Exposure to Traffic-Generated Pollutants Exacerbates the Expression of Factors Associated with the Pathophysiology of Alzheimer’s Disease in Aged C57BL/6 Wild-Type Mice
Restricted accessResearch articleFirst published online December 8, 2020
Exposure to Traffic-Generated Pollutants Exacerbates the Expression of Factors Associated with the Pathophysiology of Alzheimer’s Disease in Aged C57BL/6 Wild-Type Mice
Multiple studies report a strong correlation between traffic-generated air pollution-exposure and detrimental outcomes in the central nervous system (CNS), including Alzheimer’s disease (AD). Incidence of AD is rapidly increasing and, worldwide, many live in regions where pollutants exceed regulatory standards. Thus, it is imperative to identify environmental pollutants that contribute to AD, and the mechanisms involved.
Objective:
We investigated the effects of mixed gasoline and diesel engine emissions (MVE) on the expression of factors involved in progression of AD in the hippocampus and cerebrum in a young versus aged mouse model.
Methods:
Young (2 months old) and aged (18 months old) male C57BL/6 mice were exposed to either MVE (300μg/m3 PM) or filtered air (FA) for 6 h/d, 7 d/wk, for 50 d. Immunofluorescence and RT-qPCR were used to quantify oxidative stress (8-OHdG) and expression of amyloid-β protein precursor (AβPP), β secretase (BACE1), amyloid-β (Aβ), aryl hydrocarbon receptor (AhR), cytochrome P450 (CYP) 1B1, angiotensin-converting enzyme (ACE1), and angiotensin II type 1 (AT1) receptor in the cerebrum and hippocampus, in addition to cerebral microvascular tight junction (TJ) protein expression.
Results:
We observed age-related increases in oxidative stress, AhR, CYP1B1, Aβ, BACE1, and AT1 receptor in the CA1 region of the hippocampus, and elevation of cerebral AβPP, AhR, and CYP1B1 mRNA, associated with decreased cerebral microvascular TJ protein claudin-5. MVE-exposure resulted in further promotion of oxidative stress, and significant increases in AhR, CYP1B1, BACE1, ACE1, and Aβ, compared to the young and aged FA-exposed mice.
Conclusion:
Such findings suggest that MVE-exposure exacerbates the expression of factors in the CNS associated with AD pathogenesis in aged populations.
BondiMW, EdmondsEC, SalmonDP (2017) Alzheimer’s disease: Past, present, and future. J Int Neuropsychol Soc23, 818–831.
4.
VassarR, KovacsDM, YanR, WongPC (2009) The β-secretase enzyme BACE in health and Alzheimer’s disease: Regulation, cell biology, function, and therapeutic potential. J Neurosci29, 12798–12794.
5.
MayeuxR, SternY (2012) Epidemiology of Alzheimer disease.a. Cold Spring Harb Perspect Med2, 006239.
6.
Calderón-GarcidueñasL, Torres-JardónR, KuleszaRJ, MansourY, González-GonzálezLO, Gónzalez-MacielA, Reynoso-RoblesR, MukherjeePS (2020) Alzheimer disease starts in childhood in polluted Metropolitan Mexico City. A major health crisis in progress. Environ Res183, 109137.
7.
YuchiW, SbihiH, DaviesH, TamburicL, BrauerM (2020) Road proximity, air pollution, noise, green space and neurologic disease incidence: A population-based cohort study. Environ Health Glob Access Sci Source19, 8.
8.
YounanD, PetkusAJ, WidamanKF, WangX, CasanovaR, EspelandMA, GatzM, HendersonVW, MansonJE, RappSR, SachsBC, SerreML, GaussoinSA, BarnardR, SaldanaS, VizueteW, BeaversDP, SalinasJA, ChuiHC, ResnickSM, ShumakerSA, ChenJ-C (2020) Particulate matter and episodic memory decline mediated by early neuroanatomic biomarkers of Alzheimer’s disease. Brain143, 289–302.
