Long-term neprilysin gene transfer is associated with reduced levels of intracellular Abeta and behavioral improvement in APP transgenic mice

We show that the sustained expression of neprilysin for up to 6 months lowered not only the amyloid plaque load but also reduced the levels of intracellular Aβ immunoreactivity. This was associated with improved behavioral performance in the water maze and ameliorated the dendritic and synaptic pathology in the APP transgenic mice.These data support the possibility that long-term neprilysin gene therapy improves behavioral and neurodegenerative pathology by reducing intracellular Aβ.Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting the elderly and is the most common form of dementia [1]. Synaptic pathology is an early indicator of neurodegeneration in the brains of patients with AD [2-4] and in amyloid precursor protein (APP) transgenic (tg) mice [5]. Damage to the nerve terminals is strongly correlated with the severity of the cognitive impairment in patients with AD [2-4]. A key mediator of this disease is believed to be the accumulation of amyloid-β (Aβ) peptides, produced by proteolytic processing of the APP, in the central nervous system [6]. Most recent studies indicate that Aβ oligomers rather than fibrils are responsible for the synaptic pathology in AD [7-9] and other lines of investigation also support a role for intraneuronal accumulation of Aβ in neurodegeneration [10-13].Extracellular and intracellular accumulation of Aβ peptides might result from alterations in the balance between production, aggregation and degradation [14]. Mutations in the APP and presenillin-1 (PS1) genes have been found to be associated with familial/heritable forms of early-onset AD by increasing the production of Aβ peptides, which has greatly added to our understanding of potential mechanisms leading to aberrant anabolism of Aβ [15-19]. However, the mechanisms of catabolism and clearance of Aβ are less well understood. Endopeptidases, which directly degrade Aβ, have emerged as important players in the homeostatic control of this peptide. Neprilysin