Intranasal Formaldehyde Exposure Induces RAGE-Mediated Alteration of the ADAM10/BACE1 Expression Balance and Amyloid...

Background: Alzheimer's disease (AD) remains an incurable disorder with severe clinical consequences. The type 3 diabetes hypothesis posits that AD may constitute a neuroendocrine disorder driven by disrupted insulin and insulin-like growth factor signaling. Amyloid pathogenesis in AD is characterized by the accumulation of beta-amyloid (Aβ) monomers, their subsequent oligomerization, and amyloid deposition. One of the causes of Aβ accumulation is disruption of amyloid precursor protein (APP) processing due to imbalance in ADAM10 and BACE1 expression. In recent years, increasing attention has been devoted to investigating the role of environmental factors in AD pathogenesis. The receptor for advanced glycation end products (RAGE) serves as a key molecular link between environmental exposure and neuroinflammatory pathology. Formaldehyde (FA) is one of the most widespread environmental pollutants. Its involvement in amyloid plaque formation has been previously reported; however, the molecular mechanisms underlying this process remain insufficiently understood. Moreover, most available data are based on prolonged FA exposure, whereas industrial FA emissions are often short-term. The objective of this study was to determine whether brief intranasal administration of FA, modeling episodic industrial pollution, induces RAGE-mediated neuroinflammation and amyloid deposition in CD1 mice. Methods: Mice received intranasal FA at environmentally relevant 0.02 mg/day or 0.2 mg/day doses for seven days; an additional group was co-treated with insulin. Cognitive function was assessed using passive avoidance (PA) and radial arm maze (RAM) tests, and synaptic plasticity was evaluated by electrophysiology. Hippocampal tissue was analyzed for RAGE expression, ADAM10/BACE1 gene balance, Aβ42 monomer levels, and amyloid deposits using optimized Thioflavin-S (Th-S) staining. Results: We observed cognitive decline in mice receiving intranasal FA administration. Elevated blood glucose levels were also observed following intranasal FA exposure. Sustained impairment of glucose metabolism led to overexpression of the RAGE in the hippocampus. There was also an imbalance of ADAM10 and BACE1 expression in the hippocampus. This was caused by overexpression of RAGE, as the enhanced interaction of the ligand and RAGE is a key factor disrupting this balance. Finally, Th-S staining confirmed amyloid deposition in mice subjected to intranasal FA exposure. Conclusions: This study provides new insights into the RAGE-mediated mechanisms by which FA contributes to the pathogenesis of AD.