9.
KilianJ, KitazawaM (2018) The emerging risk of exposure to air pollution on cognitive decline and Alzheimer’s disease - Evidence from epidemiological and animal studies. Biomed J41, 141–162.
10.
OudinA, SegerssonD, AdolfssonR, ForsbergB (2018) Association between air pollution from residential wood burning and dementia incidence in a longitudinal study in Northern Sweden. PLoS One13, e0198283.
11.
WoodwardNC, PakbinP, SaffariA, ShirmohammadiF, HaghaniA, SioutasC, CacciottoloM, MorganTE, FinchCE (2017) Traffic-related air pollution impact on mouse brain accelerates myelin and neuritic aging changes with specificity for CA1 neurons. Neurobiol Aging53, 48–58.
12.
OudinA, AnderssonJ, SundströmA, Nordin AdolfssonA, Oudin ÅströmD, AdolfssonR, ForsbergB, NordinM (2019) Traffic-related air pollution as a risk factor for dementia: No clear modifying effects of APOEɛ4 in the Betula Cohort. J Alzheimers Dis71, 733–740.
13.
CacciottoloM, MorganTE, SaffariAA, ShirmohammadiF, FormanHJ, SioutasC, FinchCE (2020) Traffic-related air pollutants (TRAP-PM) promote neuronal amyloidogenesis through oxidative damage to lipid rafts. Free Radic Biol Med147, 242–251.
14.
Calderón-GarcidueñasL, Gónzalez-MacielA, Reynoso-RoblesR, Delgado-ChávezR, MukherjeePS, KuleszaRJ, Torres-JardónR, Ávila-RamírezJ, Villarreal-RíosR (2018) Hallmarks of Alzheimer disease are evolving relentlessly in Metropolitan Mexico City infants, children and young adults. APOE4 carriers have higher suicide risk and higher odds of reaching NFT stage V at ≤40 years of age. Environ Res164, 475–487.
LevesqueS, SuraceMJ, McDonaldJ, BlockML (2011) Air pollution & the brain: Subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease. J Neuroinflammation8, 105.
17.
HullmannM, AlbrechtC, van BerloD, Gerlofs-NijlandME, WahleT, BootsAW, KrutmannJ, CasseeFR, BayerTA, SchinsRPF (2017) Diesel engine exhaust accelerates plaque formation in a mouse model of Alzheimer’s disease. Part Fibre Toxicol14, 35.
18.
BlockML, ElderA, AutenRL, BilboSD, ChenH, ChenJ-C, Cory-SlechtaDA, CostaD, Diaz-SanchezD, DormanDC, GoldD, GrayK, JengHA, KaufmanJD, KleinmanMT, KirshnerA, LawlerC, MillerDS, NadadurS, RitzB, SemmensEO, TonelliLH, VeronesiB, WrightRO, WrightR (2012) The outdoor air pollution and brain health workshop. Neurotoxicology33, 972–984.
19.
BrookRD, RajagopalanS, PopeCA, BrookJR, BhatnagarA, Diez-RouxAV, HolguinF, HongY, LuepkerRV, MittlemanMA, PetersA, SiscovickD, SmithSC, WhitselL, KaufmanJD, American Heart Association Council on Epidemiology and Prevention, Council on the Kidney in Cardiovascular Disease, and Council on Nutrition, Physical Activity and Metabolism (2010) Particulate matter air pollution and cardiovascular disease: An update to the scientific statement from the American Heart Association. Circulation121, 2331–2378.
20.
Calderón-GarcidueñasL, Reynoso-RoblesR, Vargas-MartínezJ, Gómez-Maqueo-ChewA, Pérez-GuilléB, MukherjeePS, Torres-JardónR, PerryG, Gónzalez-MacielA (2016) Prefrontal white matter pathology in air pollution exposed Mexico City young urbanites and their potential impact on neurovascular unit dysfunction and the development of Alzheimer’s disease. Environ Res146, 404–417.
