Lipopolysaccharide alters the blood-brain barrier transport of amyloid β protein: A mechanism for inflammation in the progression of Alzheimer's disease

Alzheimer's disease (AD) brains are characterized by accumulation of amyloid p protein (A beta) and neuro-inflammation. Increased blood-to-brain influx and decreased brain-to-blood efflux across the blood-brain barrier (BBB) have been proposed as mechanisms for A beta accumulation. Epidemiological studies suggest that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the progression of AD. We hypothesized that inflammation alters BBB handling of A beta. Mice treated with lipopolysaccharide (LPS) had increased brain influx and decreased brain efflux of AD, recapitulating the findings in AD. Neither influx nor efflux was mediated by LPS acting directly on BBB cells. Increased influx was mediated by a blood-borne factor, indomethacin-independent, blocked by the triglyceride triolein, and not related to expression of the blood-to-brain transporter of A beta, RAGE. Serum levels of IL-6, IL-10, IL-13, and MCP-1 mirrored changes in A beta influx. Decreased efflux was blocked by indomethacin and accompanied by decreased protein expression of the brain-to-blood transporter of A beta, LRP-1. LPS paradoxically increased expression of neuronal LRP-1, a major source of A beta. Thus, inflammation potentially increases brain levels of A beta by three mechanisms: increased influx, decreased efflux, and increased neuronal production. Published by Elsevier Inc.