Clearance of Extracellular and Cell-Associated Amyloid .BETA. Peptide through Viral Expression of Neprilysin in Primary Neurons.

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Amyloid β peptide (Aβ), the pathogenic agent of Alzheimer's disease (AD), is a physiolog-ical metabolite constantly anabolized and catabolized in the brain. We previously dem-onstrated that neprilysin is the major Aβ-degrading enzyme in rico. To investigate whether or not manipulation of neprilysin activity in the brain would be an effective strategy for regulating Aβ levels, we expressed neprilysin in primary cortical neurons using a Sindbis viral vector and examined the effect on Aβ metabolism. The correspond-ing recombinant protein, expressed in the cell bodies and processes, exhibited thior-phan-sensitive endopeptidase activity, whereas a mutant neprilysin with an amino acid substitution in the active site did not show any such activity. Expression of the wild-type neprilysin, but not the mutant, led to significant decreases in both the Aβ40 and 42 levels in the culture media in a dose-dependent manner. Moreover, neprilysin expres-sion also resulted in reducing cell-associated Aβ, which could be more neurotoxic than extracellular Aβ. These results indicate that the manipulation of neprilysin activity in neurons, the major source of Aβ in the brain, would be a relevant strategy for control-ling the All levels and thus the Aβ-associated pathology in brain tissues.
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