Neprilysin protects neurons against Abeta peptide toxicity.
In recent years, studies have suggested that accumulation of amyloid beta (Abeta) peptide in the brain plays a key role in the development of Alzheimer's disease (AD). The steady-state level of Abeta 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 Abeta 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 Abeta 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 Abeta peptide in vitro. Incubation of hippocampal neuronal cells (HT22) over-expressing NEP with the monomeric from of Abeta peptide decreases the toxicity of Abeta 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 Abeta peptide aggregation in AD brain may protect the neurons from the toxicity effects of Abeta peptide and this promises a great potential target for altering the development of AD.
El-Amouri
Salim S
SS
Department of Molecular and Cellular Biochemistry, Medical University of South Carolina, Charleston, SC 29425, USA.
Zhu
Hong
H
Yu
Jin
J
Gage
Fred H
FH
Verma
Inder M
IM
Kindy
Mark S
MS
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D002460:Cell Line; D005240:Feasibility Studies; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D015260:Neprilysin / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D014161:Transduction, Genetic
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D049452:Green Fluorescent Proteins; D015260:Neprilysin