PM2.5 triggers tau aggregation in a mouse model of tauopathy
Congcong Liu, … , Tao Li, Zhentao Zhang
Congcong Liu, … , Tao Li, Zhentao Zhang
Published July 22, 2024
Citation Information: JCI Insight. 2024;9(14):e176703. https://doi.org/10.1172/jci.insight.176703.
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Research Article Neuroscience

PM2.5 triggers tau aggregation in a mouse model of tauopathy

Abstract

The aggregation and prion-like propagation of tau are the hallmarks of Alzheimer’s disease (AD) and other tauopathies. However, the molecular mechanisms underlying the assembly and spread of tau pathology remain elusive. Epidemiological data show that exposure to fine particulate matter (PM2.5) is associated with an increased risk of AD. However, the molecular mechanisms remain unknown. Here, we showed that PM2.5 triggered the aggregation of tau and promoted the formation of tau fibrils. Injection of PM2.5-induced tau preformed fibrils (PFFs) into the hippocampus of tau P301S transgenic mice promoted the aggregation of tau and induced cognitive deficits and synaptic dysfunction. Furthermore, intranasal administration of PM2.5 exacerbated tau pathology and induced cognitive impairment in tau P301S mice. In conclusion, our results indicated that PM2.5 exposure promoted tau pathology and induced cognitive impairments. These results provide mechanistic insight into how PM2.5 increases the risk of AD.

Authors

Congcong Liu, Lanxia Meng, Yan Gao, Jiehui Chen, Min Zhu, Min Xiong, Tingting Xiao, Xiaoling Gu, Chaoyang Liu, Tao Li, Zhentao Zhang

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Figure 2

PM2.5-tau PFFs show enhanced seeding activity in vitro.

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PM2.5-tau PFFs show enhanced seeding activity in vitro. (A and B) Tau ag...
(A and B) Tau aggregates in tau-HEK293 cells with different treatments. (A) Shown are insoluble tau aggregates at 48 hours of transduction. (B) Quantification of tau aggregates. n = 6 independent biological experiments (each point represents the average of 10 random fields from each experiment). (C) Immunofluorescence showing that tau aggregates colocalize with ubiquitin and p62 in tau-HEK293 cells. (D and E) Tau-HEK293 cells with different treatments were sequentially extracted with 1% Triton X-100 in TBS with protease and phosphatase inhibitors (TX-100) lysis buffer and 2% SDS lysis buffer. The bar graph shows the quantitative analysis of tau level. n = 6 biologically independent experiments. (F and G) Sedimentation analysis of tau-HEK293 cells transduced with different treatments. The bar graph shows the quantification of tau levels in the pellets relative to total tau. n = 6 biologically independent experiments. (H and I) Representative images of p-tau (AT8) immunostaining in primary neurons with different treatments for 10 days. (H) p-tau (AT8) staining. (I) The bar graph shows the quantification of AT8. n = 6 independent biological experiments (each point represents the average of 10 random fields from each experiment). (J and K) Representative images of p-tau (AT100) in primary neurons with different treatments for 10 days. (J) p-tau (AT100) staining. (K) The bar graph shows the quantification of AT100. n = 6 independent biological experiments (each point represents the average of 10 random fields from each experiment). (L) Western blot assay of AT8, AT100, and total tau levels in neurons treated with different treatments. The bar graphs are the quantification of AT8 and AT100 levels relative to GAPDH. n = 6 biologically independent experiments. Data are presented as mean ± SEM. P values were determined by 1-way ANOVA followed by Tukey’s multiple comparisons test. Scale bar: 20 μm.