21.
CrichtonS, BarrattB, SpiridouA, HoangU, LiangSF, KovalchukY, BeeversSD, KellyFJ, DelaneyB, WolfeCD (2016) Associations between exhaust and non-exhaust particulate matter and stroke incidence by stroke subtype in South London. Sci Total Environ568, 278–284.
22.
Calderón-GarcidueñasL, LerayE, HeydarpourP, Torres-JardónR, ReisJ (2016) Air pollution, a rising environmental risk factor for cognition, neuroinflammation and neurodegeneration: The clinical impact on children and beyond. Rev Neurol (Paris)172, 69–80.
23.
StafoggiaM, CesaroniG, PetersA, AndersenZJ, BadaloniC, BeelenR, CaraccioloB, CyrysJ, de FaireU, de HooghK, EriksenKT, FratiglioniL, GalassiC, GiganteB, HavulinnaAS, HennigF, HildingA, HoekG, HoffmannB, HouthuijsD, KorekM, LankiT, LeanderK, MagnussonPK, MeisingerC, MiglioreE, OvervadK, OstensonC-G, PedersenNL, PekkanenJ, PenellJ, PershagenG, PundtN, PykoA, Raaschou-NielsenO, RanziA, RicceriF, SacerdoteC, SwartWJR, TurunenAW, VineisP, WeimarC, WeinmayrG, WolfK, BrunekreefB, ForastiereF (2014) Long-term exposure to ambient air pollution and incidence of cerebrovascular events: Results from 11 European cohorts within the ESCAPE project. Environ Health Perspect122, 919–925.
24.
Calderón-GarcidueñasL, SoltAC, Henríquez-RoldánC, Torres-JardónR, NuseB, HerrittL, Villarreal-CalderónR, OsnayaN, StoneI, GarcíaR, BrooksDM, González-MacielA, Reynoso-RoblesR, Delgado-ChávezR, ReedW (2008) Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults. Toxicol Pathol36, 289–310.
25.
SuwannasualU, LuceroJ, DavisG, McDonaldJD, LundAK (2019) Mixed vehicle emissions induces angiotensin II and cerebral microvascular angiotensin receptor expression in C57Bl/6 mice and promotes alterations in integrity in a blood-brain barrier coculture model. Toxicol Sci170, 525–535.
26.
SuwannasualU, LuceroJ, McDonaldJD, LundAK (2018) Exposure to traffic-generated air pollutants mediates alterations in brain microvascular integrity in wildtype mice on a high-fat diet. Environ Res160, 449–461.
27.
OppenheimHA, LuceroJ, GuyotA-C, HerbertLM, McDonaldJD, MabondzoA, LundAK (2013) Exposure to vehicle emissions results in altered blood brain barrier permeability and expression of matrix metalloproteinases and tight junction proteins in mice. Part Fibre Toxicol10, 62.
28.
ZhengW, Ghersi-EgeaJ-F (2020) Brain barrier systems play no small roles in toxicant-induced brain disorders. Toxicol Sci175, 147–148.
GantenD, HermannK, UngerT, LangRE (1983) The tissue renin-angiotensin systems: Focus on brain angiotensin, adrenal gland and arterial wall. Clin Exp Hypertens A5, 1099–1118.
31.
GrobeJL, GrobeCL, BeltzTG, WestphalSG, MorganDA, XuD, de LangeWJ, LiH, SakaiK, ThedensDR, CassisLA, RahmouniK, MarkAL, JohnsonAK, SigmundCD (2010) The brain Renin-angiotensin system controls divergent efferent mechanisms to regulate fluid and energy balance. Cell Metab12, 431–442.
32.
BragaVA (2011) Differential brain angiotensin-II type I receptor expression in hypertensive rats. J Vet Sci12, 291–293.
33.
GuimondM-O, Gallo-PayetN (2012) The angiotensin II type 2 receptor in brain functions: An update. Int J Hypertens2012, 1–18.
34.
