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 contribution||Accumulation of insoluble amyloid-β in down's syndrome is associated with increased BACE-1 and neprilysin activities|
|Pages (from-to)||101 - 108|
|Number of pages||8|
|Journal||Journal of Alzheimer's Disease|
|Early online date||7 Oct 2010|
|Publication status||Published - Jan 2011|