Neuroinflammation, Hyperphosphorylated Tau, Diffuse Amyloid Plaques, and Down-Regulation of the Cellular Prion Protein in Air Pollution Exposed Children and Young Adults

Article type: Research Article

Authors: Calderón-Garcidueñas, Lilian^{a; b; *} | Kavanaugh, Michael^b | Block, Michelle^c | D'Angiulli, Amedeo^d | Delgado-Chávez, Ricardo^e | Torres-Jardón, Ricardo^f | González-Maciel, Angelica^a | Reynoso-Robles, Rafael^a | Osnaya, Norma^a | Villarreal-Calderon, Rodolfo^g | Guo, Ruixin^h | Hua, Zhaowei^h | Zhu, Hongtu^h | Perry, Georgeⁱ | Diaz, Philippe^j

Affiliations: [a] Instituto Nacional de Pediatría, Mexico City, Mexico | [b] The Center for Structural and Functional Neurosciences, The University of Montana, Missoula, MT, USA | [c] Virginia Commonwealth University Medical Campus, Richmond, VA, USA | [d] Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada | [e] Pathology Department, Instituto Nacional de Cancerologia, Mexico City, Mexico | [f] Centro de Ciencias de la Atmósfera, Universidad Nacional Autónoma de México, Mexico City, Mexico | [g] Davidson Honors College, The University of Montana, Missoula, MT, USA | [h] Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA | [i] College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA | [j] Core Laboratory for Neuromolecular Production, The University of Montana, Missoula, MT, USA

Correspondence: [*] Correspondence to: Lilian Calderón-Garcidueñas, MD. Ph.D., The Center for Structural and Functional Neurosciences, The University of Montana, 32 Campus Drive, 287 Skaggs Building, Missoula, MT 59812, USA. E-mail: lilian.calderon-garciduenas@umontana.edu.

Abstract: Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) pathology was also explored. Exposed urbanites displayed differential (>2-fold) regulation of 134 genes. Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% had amyloid-β (Aβ) diffuse plaques compared with 0% in controls. APOE4 carriers had greater hyperphosphorylated tau and diffuse Aβ plaques versus E3 carriers (Q = 7.82, p = 0.005). Upregulated gene network clusters included IL1, NFκB, TNF, IFN, and TLRs. A 15-fold frontal down-regulation of the prion-related protein (PrPC) was seen in highly exposed subjects. The down-regulation of the PrPC is critical given its important roles for neuroprotection, neurodegeneration, and mood disorder states. Elevation of indices of neuroinflammation and oxidative stress, down-regulation of the PrPC and AD-associated pathology are present in young megacity residents. The inducible regulation of gene expression suggests they are evolving different mechanisms in an attempt to cope with the constant state of inflammation and oxidative stress related to their environmental exposures. Together, these data support a role for air pollution in CNS damage and its impact upon the developing brain and the potential etiology of AD and mood disorders.

Keywords: Alzheimer's disease, air pollution, cellular prion protein, children, inflammasomes, neuroinflammation, oxidative stress, particulate matter

DOI: 10.3233/JAD-2011-110722

Journal: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 93-107, 2012