Gene therapy for Alzheimer's disease by viral vector-mediated neprilysin, an Aβ-degrading enzyme, gene transfer

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Accumulation of amyloid-β peptide (Aβ) in the brain is a triggering event leading to the pathological cascade of Alzheimer's disease (AD). It is necessary for therapy and prevention of AD to treat a great backlog of Aβ clearance. Neprilysin is a rate-limiting peptidase, which participates in Aβ degradation in brain. As demonstrated by reverse genetics, the disruption of neprilysin gene causes elevation of the endogenous Aβ levels in mouse brain in a gene-close-dependent manner. Therefore, reduction of neprilysin activity will contribute to Aβ deposition and thus to AD development. Recent evidence that expression levels of neprilysin were reduced in the hippocampus of sporadic AD patients and aged laboratory mice suggests a close association of neprilysin with the etiology and pathogenesis of AD. We attempted to express neprilysin, an Aβ-degrading enzyme, in the hippocampal formation of mice in vivo by recombinant adeno-associated virus-mediated gene transfer. Neprilysin expressed by th … More e gene transfer was axonally transported to presynaptic sites through afferent projections of neuronal circuits. This gene transfer abolished the increase in Aβ levels in the hippocampal formations of neprilysin-deficient mice, and also reduced the increase in young mutant amyloid precursor protein (APP) transgenic mice. In the latter case, Aβ levels in the hippocampal formation contralateral to the vector-injected side were also significantly reduced as a result of transport of neprilysin from the ipsilateral side. Furthermore, amyloid deposition in aged mutant APP transgenic mice was remarkably decelerated. These results indicate that presynaptic localization of neprilysin contributes to efficient and extensive clearance of Aβ and protects synapses from synaptic toxicity by Aβ, and that Lip-regulation of neprilysin activity would be a promising strategy for therapy and prevention of AD. In addition, these results suggest that gene therapy to directly introduce an Aβ-degradler into the brain may have potential as a treatment for AD. Less