期刊
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
卷 68, 期 8, 页码 902-914出版社
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0b013e3181afe475
关键词
Alzheimer disease; Amyloid-beta peptide; Apolipoprotein E; Insulin-degarding enzyme; Neprilysin; Neuron-specific enolase
资金
- Bristol Research into Alzheimer's and Care of the Elderly (BRACE)
- James Tudor Foundation
- MRC [G0900627] Funding Source: UKRI
- Alzheimers Research UK [ART-EG2005B-1] Funding Source: researchfish
- Medical Research Council [G0900627] Funding Source: researchfish
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 front 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.
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