Neprilysin protects neurons against Aβ peptide toxicity

In recent years, studies have suggested that accumulation of amyloid beta (A beta) peptide in the brain plays a key role in the development of Alzheimer's disease (AD). The steady-state level of A beta peptide in the brain is determined by the rate of production from amyloid precursor protein (APP) via beta- and gamma-secretases and degradation by the activity of several enzymes. Neprilysin (NEP) appears to be the most potent A beta peptide-degrading enzyme in the brain. Decreasing the activity of NEP (due to genetic mutations, age or diseases that alter the expression or activity of NEP) may lead to accumulation of the neurotoxic A beta peptide in the brain; in turn this leads to neuronal loss. We investigated the efficacy of lentivirus-mediated over-expression of NEP to protect neuronal cells from A beta peptide in vitro. Incubation of hippocampal neuronal cells (HT22) over-expressing NEP with the monomeric from of A beta peptide decreases the toxicity of A beta peptide on the neuronal cells, as measured through cell viability. We conclude that over-expression of NEP by a gene therapy approach in areas vulnerable to A beta peptide aggregation in AD brain may protect the neurons from the toxicity effects of A beta peptide and this promises a great potential target for altering the development of AD. (c) 2007 Elsevier B.V. All rights reserved.