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Distinctive contribution of two additional residues in protein aggregation of Aβ42 and Aβ40 isoforms

최태수|Dongjoon Im
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2024.06|BMB Reports|제57권 제6호|pp. 263-272|DOI https://doi.org/10.5483/BMBRep.2024-0044

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키워드

Alzheimer’s diseaseAmyloid-β precursor proteinBiophysicsNeurodegeneration
주제분류화학

초록

Amyloid-β (Aβ) is one of the amyloidogenic intrinsically disorderedproteins (IDPs) that self-assemble to protein aggregates,incurring cell malfunction and cytotoxicity. While Aβhas been known to regulate multiple physiological functions,such as enhancing synaptic functions, aiding in the recovery ofthe blood-brain barrier/brain injury, and exhibiting tumor suppression/antimicrobial activities, the hydrophobicity of the primarystructure promotes pathological aggregations that are closelyassociated with the onset of Alzheimer’s disease (AD). Aβproteins consist of multiple isoforms with 37-43 amino acid residuesthat are produced by the cleavage of amyloid-β precursorprotein (APP). The hydrolytic products of APP are secretedto the extracellular regions of neuronal cells. Aβ 1-42 (Aβ42)and Aβ 1-40 (Aβ40) are dominant isoforms whose significancein AD pathogenesis has been highlighted in numerous studiesto understand the molecular mechanism and develop AD diagnosisand therapeutic strategies. In this review, we focus onthe differences between Aβ42 and Aβ40 in the molecular mechanismof amyloid aggregations mediated by the two additionalresidues (Ile41 and Ala42) of Aβ42. The current comprehensionof Aβ42 and Aβ40 in AD progression is outlined, togetherwith the structural features of Aβ42/Aβ40 amyloid fibrils,and the aggregation mechanisms of Aβ42/Aβ40. Furthermore,the impact of the heterogeneous distribution of Aβ isoformsduring amyloid aggregations is discussed in the systemmimicking the coexistence of Aβ42 and Aβ40 in human cerebrospinalfluid (CSF) and plasma.

Abstract

Amyloid-β (Aβ) is one of the amyloidogenic intrinsically disorderedproteins (IDPs) that self-assemble to protein aggregates,incurring cell malfunction and cytotoxicity. While Aβhas been known to regulate multiple physiological functions,such as enhancing synaptic functions, aiding in the recovery ofthe blood-brain barrier/brain injury, and exhibiting tumor suppression/antimicrobial activities, the hydrophobicity of the primarystructure promotes pathological aggregations that are closelyassociated with the onset of Alzheimer’s disease (AD). Aβproteins consist of multiple isoforms with 37-43 amino acid residuesthat are produced by the cleavage of amyloid-β precursorprotein (APP). The hydrolytic products of APP are secretedto the extracellular regions of neuronal cells. Aβ 1-42 (Aβ42)and Aβ 1-40 (Aβ40) are dominant isoforms whose significancein AD pathogenesis has been highlighted in numerous studiesto understand the molecular mechanism and develop AD diagnosisand therapeutic strategies. In this review, we focus onthe differences between Aβ42 and Aβ40 in the molecular mechanismof amyloid aggregations mediated by the two additionalresidues (Ile41 and Ala42) of Aβ42. The current comprehensionof Aβ42 and Aβ40 in AD progression is outlined, togetherwith the structural features of Aβ42/Aβ40 amyloid fibrils,and the aggregation mechanisms of Aβ42/Aβ40. Furthermore,the impact of the heterogeneous distribution of Aβ isoformsduring amyloid aggregations is discussed in the systemmimicking the coexistence of Aβ42 and Aβ40 in human cerebrospinalfluid (CSF) and plasma.

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