Localization and Pathological Implications of Lipopolysaccharide in the Brains of 5XFAD Mice

Alzheimer's disease (AD) is an irreversible disease characterized by a complex pathophysiology. Recent evidence consistently identifies inflammation as one of the contributing factors, along with the pathological aggregation and accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau protein. Inflammation is suggested to have specific causative agents, of which lipopolysaccharide (LPS) may be important in AD. Interestingly, elevated LPS levels are found in patients with AD, and these elevated levels cause cognitive dysfunction in AD patients. Moreover, LPS contributes to neuroinflammation and Aβ and tau pathology in AD. However, questions remain about LPS presence/distribution in AD brains and its relationship with AD pathology. This study investigated (1) the changes in LPS presence/distribution in wild-type (WT) and 5XFAD mice, (2) the pathological role of LPS on Aβ and tau aggregation, and (3) the effect of LPS on neuroinflammatory response in vitro and in vivo. LPS accumulations were significantly increased in the 5XFAD brains compared to WT brains. Particularly, LPS distribution is increasing in the 5XFAD brains in an AD progression-dependent manner. Furthermore, LPS significantly increased aggregation of Aβ and tau and deteriorated neuroinflammatory response in vitro and in vivo. Thus, our results suggest that LPS contributes to AD pathology and modulation of LPS levels could be an effective therapeutic strategy for AD.