Distinct Aggregation Behavior of N-Terminally Truncated Aβ4-42 Over Aβ1-42 in the Presence of Zn(II).

Abstract

The deposition of amyloid-β (Aβ) aggregates and metal ions within senile plaques is a hallmark of Alzheimer's disease (AD). Among the modifications observed in Aβ peptides, N-terminal truncation at Phe4, yielding Aβ_4-x, is highly prevalent in AD-affected brains and significantly alters Aβ's metal-binding and aggregation profiles. Despite the abundance of Zn(II) in senile plaques, its impact on the aggregation and toxicity of Aβ_4-x remains unexplored. Here, we report the distinct aggregation behavior of N-terminally truncated Aβ, specifically Aβ_4-42, in the absence and presence of either Zn(II), Aβ seeds, or both, and compare it to that of full-length Aβ_1-42. Our findings reveal notable differences in the aggregation profiles of Aβ_4-42 and Aβ_1-42, largely influenced by their different Zn(II)-binding properties. These results provide insights into the mechanisms underlying the distinct aggregation behavior of truncated and full-length Aβ in the presence of Zn(II), contributing to a deeper understanding of AD pathology.