title: Isoform specific amyloid-beta protein precursor metabolism.
abstract: Alzheimer's amyloid-beta protein precursor (AbetaPP) can occur in different isoforms, among them AbetaPP(751), which is the most abundant isoform in non-neuronal tissues, and AbetaPP(695), often referred to as the neuronal isoform. However, few isoform-specific roles have been addressed. In the work here described, AbetaPP 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 AbetaPP(751) having a faster turnover rate than AbetaPP(695) (0.8 h and 1.2 h respectively for endogenous proteins and 1.1 h and 2.3 h for transfected proteins). Hence, AbetaPP(751) matures faster. Additionally, AbetaPP(751) responded to both okadaic acid (OA) and phorbol 12-myristate 13-acetate (PMA), as determined by sAbetaPP production, with PMA inducing a more robust response. For the AbetaPP(695) isoform, however, although PMA produced a strong response, OA failed to elicit such an induction in sAbetaPP production, implicating isoform specificity in phosphorylation regulated events. In conclusion, it seems that the AbetaPP(695) isoform is processed/metabolized at a slower rate and responds differently to OA when compared to the AbetaPP(751) isoform. The relevance of isoform-specific processing in relation to Alzheimer's disease needs to be further investigated, given the predominance of the AbetaPP(695) isoform in neuronal tissues and isoform-specific alterations in expression levels associated with the pathology.
authors.affiliation: Laboratório de Neurociências, Centro de Biologia Celular, Universidade de Aveiro, Aveiro, Portugal.
authors.forename: Ana Gabriela
authors.initials: AG
authors.lastname: Henriques
authors.forename: Sandra Isabel
authors.initials: SI
authors.lastname: Vieira
authors.forename: Sandra
authors.initials: S
authors.lastname: Rebelo
authors.forename: Sara C T S
authors.initials: SC
authors.lastname: Domingues
authors.forename: Edgar F
authors.initials: EF
authors.lastname: da Cruz e Silva
authors.forename: Odete A B
authors.initials: OA
authors.lastname: da Cruz e Silva
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D018076:DNA, Complementary; D020033:Protein Isoforms