Our findings indicate that ACE-1 activity is increased in AD, in direct relationship to parenchymal Abeta load. Increased ACE-1, probably of neuronal origin, accumulates perivascularly in severe CAA and colocalizes with vascular ECM. The possible relationship of ACE-1 to the deposition of perivascular ECM remains to be determined.

Neprilysin (NEP) degrades amyloid-beta (Abeta) and is thought to contribute to its clearance from the brain. In Alzheimer disease (AD), downregulation of NEP has been suggested to contribute to the development of cerebral amyloid angiopathy (CAA). We examined the relationship among NEP, CAA, and APOE status in AD and elderly control cases. NEP was most abundant in the tunica media of cerebrocortical blood vessels and in pyramidal neurons. In homogenates of the frontal cortex, NEP protein levels were reduced in AD but not significantly; NEP enzymatic activity was significantly reduced in AD. Immunohistochemistry revealed a reduction of both vascular and parenchymal NEP. The loss of vessel-associated NEP in AD was inversely related to the severity of CAA, and analysis of cases with severe CAA showed that levels of vascular NEP were reduced to the same extent in Abeta-free and Abeta-laden vessels, strongly suggesting that the reduction in NEP is not simply secondary to CAA. Possession of APOE epsilon4 was associated with significantly lower levels of both parenchymal and vascular NEP. Colinearity of epsilon4 with the presence of moderate to severe CAA precluded assessment of the independence of this association from NEP levels. However, logistic regression analysis showed low NEP levels to be a significant independent predictor of moderate to severe CAA.

We recently found that insoluble Abeta increases, but soluble Abeta decreases with age in normal brains. We now report the changes in activities of beta-secretase (BACE-1) and Abeta-degrading enzymes with age, and their relationships to concentrations of soluble and insoluble Abeta. We measured BACE-1 activity and the levels and activities of neprilysin (NEP), insulin-degrading enzyme (IDE) and angiotensin-converting enzyme (ACE) in normal control brains (16 years-95 years). We also compared the measurements to those in AD. BACE-1 activity correlated closely with age in controls and was significantly higher in AD. In controls, NEP and IDE activities (but not protein levels) increased with age but ACE activity and level did not. BACE-1 activity correlated directly with insoluble but inversely with soluble Abeta. IDE activity correlated directly with insoluble Abeta and NEP activity was inversely related to soluble Abeta. ACE level correlated directly with insoluble and inversely with soluble Abeta in controls but not AD. Both Abeta-synthesizing and -degrading enzyme activities increase with age, coinciding with declining soluble Abeta and increasing insoluble Abeta. Further research is needed to establish whether these changes in enzyme activity and Abeta levels are causally related and if so how.