| First Author | Gao Y | Year | 2023 |
| Journal | Front Aging Neurosci | Volume | 15 |
| Pages | 1098034 | PubMed ID | 36875692 |
| Mgi Jnum | J:333985 | Mgi Id | MGI:7443357 |
| Doi | 10.3389/fnagi.2023.1098034 | Citation | Gao Y, et al. (2023) Presenilin 1 deficiency impairs Abeta42-to-Abeta40- and angiotensin-converting activities of ACE. Front Aging Neurosci 15:1098034 |
| abstractText | INTRODUCTION: Alzheimer's disease (AD) is associated with amyloid beta-protein 1-42 (Abeta42) accumulation in the brain. Abeta42 and Abeta40 are the major two species generated from amyloid precursor protein. We found that angiotensin-converting enzyme (ACE) converts neurotoxic Abeta42 to neuroprotective Abeta40 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 Abeta42/40 ratio. However, the mechanism by which PSEN1 mutations induce a higher Abeta42/40 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 Abeta42-to-Abeta40- 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 Abeta42-to-Abeta40- and angiotensin-converting activities compared with ACE from wild-type fibroblasts. Overexpression of wild-type PS1 in PS1-deficient fibroblasts restored the Abeta42-to-Abeta40- 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 Abeta42-to-Abeta40-converting activity. We also found that the glycosylation of ACE in adult mouse brain differed from that of embryonic brain and that the Abeta42-to-Abeta40-converting activity in adult mouse brain was lower than that in embryonic brain. CONCLUSION: PS1 deficiency altered ACE glycosylation and impaired its Abeta42-to-Abeta40- and angiotensin-converting activities. Our findings suggest that PS1 deficiency and PSEN1 mutations increase the Abeta42/40 ratio by reducing the Abeta42-to-Abeta40-converting activity of ACE. |
