Neprilysin Overexpression Inhibits Plaque Formation But Fails to Reduce Pathogenic Aβ Oligomers and Associated Cognitive Deficits in Human Amyloid Precursor Protein Transgenic Mice

The accumulation of amyloid-beta (A beta) peptides in the brain of patients with Alzheimer's disease (AD) may arise from an imbalance between A beta production and clearance. Overexpression of the A beta-degrading enzyme neprilysin in brains of human amyloid precursor protein (hAPP) transgenic mice decreases overall A beta levels and amyloid plaque burdens. Because AD-related synaptic and cognitive deficits appear to be more closely related to A beta oligomers than to plaques, it is important to determine whether increased neprilysin activity also diminishes the levels of pathogenic A beta 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 A beta levels by 50% and effectively prevented early A beta deposition in the neocortex and hippocampus. However, it did not reduce levels of A beta trimers and A beta*56 or improve deficits in spatial learning and memory. The differential effect of neprilysin on plaques and oligomers suggests that neprilysin-dependent degradation of A beta 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 A beta oligomers. Reduction of A beta oligomers will likely be required for anti-A beta treatments to improve cognitive functions.