Inflammatory regulation of amyloid beta transport across the blood-brain barrier: Implications for Alzheimer's disease

Accumulation of amyloid beta peptide (AB) in the brain is thought to be a causative event in Alzheimer's disease (AD). The blood-brain barrier (BBB) expresses the low-density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein (Pgp), which are transporters that facilitate the removal (efflux) of AB from the brain. The neurovascular hypothesis of AD states that dysfunction in AB transport across the BBB contributes to its accumulation in the brain and progression of AD. What initiates this impaired efflux in AD is unknown. Inflammation impairs AB efflux, and increased oxidative damage to LRP-1 has been observed in AD. This led us to postulate that inflammation could be an initiating event in AD, inducing oxidative stress which results in dysfunction of LRP-1 at the BBB and ultimately causes AB accumulation in brain. Our goal was to investigate mechanisms by which inflammation-induced oxidative stress alters AB efflux from the brain. We induced inflammation in CD-1 mice by administering repeated doses of lipopolysaccharide (LPS) intraperiotneally (IP), and some groups were pre-treated with the antioxidant N-acetylcysteine (Nac) IP. To determine effects of treatment on BBB function, we measured protein levels of LRP-1 and Pgp, oxidative damage to LRP-1, and the function of LRP-1 and Pgp at the BBB. To characterize each treatment's systemic effects, expression profiles of cytokines and oxidative markers in the brain and periphery were measured. The major findings from this study were that 1) Nac blocked LPS inhibition of AB efflux through effects on LRP-1 but not Pgp, 2) LPS did not alter the protein levels of LRP-1 or Pgp at the BBB, 3) LPS did not increase the oxidation of BBB LRP-1, 4) Nac blocked LPS-induced oxidative stress in the periphery but not the brain, and 5) Nac inhibited the LPS-induced expression of five cytokines in serum and one in brain Together, these results suggest that systemic inflammation impairs LRP-1 function at the BBB through oxidative stress-dependent mechanisms in the periphery. This may reflect a novel target to prevent accumulation of AB in the brain during inflammation and be useful in the prevention or treatment of AD.