It has been known for some time that there is a pro-inflammatory state in blood and brain of subjects with Alzheimer?s Disease (AD). The explanation for this inflammation has been unknown. However, we have made several discoveries: Lipopolysaccharide (LPS) from Gram negative bacteria combined with cerebral ischemia and hypoxia causes amyloid-like plaques in rat brain; LPS levels in human AD brains are much greater than controls; and LPS levels in peripheral blood increase with age in controls; and LPS blood levels in AD subjects are three times those of controls. Thus, we hypothesize that LPS from the gut, gums and exogenous Gram-negative bacteria increases in blood and brain with age and promotes inflammation in blood and brain of AD patients. Moreover, LPS causes an increase in levels of Lipopolysacch- aride Binding Protein (LBP) in blood and brain to detoxify LPS. In this proposal we will: (1) demonstrate LPS and LBP levels increase in blood of controls with increasing age since age is the number one risk factor for AD; (2) demonstrate that LPS and LPB levels are higher in blood of patients with AD compared to age, sex and race matched controls; and (3) demonstrate that LPS and LBP levels are higher in AD compared to control brains, and in AD brain that LPS and LBP co-localize with amyloid plaques. This will be one of the first studies to explain the pro- inflammatory state in blood and brain of patients with AD. Thus, the results of this study will be used to support future studies that will aim to show that blood levels of LBP and LPS can be used to: (a) identify those patients at greatest risk for developing AD; (b) identify those patients who likely have AD; (c) and use blood LBP or LPS levels to assess the efficacy of various treatment or prevention strategies including probiotics, antibiotics, supplements and formal drug trials.
This proposal will demonstrate that Lipopolysaccharide Binding Protein (LBP) and Lipopolysaccharide (LPS) levels increase in blood with increasing age and the LBP and LPS levels are higher in blood and brain of patients with Alzheimer?s Disease (AD). It will also show that LPS and LBP co-localize with amyloid plaques in AD brain which could explain Abeta directly binding to LPS because Abeta is an anti-microbial peptide.
