Three month inhalation exposure to low-level PM2.5 induced brain toxicity in an Alzheimer’s disease mouse model

Abstract

Although numerous epidemiological studies revealed an association between ambient fine particulate matter (PM2.5) exposure and Alzheimer’s disease (AD), the PM2.5-induced neuron toxicity and associated mechanisms were not fully elucidated. The present study assessed brain toxicity in 6-month-old female triple-transgenic AD (3xTg-AD) mice following subchronic exposure to PM2.5 via an inhalation system. The treated mice were whole-bodily and continuously exposed to real-world PM2.5 for 3 months, while the control mice inhaled filtered air. Changes in cognitive and motor functions were evaluated using the Morris Water Maze and rotarod tests. Magnetic resonance imaging analysis was used to record gross brain volume alterations, and tissue staining with hematoxylin and eosin, Nissl, and immunohistochemistry methods were used to monitor pathological changes in microstructures after PM2.5 exposure. The levels of AD-related hallmarks and the oxidative stress biomarker malondialdehyde (MDA) were assessed using Western blot analysis and liquid chromatography-mass spectrometry, respectively. Our results showed that subchronic exposure to environmental levels of PM2.5 induced obvious neuronal loss in the cortex of exposed mice, but without significant impairment of cognitive and motor function. Increased levels of phosphorylated-tau and MDA were also observed in olfactory bulb or hippocampus after PM2.5 exposure, but no amyloid pathology was detected, as reported in previous studies. These results revealed that a relatively lower level of PM2.5 subchronic exposure from the environmental atmosphere still induced certain neurodegenerative changes in the brains of AD mice, especially in the olfactory bulb, entorhinal cortex and hippocampus, which is consistent with the nasal entry and spreading route for PM exposure. Systemic factors may also contribute to the neuronal toxicity. The effects of PM2.5 after a more prolonged exposure period are needed to establish a more comprehensive picture of the PM2.5-mediated development of AD.

Air pollution and mental health: associations, mechanisms and methods

“…Recent neuroimaging studies report findings consistent with others, but are not able to resolve the ongoing inconsistencies in this area [63,64], despite further experimental mouse modelling [65 ▪ ].…”

Particulate matter and Alzheimer’s disease: an intimate connection

“…Motor coordination deficits have been found in 5xFAD mice exposed to diesel engine exhaust for 13 weeks with a 0.95 mg/m 3 dose (6 h/day, 5 days/week) compared with FA-exposed controls regardless of indistinguishable Aβ plaque loads between exposures [30]. Exposing 6-month-old 3xTgAD mice to PM 2.5 at a mean concentration of 11.38 μg/m 3 for 3 months failed to elicit spatial learning/ memory and motor activity differences [31]. The failure of this PM 2.5 exposure to elicit changes associated with clinical presentation of disease while promoting differences in p-tau and oxidative stress levels serves as an important reminder that hallmarks develop far before clinical diagnoses [31].…”

“…The failure of this PM 2.5 exposure to elicit changes associated with clinical presentation of disease while promoting differences in p-tau and oxidative stress levels serves as an important reminder that hallmarks develop far before clinical diagnoses [31]. While findings vary in terms of the age at which behavioral changes present based on PM 2.5 concentrations, exposure duration, and genotype, spatial learning and memory and motor coordination challenges are signs consistently found among PM-exposed animals, aligning with the clinical presentation of AD (Box 2) [19,[29][30][31].…”

The pathogenic effects of particulate matter on neurodegeneration: a review

“…UFPM exposure for 2 weeks at human-relevant concentration resulted in memory deficits in reference memory and short-term memory since 1 month to 6.5 months post-exposure in both nontransgenic mice and aged male 3 × TgAD mice, a transgenic mice model for AD that manifested deposition of AD pathological hallmarks and cognitive impairment [ 53 ]. Although in another study which continuously exposed 6-month-old female 3 × TgAD mice to real world PM2.5 for 3 months, the mice did not show cognitive decline in Morris water maze test, PM2.5 induced obvious neuronal loss accompanied with phosphorylated tau in the olfactory bulb and the hippocampus in the cortex of exposed mice [ 54 ]. (Table 3 ).…”