Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo.
Accumulation of the beta-amyloid peptide (Abeta) in the brain is a major pathological hallmark of Alzheimer's disease (AD), leading to synaptic dysfunction, neuronal death, and memory impairment. The levels of neprilysin, a major Abeta-degrading enzyme, are decreased in AD brains and during aging. Because neprilysin cleaves Abeta in vivo, its down-regulation may contribute to the pathophysiology of AD. The aim of this study was to assess the consequences of neprilysin deficiency on accumulation of murine Abeta in brains and associated pathologies in vivo by investigating neprilysin-deficient mice on biochemical, morphological, and behavioral levels. Aged neprilysin-deficient mice expressed physiological amyloid precursor protein (APP) levels and exhibited elevated brain Abeta concentrations and amyloid-like deposits in addition to signs of neuronal degeneration in their brains. Behaviorally, neprilysin-deficient mice acquired a significantly weaker conditioned taste aversion that extinguished faster than the aversion of age-matched controls. Our data establish that, under physiological APP expression levels, neprilysin deficiency is associated with increased Abeta accumulation in the brain and leads to deposition of amyloid-like structures in vivo as well as with signs of AD-like pathology and with behavioral deficits.
Madani
Rime
R
Institute of Anatomy, University of Zurich, Zurich, Switzerland.
Poirier
Raphael
R
Wolfer
David P
DP
Welzl
Hans
H
Groscurth
Peter
P
Lipp
Hans-Peter
HP
Lu
Bao
B
El Mouedden
Mohammed
M
Mercken
Marc
M
Nitsch
Roger M
RM
Mohajeri
M Hasan
MH
D000367:Age Factors; D000682:Amyloid / Q000378:metabolism* / Q000648:ultrastructure; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D003216:Conditioning, Operant / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D015260:Neprilysin / Q000172:deficiency*; D014868:Water Deprivation / Q000502:physiology
D000682:Amyloid; D015260:Neprilysin