Accumulation of insoluble amyloid-β in down's syndrome is associated with increased BACE-1 and neprilysin activities

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Abstract

We previously reported age- and Alzheimer’s disease (AD)-related increases in the activities of-secretase (BACE-1) and A-degrading enzymes including neprilysin (NEP) and angiotensin-converting enzyme (ACE) in the frontal cortex. We suggested that these increases were secondary to the accumulation of insoluble amyloid- (A) and a decline in soluble A.We have further tested this hypothesis by examination of frontal cortex obtained postmortem from individuals with Down’s syndrome (DS), in whom AD-like neuropathological changes occur in association with early-onset dementia. We measured total soluble and insoluble (guanidine-extractable) A, BACE-1 activity, and the concentrations and activities of NEP and ACE in two independent DS cohorts: an initial, Bristol cohort (9 DS cases, 8 controls matched for age-at-death) and a validation Newcastle cohort (20 DS, 18 controls with a wider spectrum of age-at-death). In both cohorts the level of insoluble (but not soluble) Awas significantly higher in DS than controls and was comparable to previously measured levels in AD. NEP protein concentration and activity were significantly increased in DS; a trend towards increased BACE-1 activity was observed in DS but did not reach statistical significance. Both NEP and BACE-1 correlated with the level of insoluble A. The concentration of ACE in DS was elevated in the pilot cohort only and ACE activity was unchanged. These findings provide strong support that BACE-1 and NEP activities, but not ACE, increase in response to the accumulation of insoluble A within the brain.
Translated title of the contributionAccumulation of insoluble amyloid-β in down's syndrome is associated with increased BACE-1 and neprilysin activities
Original languageEnglish
Pages (from-to)101 - 108
Number of pages8
JournalJournal of Alzheimer's Disease
Volume23
Issue number1
Early online date7 Oct 2010
DOIs
Publication statusPublished - Jan 2011

Bibliographical note

Publisher: IOS Press

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