Presenilin 1 deficiency impairs Aβ42-to-Aβ40- and angiotensin-converting activities of ACE.

Alzheimer's disease (AD) is associated with amyloid β-protein 1-42 (Aβ42) accumulation in the brain. Aβ42 and Aβ40 are the major two species generated from amyloid precursor protein. We found that angiotensin-converting enzyme (ACE) converts neurotoxic Aβ42 to neuroprotective Aβ40 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 Aβ42/40 ratio. However, the mechanism by which We over expressed human ACE in mouse wild-type and PS1-deficient fibroblasts. The purified ACE protein was used to analysis the Aβ42-to-Aβ40- and angiotensin-converting activities. The distribution of ACE was determined by Immunofluorescence staining. We found that ACE purified from PS1-deficient fibroblasts exhibited altered glycosylation and significantly reduced Aβ42-to-Aβ40- and angiotensin-converting activities compared with ACE from wild-type fibroblasts. Overexpression of wild-type PS1 in PS1-deficient fibroblasts restored the Aβ42-to-Aβ40- 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 Aβ42-to-Aβ40-converting activity. We also found that the glycosylation of ACE in adult mouse brain differed from that of embryonic brain and that the Aβ42-to-Aβ40-converting activity in adult mouse brain was lower than that in embryonic brain. PS1 deficiency altered ACE glycosylation and impaired its Aβ42-to-Aβ40- and angiotensin-converting activities. Our findings suggest that PS1 deficiency and

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Copyright © 2023 Gao, Sun, Islam, Nakamura, Tomita, Zou and Michikawa.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.