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J Neurosci. 2009 Feb 18;29(7):1977-86. doi: 10.1523/JNEUROSCI.2984-08.2009.

Neprilysin overexpression inhibits plaque formation but fails to reduce pathogenic Abeta oligomers and associated cognitive deficits in human amyloid precursor protein transgenic mice.

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  • 1Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.

Abstract

The accumulation of amyloid-beta (Abeta) peptides in the brain of patients with Alzheimer's disease (AD) may arise from an imbalance between Abeta production and clearance. Overexpression of the Abeta-degrading enzyme neprilysin in brains of human amyloid precursor protein (hAPP) transgenic mice decreases overall Abeta levels and amyloid plaque burdens. Because AD-related synaptic and cognitive deficits appear to be more closely related to Abeta oligomers than to plaques, it is important to determine whether increased neprilysin activity also diminishes the levels of pathogenic Abeta oligomers and related neuronal deficits in vivo. To address this question, we crossed hAPP transgenic mice with neprilysin transgenic mice and analyzed their offspring. Neprilysin overexpression reduced soluble Abeta levels by 50% and effectively prevented early Abeta deposition in the neocortex and hippocampus. However, it did not reduce levels of Abeta trimers and Abeta*56 or improve deficits in spatial learning and memory. The differential effect of neprilysin on plaques and oligomers suggests that neprilysin-dependent degradation of Abeta affects plaques more than oligomers and that these structures may form through distinct assembly mechanisms. Neprilysin's inability to prevent learning and memory deficits in hAPP mice may be related to its inability to reduce pathogenic Abeta oligomers. Reduction of Abeta oligomers will likely be required for anti-Abeta treatments to improve cognitive functions.

PMID:
19228952
[PubMed - indexed for MEDLINE]
PMCID:
PMC2768427
Free PMC Article
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