(229g) Modulation Effect of Acidulated Human Serum Albumin on Cu2+-Mediated Amyloid β-Protein Aggregation and Cytotoxicity

Alzheimer’s disease (AD), a prevalent neurodegenerative disease, is characterized by dysfunction of memory. The main histofpathological hallmark of AD is senile plaques formed by amyloid β-proteins (Aβ) in the hippocampus and cortex. In addition, elevated levels of metal ions in plaques, mainly Cu²⁺ and Zn²⁺, indicate that they play a crucial role in Aβ aggregation in vivo. It has been proven that metal ions not only induce the generation of off-pathway Aβ aggregates but also lead to the formation of reactive oxygen species (ROS), which are harmful for nerve cells. Cerebral acidosis is another common complication of AD. Under mildly acidic conditions, Cu²⁺-Aβ species have a higher tendency to generate neurotoxic aggregates. In this work, we fabricated acidulated human serum albumin (A-HSA) to mitigate Cu²⁺-mediated Aβ₄₂ aggregation and cytotoxicity at pH 6.6. Extensive experiments showed that A-HSA could alter the pathway of Cu²⁺-mediated Aβ₄₂ aggregation and protect SH-SY5Y cells from cytotoxicity and oxidative damage induced by Cu²⁺-Aβ₄₂species. Noticeably, stopped-flow fluorescence analysis revealed that A-HSA changed the Cu²⁺-Aβ₄₂ coordination mode from complex I to complex II on the millisecond timescale, which avoided the formation of aggregation-prone Cu²⁺-Aβ₄₂ aggregates. Based on the findings, we proposed a mechanism of the modulation effect of A-HSA on inhibiting Cu²⁺-mediated Aβ₄₂ aggregation and cytotoxicity under the mildly acidic condition.