Chronic Lipopolysaccharide Exposure Causes AD‐Like Pathology in Male Mice With Intact Blood–Brain Barrier

ABSTRACT Chronic inflammatory conditions like periodontitis and inflammatory bowel disease (IBD) are reported to contribute to the pathogenesis of late‐onset Alzheimer's disease (AD). Gram‐negative bacteria are the main bacterial species causing oral and gut mucosal infections. Lipopolysaccharide (LPS) is a major inflammation‐inducing molecule in Gram‐negative bacteria. LPS derived from the oral bacterium Porphyromonas gingivalis exhibits heterogeneous tetra‐acylated and penta‐acylated lipid A, while LPS from Escherichia coli exhibits the classical hexa‐acylated lipid A. Whether P. gingivalis ‐LPS and E. coli ‐LPS play a similar role in the progression of late‐onset AD is unknown. Using adult, wild‐type C57BL/6J mice to mimic the adult population without genetically determined predisposition to AD, we showed that chronic inflammation induced by a 28‐day, subcutaneous infusion of P. gingivalis ‐LPS or E. coli ‐LPS can lead to neuroinflammation and AD‐like cognitive decline and pathology in male mice. At this relatively early stage (4 weeks) of chronic inflammation when the blood–brain barrier is intact, both P. gingivalis ‐LPS and E. coli ‐LPS cause neuroinflammation through Toll‐like receptor 4 (TLR4) and Toll‐like receptor 2 (TLR2) expressed at microglia in the brain. Notably, only E. coli ‐LPS induces significant inflammatory responses systemically. In short, our results suggest that chronic P. gingivalis ‐LPS release (occurring in chronic periodontitis) or E. coli ‐LPS release (occurring in IBD) could harm the brain before the blood–brain barrier is disrupted; continuous local P. gingivalis ‐LPS release might do harm to the brain before exhibiting adverse effects systemically.