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

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 Aβ4–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 Aβ4–x remains unexplored. Here, we report the distinct aggregation behavior of N-terminally truncated Aβ, specifically Aβ4–42, in the absence and presence of either Zn(II), Aβ seeds, or both, and compare it to that of full-length Aβ1–42. Our findings reveal notable differences in the aggregation profiles of Aβ4–42 and Aβ1–42, 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.