al.
Mid-life smoking and late-life dementia: the Honolulu-Asia aging study. Neurobiol Aging2003;
24: 589–596.
48.
MünzelTHahadOKunticM, et al.
Effects of tobacco cigarettes, e-cigarettes, and waterpipe smoking on endothelial function and clinical outcomes. Eur Heart J2020;
41: 4057–4070.
49.
Kruk-SlomkaMBoguszewska-CzubaraASlomkaT, et al.
Correlations between the memory-related behavior and the level of oxidative stress biomarkers in the mice brain, provoked by an acute administration of CB receptor ligands. Neural Plast2016;
2016: 9815092.
50.
ShabirOBerwickJFrancisSE.Neurovascular dysfunction in vascular dementia, Alzheimer’s and atherosclerosis. BMC Neurosci2018;
19: 62.
51.
AbdelghanyTMIsmailRSMansoorFA, et al.
Cigarette smoke constituents cause endothelial nitric oxide synthase dysfunction and uncoupling due to depletion of tetrahydrobiopterin with degradation of GTP cyclohydrolase. Nitric Oxide2018;
76: 113–121.
52.
HannawiYCaceresEEweesMG, et al.
Characterizing the neuroimaging and histopathological correlates of cerebral small vessel disease in spontaneously hypertensive stroke-prone rats. Front Neurol2021;
12: 740298.
53.
HannawiYEweesMGMooreJT, et al.
Characterizing CD38 expression and enzymatic activity in the brain of spontaneously hypertensive stroke-prone rats. Front Pharmacol2022;
13: 881708.
54.
RajaniRMQuickSRuigrokSR, et al.
Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats. Sci Transl Med2018;
10: eaam9507.
55.
HannawiY.Cerebral small vessel disease: a review of the pathophysiological mechanisms. Transl Stroke Res2023. DOI: 10.1007/s12975-023-01195-9.
56.
ValavanidisAVlachogianniTFiotakisK.Tobacco smoke: involvement of reactive oxygen species and stable free radicals in mechanisms of oxidative damage, carcinogenesis and synergistic effects with other respirable particles. Int J Environ Res Public Health2009;
6: 445–462.
57.
Michael PittiloR.Cigarette smoking, endothelial injury and cardiovascular disease. Int J Exp Pathol2000;
81: 219–230.
58.
MullickAEMcDonaldJMMelkonianG, et al.
Reactive carbonyls from tobacco smoke increase arterial endothelial layer injury. Am J Physiol Heart Circ Physiol2002;
283: H591–7.
59.
SchaefferSIadecolaC.Revisiting the neurovascular unit. Nat Neurosci2021;
24: 1198–1209.
60.
TakataFNakagawaSMatsumotoJ, et al.
Blood-Brain barrier dysfunction amplifies the development of neuroinflammation: Understanding of cellular events in brain microvascular endothelial cells for prevention and treatment of BBB dysfunction. Front Cell Neurosci2021;
15: 661838.
61.
BosIVerheyFRRamakersIHGB, et al.
Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline. Alzheimers Res Ther2017;
9: 101.
62.
MurphyMPLeVineH3rd.Alzheimer’s disease and the amyloid-beta peptide. J Alzheimers Dis2010;
19: 311–323.
63.
StineWBJungbauerLYuC, et al.
Preparing synthetic Aβ in different aggregation states. Methods Mol Biol2011;
670: 13–32.
64.
ZhengWHBastianettoSMennickenF, et al.
Amyloid beta peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures. Neuroscience2002;
115: 201–211.
65.
Mondragon-RodriguezSPerryGLuna-MunozJ, et al.
Phosphorylation of tau protein at sites ser(396-404) is one of the earliest events in Alzheimer’s disease and down syndrome. Neuropathol Appl Neurobiol2014;
40: 121–135.
66.
HoY-SYangXYeungS-C, et al.
Cigarette smoking accelerated brain aging and induced Pre-Alzheimer-like neuropathology in rats. Plos ONE2012;
7: e36752.
67.
KeppKPRobakisNKHøilund-CarlsenPF, et al.
The amyloid Cascade hypothesis: an updated critical review. Brain2023;
146: 3969–3990.
68.
CataldoJKProchaskaJJGlantzSA.Cigarette smoking is a risk factor for Alzheimer’s disease: an analysis controlling for tobacco industry affiliation. J Alzheimers Dis2010;
19: 465–480.
69.
BachmanDLGreenRCBenkeKS, et al.
Comparison of Alzheimer’s disease risk factors in white and African American families. Neurology2003;
60: 1372–1374.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
