Clearing the brain of amyloid peptides

December 12, 2000

Although the synthesis and pathological role of amyloid peptides are matters of great interest and controversy, the opposing process of amyloid clearance from the brain has received far less attention. Derived from the amyloid precursor protein, the amyloid b1-40 peptide is found in soluble form in the interstitial fluid of the brain, as well as in plaques that form in the brains of individuals with Alzheimer's disease (AD). This peptide also interacts with numerous cell surface proteins, such as the LDL receptor-related proteins LRP-1 and -2, and with secreted proteins such as apolipoprotein E. Here, Shibata et al. analyze the kinetics of efflux of this peptide by injecting it in radiolabeled form into the brains of mice. They show that the peptide is cleared from the central nervous system primarily by vascular transport and that the peptide is not degraded by local proteinases but remains stable until it crosses the blood-brain barrier. This vascular transport is significantly less efficient in older mice, suggesting a possible explanation of the age-dependence of AD. The authors also show that interfering with LRP-1 partially blocks the efflux of the peptide, and they suggest that the downregulation of this receptor could account for both the timing and the tissue localization of amyloid in AD patients. Shibata and coworkers have also tested the efflux of amyloid b1-40 peptide in ApoE-deficient mice. Their finding that amyloid clearance is diminished in these mice suggests a previously unsuspected role for ApoE in this disease pathway, distinct from its putative role in amyloidogenesis. If confirmed, this finding could complicate the interpretation of genetic variation in ApoE and its relevance to the risk of AD.
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JCI Journals

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