PrustySK, SahuPK, SubudhiBB (2017) Angiotensin mediated oxidative stress and neuroprotective potential of antioxidants and AT1 receptor blockers. Mini Rev Med Chem17, 518–528.
35.
XiaoX, ZhangC, MaX, MiaoH, WangJ, LiuL, ChenS, ZengR, ChenY, BihlJC (2015) Angiotensin-(1-7) counteracts angiotensin II-induced dysfunction in cerebral endothelial cells via modulating Nox2/ROS and PI3K/NO pathways. Exp Cell Res336, 58–65.
36.
Rodriguez-PerezAI, BorrajoA, Rodriguez-PallaresJ, GuerraMJ, Labandeira-GarciaJL (2015) Interaction between NADPH-oxidase and Rho-kinase in angiotensin II-induced microglial activation. Glia63, 466–482.
37.
YamamotoE, TamamakiN, NakamuraT, KataokaK, TokutomiY, DongY-F, FukudaM, MatsubaS, OgawaH, Kim-MitsuyamaS (2008) Excess salt causes cerebral neuronal apoptosis and inflammation in stroke-prone hypertensive rats through angiotensin II-induced NADPH oxidase activation. Stroke39, 3049–3056.
38.
LiuG, HosomiN, HitomiH, PelischN, FuH, MasugataH, MuraoK, UenoM, MatsumotoM, NishiyamaA (2011) Angiotensin II induces human astrocyte senescence through reactive oxygen species production. Hypertens Res34, 479–483.
39.
KehoePG (2009) Angiotensins and Alzheimer’s disease: A bench to bedside overview. Alzheimers Res Ther1, 3.
40.
NakagawaT, HasegawaY, UekawaK, SenjuS, NakagataN, MatsuiK, Kim-MitsuyamaS (2017) Transient Mild cerebral ischemia significantly deteriorated cognitive impairment in a mouse model of Alzheimer’s disease via angiotensin AT1 receptor. Am J Hypertens30, 141–150.
LiF, ZhuW, GonzalesFJ (2017) Potential role of CYP1B1 in the development and treatment of metabolic diseases. Pharmacol Ther178, 18–30.
47.
JuricekL, CarcaudJ, PelhaitreA, RidayTT, ChevallierA, LanziniJ, AuzeilN, LaprévoteO, DumontF, JacquesS, LetourneurF, MassaadC, AgulhonC, BaroukiR, BeraneckM, CoumoulX (2017) AhR-deficiency as a cause of demyelinating disease and inflammation. Sci Rep7, 9794.
48.
Ramos-GarcíaNA, Orozco-IbarraM, EstudilloE, ElizondoG, Gómez ApoE, Chávez MacíasLG, Sosa-OrtizAL, Torres-RamosMA. (2020) Aryl hydrocarbon receptor in post-mortem hippocampus and in serum from young, elder, and Alzheimer’s patients. Int J Mol Sci21, 1983.
49.
MumawCL, LevesqueS, McGrawC, RobertsonS, LucasS, StafflingerJE, CampenMJ, HallP, NorenbergJP, AndersonT, LundAK, McDonaldJD, OttensAK, BlockML (2016) Microglial priming through the lung-brain axis: The role of air-pollution induced circulating factors. FASEB J30, 1880–1894.
50.
LundAK, LuceroJ, HarmanM, MaddenMC, McDonaldJD, SeagraveJC, CampenMJ (2011) The oxidized low-density lipoprotein receptor mediates vascular effects of inhaled vehicle emissions. Am J Respir Crit Care Med184, 82–91.
51.
McDonaldJD, BarrEB, WhiteRK, ChowJC, SchauerJJ, ZielinskaB, GrosjeanE (2004) Generation and characterization of four dilutions of diesel engine exhaust for a subchronic inhalation study. Environ Sci Technol38, 2513–2522.
52.
PowerMC, WeisskopfMG, AlexeeffSE, CoullBA, SpiroA, SchwartzJ (2011) Traffic-related air pollution and cognitive function in a cohort of older men. Environ Health Perspect119, 682–687.
