%0 Journal Article
%T Long-term neprilysin gene transfer is associated with reduced levels of intracellular Abeta and behavioral improvement in APP transgenic mice
%A Brian Spencer
%A Robert A Marr
%A Edward Rockenstein
%A Leslie Crews
%A Anthony Adame
%A Rewati Potkar
%A Christina Patrick
%A Fred H Gage
%A Inder M Verma
%A Eliezer Masliah
%J BMC Neuroscience
%D 2008
%I BioMed Central
%R 10.1186/1471-2202-9-109
%X 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 A¦Â 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 A¦Â.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-¦Â (A¦Â) peptides, produced by proteolytic processing of the APP, in the central nervous system [6]. Most recent studies indicate that A¦Â 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 A¦Â in neurodegeneration [10-13].Extracellular and intracellular accumulation of A¦Â 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 A¦Â peptides, which has greatly added to our understanding of potential mechanisms leading to aberrant anabolism of A¦Â [15-19]. However, the mechanisms of catabolism and clearance of A¦Â are less well understood. Endopeptidases, which directly degrade A¦Â, have emerged as important players in the homeostatic control of this peptide. Neprilysin
%U http://www.biomedcentral.com/1471-2202/9/109