NF-κB-regulated microRNA-574-5p underlies synaptic and cognitive impairment in response to atmospheric PM 2.5 aspiration.

Background: PM _2.5 (particulate matter ≤ 2.5 μm) is one of the leading environmental risk factors for the global burden of disease. Whereas increasing evidence has linked the adverse roles of PM _2.5 with cardiovascular and respiratory diseases, limited but growing emerging evidence suggests that PM _2.5 exposure can affect the nervous system, causing neuroinflammation, synaptic dysfunction and cognitive deterioration. However, the molecular mechanisms underlying the synaptic and cognitive deficits elicited by PM _2.5 exposure are largely unknown.
Methods: C57BL/6 mice received oropharyngeal aspiration of PM _2.5 (1 and 5 mg/kg bw) every other day for 4 weeks. The mice were also stereotaxically injected with β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE1) shRNA or LV-miR-574-5p lentiviral constructs in the absence or presence of PM _2.5 aspiration at 5 mg/kg bw every other day for 4 weeks. Spatial learning and memory were assessed with the Morris water maze test, and synaptic function integrity was evaluated with electrophysiological recordings of long-term potentiation (LTP) and immunoblot analyses of glutamate receptor subunit expression. The expression of α-secretase (ADAM10), BACE1, and γ-secretase (nicastrin) and the synthesis and accumulation of amyloid β (Aβ) were measured by immunoblot and enzyme-linked immunosorbent assay (ELISA). MicroRNA (miRNA) expression was screened with a microRNA microarray analysis and confirmed by real-time quantitative reverse transcription PCR (qRT-PCR) analysis. Dual-luciferase reporter gene and chromatin immunoprecipitation (ChIP) analyses were used to detect the binding of miR-574-5p in the 3'UTR of BACE1 and NF-κB p65 in the promoter of miR-574-5p, respectively.
Results: PM _2.5 aspiration caused neuroinflammation and deteriorated synaptic function integrity and spatial learning and memory, and the effects were associated with the induction of BACE1. The action was mediated by NF-κB p65-regulated downregulation of miR-574-5p, which targets BACE1. Overexpression of miR-574-5p in the hippocampal region decreased BACE1 expression, restored synaptic function, and improved spatial memory and learning following PM _2.5 exposure.
Conclusions: Taken together, our findings reveal a novel molecular mechanism underlying impaired synaptic and cognitive function following exposure to PM _2.5 , suggesting that miR-574-5p is a potential intervention target for the prevention and treatment of PM _2.5 -induced neurological disorders.