Neuronal neprilysin overexpression is associated with attenuation of Abeta-related spatial memory deficit.
Converging evidence links abnormally high brain concentrations of amyloid-beta peptides (Abeta) to the pathology of Alzheimer's disease (AD). Lowering brain Abeta levels, therefore, is a therapeutic strategy for the treatment of AD. Neuronal neprilysin upregulation led to increased degradation of Abeta, reduced the formation of Abeta-plaques and the associated cytopathology, but whether overexpression of neprilysin can improve cognition is unknown. We show that neuronal overexpression of neprilysin improved the Morris water maze memory performance in mice with memory deficits resulting from overexpression of the AD-causing mutated human amyloid precursor protein (APP). This improvement was associated with decreased brain levels of Abeta and with unchanged endoproteolytic processing of APP. These results provide the evidence that lowering of brain Abeta levels by increasing its degradation can improve cognitive functions in vivo, and suggest that increasing the activity of neprilysin in brain may be effective in preventing cognitive decline in AD.
Poirier
Raphael
R
Division of Psychiatry Research, University of Zurich, August Forel-Strasse 1, Zurich 8008, Switzerland.
Wolfer
David P
DP
Welzl
Hans
H
Tracy
Jay
J
Galsworthy
Michael J
MJ
Nitsch
Roger M
RM
Mohajeri
M Hasan
MH
D000544:Alzheimer Disease / Q000150:complications / Q000201:enzymology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000201:enzymology; D003072:Cognition Disorders / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control; D018782:Maze Learning / Q000502:physiology*; D008569:Memory Disorders / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology*; D016037:Single-Blind Method; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015260:Neprilysin