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: Alzheimer's amyloid-β protein precursor (AβPP) can occur in different isoforms, among them AβPP751, which is the most abundant isoform in non-neuronal tissues, and AβPP695, often referred to as the neuronal isoform. However, few isoform-specific roles have been addressed. In the work here described, AβPP isoforms, both endogenous and as cDNA fusions with green fluorescent protein (GFP), were used to permit isoform-specific monitoring in terms of intracellular processing and targeting. Differences were particularly marked in the turnover rates of the immature isoforms, with AβPP751 having a faster turnover rate than AβPP695 (0.8 h and 1.2 h respectively for endogenous proteins and 1.1 h and 2.3 h for transfected proteins). Hence, AβPP751 matures faster. Additionally, AβPP751 responded to both okadaic acid (OA) and phorbol 12-myristate 13-acetate (PMA), as determined by sAβPP production, with PMA inducing a more robust response. For the AβPP695 isoform, however, although PMA produced a strong response, OA failed to elicit such an induction in sAβPP production, implicating isoform specificity in phosphorylation regulated events. In conclusion, it seems that the AβPP695 isoform is processed/metabolized at a slower rate and responds differently to OA when compared to the AβPP751 isoform. The relevance of isoform-specific processing in relation to Alzheimer's disease needs to be further investigated, given the predominance of the AβPP695 isoform in neuronal tissues and isoform-specific alterations in expression levels associated with the pathology.
