Mutations in the Amyloid-ß Protein Precursor Reduce Mitochondrial Function and Alter Gene Expression Independent of 42-Residue Amyloid-ß Peptide.

ABSTRACT

BACKGROUND: Dominant missense mutations in the amyloid-ß protein precursor (AßPP) cause early-onset familial Alzheimer's disease (FAD) and are associated with changes in the production or properties of the amyloid-ß peptide (Aß), particularly of the 42-residue variant (Aß42) that deposits in the Alzheimer's disease (AD) brain. Recent findings, however, show that FAD mutations in AßPP also lead to increased production of longer Aß variants of 45-49 residues in length. OBJECTIVE: We aimed to test neurotoxicity of Aß42 vis-á-vis longer variants, focusing specifically on mitochondrial function, as dysfunctional mitochondria are implicated in the pathogenesis of AD. METHODS: We generated SH-SY5Y human neuroblastoma cells stably expressing AßPP mutations that lead to increased production of long Aß peptides with or without Aß42. These AßPP-expressing cells were tested for oxygen consumption rates (OCR) under different conditions designed to interrogate mitochondrial function. These cell lines were also examined for expression of genes important for mitochondrial or neuronal structure and function. RESULTS: The mutant AßPP-expressing cells showed decreased basal OCRs as well as decreased OCRs associated with mitochondrial ATP production, even more so in the absence of Aß42 production. Moreover, mutant AßPP-expressing cells producing longer forms of Aß displayed altered expression of certain mitochondrial- and neuronal-associated genes, whether or not Aß42 was produced. CONCLUSION: These findings suggest that mutant AßPP can cause mitochondrial dysfunction that is associated with long Aß but not with Aß42.