Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models

TLDR

Exposure to ambient particulate matter and its interaction with APOE alleles may accelerate brain aging and contribute to Alzheimer’s disease. The study examined PM’s neurodegenerative effects in a large cohort of older women and in mouse models, showing that 15‑week exposure to urban nanosized PM increased cerebral β‑amyloid and hippocampal CA1 pathology, especially in APOE ɛ4 carriers, likely via heightened Aβ production and altered glutamate receptors. Fine particulate matter above EPA limits increased global cognitive decline and dementia risk by 81–92% in older women, particularly APOE ɛ4/4 carriers, and in mice and cell cultures PM exposure elevated β‑amyloid, Aβ oligomers, CA1 neurite atrophy, and glutamate receptor loss, indicating that airborne PM accelerates pathological brain aging, especially in ɛ4 carriers.

Abstract

Abstract Exposure to particulate matter (PM) in the ambient air and its interactions with APOE alleles may contribute to the acceleration of brain aging and the pathogenesis of Alzheimer’s disease (AD). Neurodegenerative effects of particulate air pollutants were examined in a US-wide cohort of older women from the Women’s Health Initiative Memory Study (WHIMS) and in experimental mouse models. Residing in places with fine PM exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE ɛ4/4 carriers. Female EFAD transgenic mice ( 5xFAD +/− /human APOE ɛ 3 or ɛ 4 +/+ ) with 225 h exposure to urban nanosized PM (nPM) over 15 weeks showed increased cerebral β-amyloid by thioflavin S for fibrillary amyloid and by immunocytochemistry for Aβ deposits, both exacerbated by APOE ɛ4. Moreover, nPM exposure increased Aβ oligomers, caused selective atrophy of hippocampal CA1 neurites, and decreased the glutamate GluR1 subunit. Wildtype C57BL/6 female mice also showed nPM-induced CA1 atrophy and GluR1 decrease. In vitro nPM exposure of neuroblastoma cells (N2a-APP/swe) increased the pro-amyloidogenic processing of the amyloid precursor protein (APP). We suggest that airborne PM exposure promotes pathological brain aging in older women, with potentially a greater impact in ɛ4 carriers. The underlying mechanisms may involve increased cerebral Aβ production and selective changes in hippocampal CA1 neurons and glutamate receptor subunits.