Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases

• 成果类型: Article
• 署名作者: Johnson, Elizabeth A.; Nowar, Raghad; Viola, Kirsten L.; Huang, Weijian; Zhou, Sihang; Bicca, Maira A.; Zhu, Wei; Kranz, Daniel L.; Klein, William L.; Silverman, Richard B.
• 署名单位: Northwestern University; Northwestern University; Northwestern University; Northwestern University; Northwestern University; Northwestern University; Northwestern University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11989
• DOI: 10.1073/pnas.2402117122
• 发表日期: 2025-03-11
• 关键词: sod1-dependent protein aggregation; alzheimers-disease; cathepsin-b; cyclohexane 1; 3-diones; cultured neurons; common variants; senile plaques; toxicity; peptide; memory

摘要

Protein aggregation is a hallmark of neurodegenerative diseases, which connects these neuropathologies by a common phenotype. Various proteins and peptides form aggregates that are poorly degraded, and their ensuing pathological accumulation underlies these neurodegenerative diseases. Similarities may exist in the mechanisms responsible for the buildup of these aggregates. Therefore, therapeutics designed to treat one neurodegenerative disease may be beneficial to others. In ALS models, the compound NU-9 was previously shown to block neurodegeneration produced by aggregation-inducing mutations of SOD-1 and TDP-43 [B. Gen & ccedil; et al., Glin. Transl. Med. 11, e336 (2021)]. Here, we report that NU-9 also prevents the accumulation of amyloid beta oligomers (Af3Os), small peptide aggregates that are instigators of Alzheimer's disease neurodegeneration [M. Tolar et al., Int. J. Mol. Sci. 22, 6355 (2021)]. Af3O buildup was measured by immunofluorescence imaging of cultured hippocampal neurons exposed to exogenous monomeric Af3. In this model, Af3O buildup occurs via cathepsin L-and dynamin-dependent trafficking. This is prevented by NU-9 through a cellular mechanism that is cathepsin B-and lysosome-dependent, suggesting that NU-9 enhances the ability of endolysosomal trafficking to protect against Af3O buildup. This possibility is strongly supported by a quantitative assay for autophagosomes that shows robust stimulation by NU-9. These results contribute additional understanding to the mechanisms of protein aggregation and suggest that multiple neurodegenerative diseases might be treatable by targeting common pathogenic mechanisms responsible for protein aggregation.