title: Neprilysin and insulin-degrading enzyme levels are increased in Alzheimer disease in relation to disease severity.
abstract: Experimental reduction of neprilysin (NEP) or insulin-degrading enzyme (IDE) in vivo exacerbates beta-amyloid accumulation in the brain. The level of these enzymes is reportedly reduced during aging and in postmortem brains of patients with sporadic Alzheimer disease (AD). To distinguish between primary decreases in NEP and IDE activity that might contribute to beta-amyloid accumulation and decreases secondary to neurodegenerative changes in AD, we measured NEP and IDE levels by indirect sandwich ELISA and enzyme activities by immunocapture-based fluorogenic assays in postmortem frontal cortex from patients of different ages and at different pathological stages of AD, as indicated by Braak tangle stage. The ELISA measurements of neuron-specific enolase were used to adjust for neuronal loss. Both unadjusted and neuron-specific enolase-adjusted NEP levels and activity were significantly increased in AD and positively correlated with Braak stage but negatively with age in AD patients. Insulin-degrading enzyme activity was higher in AD than controls; this was significant after adjustment for neuron-specific enolase level; unadjusted IDE protein level was decreased in AD but not after adjustment. Our findings suggest that reduction in NEP and IDE activity is not the primary cause of beta-amyloid accumulation in AD, but rather a late-stage phenomenon secondary to neurodegeneration.
authors.affiliation: Dementia Research Group, Clinical Science at North Bristol, University of Bristol, Frenchay Hospital, Frenchay, Bristol, United Kingdom. scott.miners@bristol.ac.uk
authors.forename: James Scott
authors.initials: JS
authors.lastname: Miners
authors.forename: Shabnam
authors.initials: S
authors.lastname: Baig
authors.forename: Hannah
authors.initials: H
authors.lastname: Tayler
authors.forename: Patrick Gavin
authors.initials: PG
authors.lastname: Kehoe
authors.forename: Seth
authors.initials: S
authors.lastname: Love
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D000704:Analysis of Variance; D053327:Apolipoprotein E4 / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007339:Insulysin / Q000378:metabolism*; D008297:Male; D015260:Neprilysin / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012720:Severity of Illness Index; D013223:Statistics as Topic
chemical_list: D053327:Apolipoprotein E4; D015260:Neprilysin; D007339:Insulysin; D010751:Phosphopyruvate Hydratase