NABi, a novel β-sheet breaker, inhibits Aβ aggregation and neuronal toxicity: Therapeutic implications for Alzheimer's disease

• Published in: Biochimica et biophysica acta. General subjects Vol. 1862; no. 1; pp. 71 - 80
• Main Authors: Jang, Ja-Young, Rhim, Hyangshuk, Kang, Seongman
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2018
• Subjects: Alzheimer disease; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; amyloid; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Animals; cell death; Cell Line, Tumor; cytotoxicity; Humans; Mice; neurodegenerative diseases; neurons; Neurons - metabolism; Neurons - pathology; pathogenesis; Protein Aggregation, Pathological - drug therapy; Protein Aggregation, Pathological - metabolism; Protein Aggregation, Pathological - pathology; Protein Structure, Secondary; superoxide dismutase; Superoxide Dismutase - antagonists & inhibitors; Superoxide Dismutase - metabolism
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2017.10.014

Amyloid beta (Aβ) aggregates are an important therapeutic target for Alzheimer's disease (AD), a fatal neurodegenerative disease. To date, AD still remains a big challenge due to no effective treatments. Based on the property that Aβ aggregates have the cross-β-structure, a common structural feature in amyloids, we systemically designed the Aβ-aggregation inhibitor that maintains Aβ-interacting ability but removes toxic part from SOD1 (superoxide dismutase 1)-G93A. We identified NABi (Natural Aβ Binder and Aβ-aggregation inhibitor) composed of β2–3 strands, a novel breaker of Aβ aggregation, which does not self-aggregate and has no cytotoxicity at all. The NABi blocks Aβ-fibril formation in vitro and in vivo and prevents neuronal cell death, a hallmark of AD pathogenesis. Such anti-amyloidogenic properties can provide novel strategies for treating AD. Furthermore, our study provides molecular insights into the design of amyloidogenic inhibitors to cure various neurodegenerative and amyloid-associated diseases, as NABi would regulate aggregation of other toxic β-sheet proteins other than Aβ. •Identification of NABi (Natural Aβ Binder and Aβ-aggregation inhibitor)•ΝABi specifically and strongly interacts with Aβ.•NABi is a novel inhibitor of Aβ-aggregation.•NABi prevents Aβ aggregate-induced neurodegeneration.•Implications for a potential AD therapeutic agent to block the neurodegeneration