53.
WeuveJ, PuettRC, SchwartzJ, YanoskyJD, LadenF, GrodsteinF (2012) Exposure to particulate air pollution and cognitive decline in older women. Arch Intern Med172, 219–227.
54.
WelleniusGA, BoyleLD, CoullBA, MilbergWP, GryparisA, SchwartzJ, MittlemanMA, LipsitzLA (2012) Residential proximity to nearest major roadway and cognitive function in community-dwelling seniors: Results from the MOBILIZE Boston Study. J Am Geriatr Soc60, 2075–2080.
55.
AilshireJA, ClarkeP (2015) Fine particulate matter air pollution and cognitive function among U.S. older adults. J Gerontol B Psychol Sci Soc Sci70, 322–328.
56.
TzivianL, JokischM, WinklerA, WeimarC, HennigF, SugiriD, SoppaVJ, DraganoN, ErbelR, JöckelK-H, MoebusS, HoffmannB, Heinz Nixdorf Recall Study Group (2017) Associations of long-term exposure to air pollution and road traffic noise with cognitive function-An analysis of effect measure modification. Environ Int103, 30–38.
57.
KulickER, ElkindMSV, BoehmeAK, JoyceNR, SchupfN, KaufmanJD, MayeuxR, ManlyJJ, WelleniusGA (2020) Long-term exposure to ambient air pollution, APOE-ɛ4 status, and cognitive decline in a cohort of older adults in northern Manhattan. Environ Int136, 105440.
58.
Calderón-GarcidueñasL, EngleR, Mora-TiscareñoA, StynerM, Gómez-GarzaG, ZhuH, JewellsV, Torres-JardónR, RomeroL, Monroy-AcostaME, BryantC, González-GonzálezLO, Medina-CortinaH, D’AngiulliA (2011) Exposure to severe urban air pollution influences cognitive outcomes, brain volume and systemic inflammation in clinically healthy children. Brain Cogn77, 345–355.
59.
WangS, ZhangJ, ZengX, ZengY, WangS, ChenS (2009) Association of traffic-related air pollution with children’s neurobehavioral functions in Quanzhou, China. Environ. Health Perspect117, 1612–1618.
60.
MilaniC, FarinF, BottoL, MassiminoL, LonatiE, DonzelliE, BallariniE, CrippaL, MarmiroliP, BulbarelliA, PalestiniP (2020) Systemic exposure to air pollution induces oxidative stress and inflammation in mouse brain, contributing to neurodegeneration onset. Int J Mol Sci21, 3699.
61.
SwerdlowRH, BurnsJM, KhanSM (2014) The Alzheimer’s disease mitochondrial cascade hypothesis: Progress and perspectives. Biochim Biophys Acta1842, 1219–1231.
62.
YangZ, LiH, TangY, LiuX, LiaoQ, FanC, WangS (2019) CYP1B1 deficiency ameliorates learning and memory deficits caused by high fat diet in mice. Am J Transl Res11, 2194–2206.
63.
CacciottoloM, WangX, DriscollI, WoodwardN, SaffariA, ReyesJ, SerreML, VizueteW, SioutasC, MorganTE, GatzM, ChuiHC, ShumakerSA, ResnickSM, EspelandMA, FinchCE, ChenJC (2017) Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models. Transl Psychiatry7, e1022.
64.
BhattDP, PuigKL, GorrMW, WoldLE, CombsCK (2015) A pilot study to assess effects of long-term inhalation of airborne particulate matter on early Alzheimer-like changes in the mouse brain. PLoS One10, e0127102.
65.
GebreAK, AltayeBM, AteyTM, TuemKB, BerheDF (2018) Targeting renin–angiotensin system against Alzheimer’s disease. Front Pharmacol9, 440.
66.
HemmingML, SelkoeDJ (2005) Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. J Biol Chem28, 37644–37650.
