In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 49 ( 2022-12-06)
Abstract:
Transient soluble oligomers of amyloid-β (Aβ) are toxic and accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer’s disease (AD). Synthetic cyclic D,L-α-peptides (e.g., 1 ) self-assemble into cross β-sheet nanotubes, react with early Aβ species (1-3 mers), and inhibit Aβ aggregation and toxicity in stoichiometric concentrations, in vitro. Employing a semicarbazide as an aza-glycine residue with an extra hydrogen-bond donor to tune nanotube assembly and amyloid engagement, [azaGly 6 ]- 1 inhibited Aβ aggregation and toxicity at substoichiometric concentrations. High-resolution NMR studies revealed dynamic interactions between [azaGly 6 ]- 1 and Aβ42 residues F19 and F20, which are pivotal for early dimerization and aggregation. In an AD mouse model, brain positron emission tomography (PET) imaging using stable 64 Cu-labeled (aza)peptide tracers gave unprecedented early amyloid detection in 44-d presymptomatic animals. No tracer accumulation was detected in the cortex and hippocampus of 44-d-old 5xFAD mice; instead, intense PET signal was observed in the thalamus, from where Aβ oligomers may spread to other brain parts with disease progression. Compared with standard 11 C-labeled Pittsburgh compound-B ( 11 C-PIB), which binds specifically fibrillar Aβ plaques, 64 Cu-labeled (aza)peptide gave superior contrast and uptake in young mouse brain correlating with Aβ oligomer levels. Effectively crossing the blood–brain barrier (BBB), peptide 1 and [azaGly 6 ]- 1 reduced Aβ oligomer levels, prolonged lifespan of AD transgenic Caenorhabditis elegans , and abated memory and behavioral deficits in nematode and murine AD models. Cyclic (aza)peptides offer novel promise for early AD diagnosis and therapy.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.2210766119
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2022
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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