Age-dependent decline of neprilysin in Alzheimerʹs disease and normal brain: Inverse correlation with Aβ levels

Brain deposition of amyloid-β (Aβ) is a pathological hallmark of Alzheimer disease (AD) but Aβ is also detected in non-demented elderly individuals. Neprilysin has been shown to be an important enzyme to degrade Aβ in brain. We investigated whether decreased neprilysin levels contributes to the accumulation of Aβ in AD and in normal aging. No difference in neprilysin protein and mRNA levels were found between AD subjects and age-matched controls. Protein levels of neprilysin were reduced with age in the temporal and frontal cortex of AD and normal brain. A significant positive correlation between insoluble Aβ 40 and Aβ 42 with age was found in cortex of normal brain whereas in AD brain the correlation between age and Aβ was weaker. Our findings of an inverse correlation between neprilysin and insoluble Aβ levels in both groups suggest that neprilysin is involved in the clearance of Aβ. The observed age-dependent decline in neprilysin may be related to the increased Aβ levels during normal aging. The similar rate of decline in neprilysin with age may not be the major cause of the high levels of Aβ associated with AD but is likely to be a trigger of AD pathology.