Accumulation of Insoluble Amyloid-beta in Down's Syndrome is Associated with Increased BACE-1 and Neprilysin Activities

作者：Miners James Scott^*; Morris Sean; Love Seth; Kehoe Patrick Gavin

来源：Journal of Alzheimer's Disease, 2011, 23(1): 101-108.

DOI：10.3233/JAD-2010-101395

• Alzheimer's disease
• amyloid-beta
• angiotensin-converting enzyme
• beta-secretase
• Down's syndrome
• neprilysin

We previously reported age-and Alzheimer's disease (AD)-related increases in the activities of beta-secretase (BACE-1) and A beta-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-beta (A beta) and a decline in soluble A beta. 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 beta, 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) A beta was 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 beta. 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 beta within the brain.

• 出版日期2011