. Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of beta-amyloid peptide. Neurosci Lett. 2001 Jan 12;297(2):97-100. PubMed.

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  1. Saido's team (Iwata et al.) infused labeled Aβ1-42 into rat hippocampus and found it was metabolized with a half-life of 39 minutes. They tried many classes of peptide inhibitors and found that neprilysin type were the only ones that prevented the breakdown. They then infused one inhibitor (thiorphan) into normal rat brain and produced rat amyloid deposits in 30 days. (That beats transgenic models.) We followed this up in our Neuroscience Letters paper (12 Jan 2001;297:97-100). We found low levels of neprilysin in plaque prone areas such as the hippocampus and temporal cortex, and high neprilysin levels in areas such as the striatum, cerebellum and peripheral organs, which never or rarely ever develop plaques. Moreover, we found Alzheimer patients had significantly lower neprilysin levels than normals in vulnerable areas.

    Neprilysin is a membrane-bound enzyme highly expressed on axons and nerve endings of peptide-expressing neurons. Our data help explain why plaques only appear in certain brain areas, and probably why they only begin to appear in older people when transmitter-associated enzymes begin to wane. They suggest that there should be a major focus on the breakdown of A-beta since it should be metabolized within a few minutes of formation. The data also suggest that there may be a locus on chromosome 3 at the neprilysin site where polymorphisms might affect the expression and thus vulnerability to AD. They also suggest that insulin-degrading enzyme must play only a minor role since it does not compensate for thiorphan blockade of neprilysin in rats and does not show the same correlations with plaquedevelopment in humans.

    References:

    . Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med. 2000 Feb;6(2):143-50. PubMed.

    View all comments by Pat McGeer

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