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.
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December 2013
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Research Article|
November 22 2013
Differential contribution of isoaspartate post-translational modifications to the fibrillization and toxic properties of amyloid β and the Asn23 Iowa mutation
Silvia Fossati
;
Silvia Fossati
1
*Department of Pathology, New York University School of Medicine, New York, NY 10016, U.S.A.
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Krysti Todd
;
Krysti Todd
1
*Department of Pathology, New York University School of Medicine, New York, NY 10016, U.S.A.
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Krystal Sotolongo
;
Krystal Sotolongo
*Department of Pathology, New York University School of Medicine, New York, NY 10016, U.S.A.
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Jorge Ghiso
;
Jorge Ghiso
2
*Department of Pathology, New York University School of Medicine, New York, NY 10016, U.S.A.
†Department of Psychiatry, New York University School of Medicine, New York, NY 10016, U.S.A.
2Correspondence may be addressed to either of these authors (email jorge.ghiso@nyumc.org or agueda.rostagno@nyumc.org).
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Agueda Rostagno
Agueda Rostagno
2
*Department of Pathology, New York University School of Medicine, New York, NY 10016, U.S.A.
2Correspondence may be addressed to either of these authors (email jorge.ghiso@nyumc.org or agueda.rostagno@nyumc.org).
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Biochem J (2013) 456 (3): 347–360.
Article history
Received:
May 09 2013
Revision Received:
September 04 2013
Accepted:
September 13 2013
Accepted Manuscript online:
September 13 2013
Citation
Silvia Fossati, Krysti Todd, Krystal Sotolongo, Jorge Ghiso, Agueda Rostagno; Differential contribution of isoaspartate post-translational modifications to the fibrillization and toxic properties of amyloid β and the Asn23 Iowa mutation. Biochem J 15 December 2013; 456 (3): 347–360. doi: https://doi.org/10.1042/BJ20130652
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