Affiliations: [a] Laboratório de Neurociências, Centro de Biologia Celular, Universidade de Aveiro, Aveiro, Portugal | [b] Laboratório de Transdução de Sinais, Centro de Biologia Celular, Universidade de Aveiro, Aveiro, Portugal
Correspondence:
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Corresponding author: Odete A.B. da Cruz e Silva, Laboratório de Neurociências, Centro de Biologia Celular, Universidade de Aveiro, 3810-193 Aveiro, Portugal. Tel.: +351 234 370 778; Fax: +351 234 426 408; E-mail: [email protected].
Abstract: Production of the amyloid β (Aβ) peptide via altered metabolism of the amyloid β-Protein Precursor (AβPP) appears to be a key event in the pathology of Alzheimer Disease (AD). Accordingly, altered processing of AβPP was observed under conditions of abnormal cellular stress induced by sodium azide in the presence of 2-deoxy-D-glucose (2DG). As previously reported, the production of sAβPP (the secreted fragment of AβPP) was inhibited. However, our data further suggests that 2DG alone can account for most of the observed effects on AβPP processing in COS-1 cells and PC12 cells. It appears that 2DG interferes with the normal glycosylation of AβPP and its maturation process, having direct consequences on sAβPP production. Interestingly, PMA (phorbol 12-myristate 13-acetate)-induced sAβPP production was maintained under the stress conditions used, suggesting that potential non-amyloidogenic AβPP processing can still be favoured. This is of potential therapeutic interest, since it indicates that even under adverse stress conditions drugs such as PMA can affect AβPP processing, leading to increased sAβPP production and a concomitant reduction in Aβ production. However, the induction of sAβPP production was not identical when the phosphatase inhibitor OA (okadaic acid) was used. In fact, the typical OA-induced increase in sAβPP production could be abolished under specific conditions. This constitutes an interesting precedent for the possible dissociation of the PMA and OA responses in terms of sAβPP production. The involvement of protein phosphatases, which are inhibited by OA, in AβPP processing, was reinforced by the increased co-localization of AβPP and PP1α (protein phosphatase 1α) at the cell surface upon exposure to OA and PMA. Overall, our results support the notion that signal transduction processes may be of particular relevance for our understanding of the molecular basis of AD, and for the design of rational signal transduction therapeutics.
Keywords: stress, phorbol ester, PP1, protein phosphatase 1
