Amyloid Against Amyloid: Dimeric Amyloid Fragment Ameliorates Cognitive Impairments by Direct Clearance of Oligomers and Plaques
Hee Yang Lee, Seungyeop Baek, Minhae Cha, Seung‐Hoon Yang, YoungSoo Kim- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Amyloid‐β (Aβ) in the form of neurotoxic aggregates is regarded as the main pathological initiator and key therapeutic target of Alzheimer’s disease. However, anti‐Aβ drug development has been impeded by the lack of a target needed for structure‐based drug design and low permeability of the blood–brain barrier (BBB). An attractive therapeutic strategy is the development of amyloid‐based anti‐Aβ peptidomimetics that exploit the self‐assembling nature of Aβ and penetrate the BBB.
Method
Herein, we designed a dimeric peptide drug candidate based on the N‐terminal fragment of Aβ, DAB. In vitro assays were performed to verify the dissociating ability of DAB against Aβ(1‐42) aggregation. The therapeutic efficacy of DAB against Aβ was evaluated in the 5XFAD, a transgenic AD mouse model with aggressive amyloid accumulation. Following that, peptide mapping assays and molecular docking studies were utilized to elucidate DAB‐Aβ interaction, and we assessed the dissociative activity of DAB with sequence modifications to further understand active regions of DAB.
Result
Through in vitro assay we found that DAB solubilizes both neurotoxic Aβ(1‐42) oligomers and fibrils to monomeric states. Administration of DAB reduced amyloid burden in 5XFAD mice, and down‐regulated neuroinflammation and prevented memory impairment in the Y‐maze test. In peptide mapping assays, DAB was shown to bind and dissociate Aβ aggregates in a manner distinct to the Aβ(1‐17) fragment.
Conclusion
Overall, we designed a dimeric Aβ(1‐17)‐based peptide drug and demonstrated that DAB can solubilize aggregates of Aβ and has therapeutic potential as a structural basis for anti‐amyloid peptide drugs.