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The enzyme neprilysin-capable of degrading Aβ42 peptide-is a new player in the Alzheimer's disease mystery. Writing in Neuroscience Letters, Patrick McGeer's group at the University of British Columbia adds critical circumstantial evidence that places neprilysin at the scene of neurodegeneration. Neprilysin (alias neural endopeptidase, EC3.4.24.11, enkephalinase, CD10, or common acute lymphblastic leukemia antigen [CALLA]) cleaves enkephalins, endorphins, substance P, and other small peptides throughout the body. Recent animal data show that when neprilysin is inhibited, amyloid deposits can build up quickly. The suggestion has been made that compromised neprilysin-mediated scavenging of Aβ is important to the final pathology of Alzheimer's.

McGeer and colleagues compared neprilysin mRNA and protein levels in postmortem human brain and other organs of AD and control cases. Within both study groups, the hippocampus and temporal gyrus, areas susceptible to plaques, showed particularly low levels of neprilysin mRNA. Conversely, the caudate and peripheral organs that are resistant to plaque formation had the highest levels of neprilysin mRNA. Compared to controls, neprilysin mRNA levels in AD brains were much lower in hippocampus and midtemporal gyrus, but not in other areas. Similar patterns was found for the protein product.

"If the human brain depends upon neprilysin as the main enzyme to break down Aβ, then the data reported here would help to explain why areas such as the hippocampus and temporal gyrus are highly vulnerable to plaque formation," write the authors. "They would also help to explain why Aβ deposits do not appear in peripheral organs but are confined to restricted regions of the brain."-Hakon Heimer.

Reference:
Yasojima K, Akiyama H, McGeer EG, McGeer PL. Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of beta-amyloid peptide. Neurosci Lett 2001 Jan 12;297:97-100. Abstract

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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.

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References

Paper Citations

  1. . 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.

Further Reading

Papers

  1. . 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.

Primary Papers

  1. . 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.