Role of acute exposure to environmental stressors in the gut-brain-periphery axis in the presence of cognitive resilience.

Climate change-induced environmental stressors, including ambient particulate matter (PM2.5) and extreme heat stress (HS), pose serious health risks, particularly for neurodegenerative diseases. PM2.5 exacerbates cardiovascular and neurodegenerative conditions, while HS increases mortality and worsens air pollution. Combined exposure may amplify these effects, especially in vulnerable populations at risk for Alzheimer's disease (AD). In our experimental study using a mouse model of early-onset Alzheimer's disease (EOAD), we explored the combined effects of extreme weather conditions, particularly exposure to ambient PM2.5 and HS. Our research indicated that even short, repeated exposure to these environmental stressors disrupts brain energy metabolism and mitochondrial respiratory functions, which we found to be associated with altered hippocampal synaptic functions. Additionally, we find that key mechanisms associated with impaired intestinal permeability and gut dysbiosis are affected, supporting the hypothesis that exposure to climate change communication may also disrupt the gut-brain axis, as in part evidenced in our study by peripheral changes in immune and inflammatory signaling. Moreover, despite significant disruptions in metabolic and immune-inflammatory pathways, we observed no acceleration of cognitive decline in the young asymptomatic EOAD mice subjected to short, repeated exposure to extreme heat and environmental PM2.5. These findings highlight the potential role of climate change in promoting risk factors like neuroinflammation and gut-brain axis dysfunction due to gut microbiome dysbiosis in the onset and progression of AD, particularly in asymptomatic individuals at risk for developing the condition.