Expression and functional profiling of neprilysin, insulin‐degrading enzyme, and endothelin‐converting enzyme in prospectively studied elderly and Alzheimer’s brain

Abstract

J. Neurochem. (2010) 115, 47–57. Abstract The brain steady state level of β‐amyloid (Aβ) is determined by the balance between its production and removal, the latter through egress across blood and CSF barriers as well as Aβ degradation. The major Aβ‐degrading enzymes are neprilysin (NEP), insulin‐degrading enzyme (IDE), and endothelin‐converting enzyme (ECE‐1). Although evidence suggests that NEP is down‐regulated in Alzheimer’s disease (AD), the role of IDE and ECE in the Aβ accumulation in aging and dementia remains less certain. In this study, we examined mRNA and protein expression, as well as biological activity of NEP, IDE, and ECE‐1 in human frontal cortex by real‐time RT‐PCR for mRNA, immunoblotting for protein, and highly sensitive and specific fluorescence assays for activity. The relationships between Aβ‐degrading enzymes and pathologic measures and clinical features were also assessed. The results showed that NEP mRNA, protein level, and activity were decreased in AD compared with normal controls with no cognitive impairment (NCI). In contrast, IDE activity was unchanged, but there was higher expression of IDE mRNA, indicating a possible compensatory reaction because of deficits in activity. ECE‐1 expression in AD brain showed no significant difference compared with age‐matched controls. Correlation analyses suggested that NEP expression was correlated with Aβ accumulation and clinical diagnosis, being lower in AD than in no cognitive impairment. In contrast, neither IDE nor ECE‐1 correlated with Aβ or clinical diagnosis. These findings provide additional support for NEP as the major protease involved in Aβ degradation and suggest its possible therapeutic targeting in AD.

Population differences in microRNA expression and biological implications

“…The expression of this gene product has been linked to non-small cell lung cancer, 35 diabetic nephropathy 36 and Alzheimer disease. 37 When we limited our analysis to differentially expressed mRNAs, we identified several miRNA-mRNA pairs that were inversely correlated in both CEU and YRI and have previously been implicated in studies of disease susceptibility: miR-342-3p and ANKRD49, miR-30b, d and e and ZNRF1. For example, miR-342-3p has been shown to be upregulated in neurodegenerative disease.…”

Transcriptional Regulation of Insulin-degrading Enzyme Modulates Mitochondrial Amyloid β (Aβ) Peptide Catabolism and Functionality

“…By using in vitro degradation assays with synthetic peptides as substrates, significantly lower activity of hPreP isolated from temporal lobes of the brains of AD cases and of transgenic mice as models of AD was recently reported (10), suggesting a crucial role of PreP in the clearance of mitochondrial A␤ (mitA␤) (11). In regard to expression and activity of cytosolic IDE in AD brains, there are still controversies with reports showing decrements (12)(13)(14)(15), increments (16,17), or no changes (18,19). It has been proposed that part of the loss of IDE and PreP activities in AD brain may be due to oxidative damage to which both proteases are highly sensitive (7,20).…”

Genistein, the Isoflavone in Soybean, Causes Amyloid Beta Peptide Accumulation in Human Neuroblastoma Cell Line: Implications in Alzheimer's Disease

“…The decreased levels of Aβ42 degrading enzyme IDE and neprilysin after genistein treatment of SHSY5Y cells are also likely to exacerbate the intracellular accumulation of the toxic peptide. There are several degrading enzymes for Aβ42, but neprilysin and IDE are particularly important in regulating Aβ42 load of the brain [29,30,31]. Thus, the combined effect of genistein on APP, β-secretase, IDE and neprilysin has resulted in the accumulation of Aβ42 in SHSY5Y cells (Fig.…”