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

초록

Amyloid-D D (AD) D ) is one of the amyloidogenic intrinsically disordered proteins (IDPs) that self-assemble to protein aggregates, incurring cell malfunction and cytotoxicity. While AD D has been known to regulate multiple physiological functions, such as enhancing synaptic functions, aiding in the recovery of the blood-brain barrier/brain injury, and exhibiting tumor suppression/antimicrobial activities, the hydrophobicity of the primary structure promotes pathological aggregations that are closely associated with the onset of Alzheimer's disease (AD). AD D proteins consist of multiple isoforms with 37-43 amino acid residues that are produced by the cleavage of amyloid-Dprecur- D precur- sor protein (APP). The hydrolytic products of APP are secreted to the extracellular regions of neuronal cells. AD D 1-42 (AD42) D 42) and AD D 1-40 (AD40) D 40) are dominant isoforms whose significance in AD pathogenesis has been highlighted in numerous studies to understand the molecular mechanism and develop AD diagnosis and therapeutic strategies. In this review, we focus on the differences between AD42 D 42 and AD40 D 40 in the molecular mechanism of amyloid aggregations mediated by the two additional residues (Ile41 and Ala42) of AD42. D 42. The current comprehension of AD42 D 42 and AD40 D 40 in AD progression is outlined, together with the structural features of AD42/AD40 D 42/A D 40 amyloid fibrils, and the aggregation mechanisms of AD42/AD40. D 42/A D 40. Furthermore, the impact of the heterogeneous distribution of AD D isoforms during amyloid aggregations is discussed in the system mimicking the coexistence of AD42 D 42 and AD40 D 40 in human cerebrospinal fluid (CSF) and plasma. [BMB Reports 2024; 57(6): 263-272]

키워드