Early diagnosis and treatment of Alzheimer's disease by targeting toxic soluble Aβ oligomers

Maram Habashi; Suresh Vutla; Kuldeep Tripathi; Sudipta Senapati; Pradeep S. Chauhan; Anat Haviv-Chesner; Michal Richman; Samia Ait Mohand; Véronique Dumulon-Perreault; Ramakotaiah Mulamreddy; Eitan Okun; Jordan H. Chill; Brigitte Guérin; William D. Lubell; Shai Rahimipour

doi:10.1073/pnas.2210766119

Early diagnosis and treatment of Alzheimer's disease by targeting toxic soluble Aβ oligomers

Maram Habashi, Suresh Vutla, Kuldeep Tripathi, Sudipta Senapati, Pradeep S. Chauhan, Anat Haviv-Chesner, Michal Richman, Samia Ait Mohand, Véronique Dumulon-Perreault, Ramakotaiah Mulamreddy, Eitan Okun, Jordan H. Chill, Brigitte Guérin, William D. Lubell, Shai Rahimipour

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

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, [azaGly⁶]-1 inhibited Aβ aggregation and toxicity at substoichiometric concentrations. High-resolution NMR studies revealed dynamic interactions between [azaGly⁶]-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 ⁶⁴Cu-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 ¹¹C-labeled Pittsburgh compound-B (¹¹C-PIB), which binds specifically fibrillar Aβ plaques, ⁶⁴Cu-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 [azaGly⁶]-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.

Original language	English
Article number	e2210766119
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	119
Issue number	49
DOIs	https://doi.org/10.1073/pnas.2210766119
State	Published - 6 Dec 2022

Bibliographical note

Publisher Copyright:
Copyright © 2022 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

Funding

ACKNOWLEDGMENTS. We would like to thank Jean-François Beaudoin and Otman Sarrhini from the CIMS/CRCHUS for their support in conducting preclinical PET imaging and image data analysis and Dr. Rizwanul Haque from Dr. Oren-Suissa laboratory at the Weizmann Institute of Science for assistance with real-time PCR. The authors acknowledge funding from the MOST-FRQNT-FRQS Collaboration in Biomedical Imaging Research, project # 36701 and 3-14012 entitled “Imaging agents for early assessing amyloid disease pathology”, and from the Fonds de recherche du Québec – Nature et technologies, project # 2021-PR-282135, entitled “Etude des interactions supramoléculaires des feu-illets β pour la détection précoce et la désagrégation des protéines amyloïdes“. S.R. also acknowledges partial funding from the Israel Science Foundation (grant No. 2926/21). We thank the Ministère des Relations internationales et de la Francophonie (MRIF) for supporting the project, “Israel-Quebec consortium on early diagnosis and treatment of Alzheimer’s disease”. We would like to thank Jean-François Beaudoin and Otman Sarrhini from the CIMS/CRCHUS for their support in conducting preclinical PET imaging and image data analysis and Dr. Rizwanul Haque from Dr. Oren-Suissa laboratory at the Weizmann Institute of Science for assistance with real-time PCR. The authors acknowledge funding from the MOST-FRQNT-FRQS Collaboration in Biomedical Imaging Research, project # 36701 and 3-14012 entitled “Imaging agents for early assessing amyloid disease pathology”, and from the Fonds de recherche du Québec - Nature et technologies, project # 2021-PR-282135, entitled “Etude des interactions supramoléculaires des feuillets β pour la détection précoce et la désagrégation des protéines amyloïdes“. S.R. also acknowledges partial funding from the Israel Science Foundation (grant No. 2926/21). We thank the Ministère des Relations internationales et de la Francophonie (MRIF) for supporting the project, “Israel-Quebec consortium on early diagnosis and treatment of Alzheimer's disease”.

Funders	Funder number
CIMS
CRCHUS
MOST-FRQNT-FRQS	3-14012, 36701
Ministère des relations internationales et de la Francophonie
Weizmann Institute of Science
Fonds de recherche du Québec – Nature et technologies	2021-PR-282135
Israel Science Foundation	2926/21

Keywords

Alzheimer's disease
L-α-(aza)peptide
PET imaging
cyclic D
early diagnosis and therapy
soluble Aβ oligomers

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10.1073/pnas.2210766119

Cite this

Habashi, M., Vutla, S., Tripathi, K., Senapati, S., Chauhan, P. S., Haviv-Chesner, A., Richman, M., Mohand, S. A., Dumulon-Perreault, V., Mulamreddy, R., Okun, E., Chill, J. H., Guérin, B., Lubell, W. D., & Rahimipour, S. (2022). Early diagnosis and treatment of Alzheimer's disease by targeting toxic soluble Aβ oligomers. Proceedings of the National Academy of Sciences of the United States of America, 119(49), Article e2210766119. https://doi.org/10.1073/pnas.2210766119

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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, [azaGly6]-1 inhibited Aβ aggregation and toxicity at substoichiometric concentrations. High-resolution NMR studies revealed dynamic interactions between [azaGly6]-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 64Cu-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 11C-labeled Pittsburgh compound-B (11C-PIB), which binds specifically fibrillar Aβ plaques, 64Cu-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 [azaGly6]-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.",

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note = "Publisher Copyright: Copyright {\textcopyright} 2022 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).",

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Habashi, M, Vutla, S, Tripathi, K, Senapati, S, Chauhan, PS, Haviv-Chesner, A, Richman, M, Mohand, SA, Dumulon-Perreault, V, Mulamreddy, R, Okun, E , Chill, JH, Guérin, B, Lubell, WD & Rahimipour, S 2022, 'Early diagnosis and treatment of Alzheimer's disease by targeting toxic soluble Aβ oligomers', Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 49, e2210766119. https://doi.org/10.1073/pnas.2210766119

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AU - Vutla, Suresh

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AU - Senapati, Sudipta

AU - Chauhan, Pradeep S.

AU - Haviv-Chesner, Anat

AU - Richman, Michal

AU - Mohand, Samia Ait

AU - Dumulon-Perreault, Véronique

AU - Mulamreddy, Ramakotaiah

AU - Okun, Eitan

AU - Chill, Jordan H.

AU - Guérin, Brigitte

AU - Lubell, William D.

AU - Rahimipour, Shai

N1 - Publisher Copyright: Copyright © 2022 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

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Early diagnosis and treatment of Alzheimer's disease by targeting toxic soluble Aβ oligomers

Abstract

Bibliographical note

Funding

Keywords

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