Presenilin 1 deficiency impairs A beta 42-to-A beta 40-and angiotensin-converting activities of ACE

Introduction: Alzheimer's disease (AD) is associated with amyloid beta-protein 1-42 (A beta 42) accumulation in the brain. A beta 42 and A beta 40 are the major two species generated from amyloid precursor protein. We found that angiotensin-converting enzyme (ACE) converts neurotoxic A beta 42 to neuroprotective A beta 40 in an ACE domain- and glycosylation-dependent manner. Presenilin 1 (PS1) mutations account for most of cases of familial AD and lead to an increased A beta 42/40 ratio. However, the mechanism by which PSEN1 mutations induce a higher A beta 42/40 ratio is unclear.Methods: We over expressed human ACE in mouse wild-type and PS1-deficient fibroblasts. The purified ACE protein was used to analysis the A beta 42-to-A beta 40- and angiotensin-converting activities. The distribution of ACE was determined by Immunofluorescence staining.Result: We found that ACE purified from PS1-deficient fibroblasts exhibited altered glycosylation and significantly reduced A beta 42-to-A beta 40- and angiotensin-converting activities compared with ACE from wild-type fibroblasts. Overexpression of wild-type PS1 in PS1-deficient fibroblasts restored the A beta 42-to-A beta 40- and angiotensin-converting activities of ACE. Interestingly, PS1 mutants completely restored the angiotensin-converting activity in PS1-deficient fibroblasts, but some PS1 mutants did not restore the A beta 42-to-A beta 40-converting activity. We also found that the glycosylation of ACE in adult mouse brain differed from that of embryonic brain and that the A beta 42-to-A beta 40-converting activity in adult mouse brain was lower than that in embryonic brain.Conclusion: PS1 deficiency altered ACE glycosylation and impaired its A beta 42-to-A beta 40- and angiotensin-converting activities. Our findings suggest that PS1 deficiency and PSEN1 mutations increase the A beta 42/40 ratio by reducing the A beta 42-to-A beta 40-converting activity of ACE.