Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin ββ.

Preeti Kumaran Menon, Niina Anneli Koistinen, Kerstin Iverfeldt, Anna-Lena Ström

The Journal of biological chemistry 2019 Nov 22

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of ββ-amyloid (Aββ) peptides. Aββ is a cleavage product of the amyloid precursor protein (APP), and aberrant posttranslational modifications of APP can alter APP processing and increase Aββ generation. In the AD brain, seven different residues, including Ser-675 (APP695 numbering) in the APP cytoplasmic domain has been found to be phosphorylated. Here, we show that expression of a phosphomimetic variant of Ser-675 in APP (APP-S675E), in human neuroblastoma SK-N-AS cells, reduces secretion of the soluble APP ectodomain (sAPPα), even though the total plasma membrane level of APP was unchanged compared with APP levels in cells expressing APPwt or APP-S675A. Moreover, the level of an alternative larger C-terminal fragment (CTF) increased in the APP-S675E cells, whereas the CTF form that was most abundant in cells expressing APPwt or APP-S675A decreased in the APP-S675E cells. Upon siRNA-mediated knockdown of the astacin metalloprotease meprin ββ, the levels of the alternative CTF decreased and the CTF ratio was restored back to APPwt levels. Our findings suggest that APP-Ser-675 phosphorylation alters the balance of APP processing, increasing meprin ββ-mediated and decreasing α-secretase-mediated processing of APP at the plasma membrane. As meprin ββ cleavage of APP has been shown to result in formation of highly aggregation-prone, truncated Aββ2-40/42 peptides, enhanced APP processing by this enzyme could contribute to AD pathology. We propose that it would be of interest to clarify in future studies how APP-Ser-675 phosphorylation promotes meprin ββ-mediated APP cleavage. Copyright © 2019 © 2019 Menon et al. Published by Elsevier Inc. All rights reserved.

Citation

Preeti Kumaran Menon, Niina Anneli Koistinen, Kerstin Iverfeldt, Anna-Lena Ström. Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin ββ. The Journal of biological chemistry. 2019 Nov 22;294(47):17768-17776