Isoform Specific Amyloid-β Protein Precursor Metabolism

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.