title: Differential contribution of isoaspartate post-translational modifications to the fibrillization and toxic properties of amyloid β and the Asn23 Iowa mutation.
abstract: Mutations within the Aβ (amyloid β) peptide, especially those clustered at residues 21-23, are linked to early-onset AD (Alzheimer's disease) and primarily associated with cerebral amyloid angiopathy. The Iowa variant, a substitution of an aspartic acid residue for asparagine at position 23 (D23N), associates with widespread vascular amyloid and abundant diffuse pre-amyloid lesions significantly exceeding the incidence of mature plaques. Brain Iowa deposits consist primarily of a mixture of mutated and non-mutated Aβ species exhibiting partial aspartate isomerization at positions 1, 7 and 23. The present study analysed the contribution of the post-translational modification and the D23N mutation to the aggregation/fibrillization and cell toxicity properties of Aβ providing insight into the elicited cell death mechanisms. The induction of apoptosis by the different Aβ species correlated with their oligomerization/fibrillization propensity and β-sheet content. Although cell toxicity was primarily driven by the D23N mutation, all Aβ isoforms tested were capable, albeit at different time frames, of eliciting comparable apoptotic pathways with mitochondrial engagement and cytochrome c release to the cytoplasm in both neuronal and microvascular endothelial cells. Methazolamide, a cytochrome c release inhibitor, exerted a protective effect in both cell types, suggesting that pharmacological targeting of mitochondria may constitute a viable therapeutic avenue.
authors.affiliation: *Department of Pathology, New York University School of Medicine, New York, NY 10016, U.S.A.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fossati
authors.forename: Krysti
authors.initials: K
authors.lastname: Todd
authors.forename: Krystal
authors.initials: K
authors.lastname: Sotolongo
authors.forename: Jorge
authors.initials: J
authors.lastname: Ghiso
authors.forename: Agueda
authors.initials: A
authors.lastname: Rostagno
mesh_terms: D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D006801:Humans; D026581:Isoaspartic Acid / Q000235:genetics / Q000378:metabolism*; D008704:Methazolamide / Q000494:pharmacology; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D002257:Carbonic Anhydrase Inhibitors; D026581:Isoaspartic Acid; D045304:Cytochromes c; D008704:Methazolamide
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