What is it about?

Early detection and treatment of amyloid progression are critical for intervention to mitigate protein misfolding and aggregation leading to fibrils and plaques in more than 50 degenerative conditions, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, and type II diabetes. Transient soluble oligomers of amyloid (Aβ) protein are alleged as the most toxic species that accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer’s disease (AD). A theranostic approach was employed to image early and disrupt neurotoxic Aβ oligomers in a presymptomatic transgenic mouse model of AD. Positron emission tomography (PET) imaging with novel self-assembled cyclic D,L-α-(aza)peptide nanotube radiotracers detected for the first time early Aβ oligomers in the thalamus prior to spread and aggregation as fibrils in other brain parts. Effectively crossing the blood–brain barrier, therapeutic cyclic D,L-α-(aza)peptides abated deficits in behavior, cognition, memory, and learning in experimental AD animal models.

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Why is it important?

The major cause of dementia, Alzheimer’s disease (AD) affects 5.7 million Americans in the US alone costing $277 billion/year, an onus due to increase over the next 10 years. With the recent approval of monoclonal antibody therapy targeting Aβ and more than 140 drug candidates in ongoing clinical trials worldwide, the battle against this insidious disease has gained new momentum. Inability to detect and target early prefibrillar Aβ aggregates before symptoms of cognitive decline limits however efforts to employ and develop new therapies. Anti-amyloidogenic cyclic (aza)peptides and radiotracer conjugates offer promise for early diagnosis and therapy of AD by enabling timely non-invasive PET imaging and disruption of toxic soluble Aβ oligomers prior to plaque formation in presymptomatic murine models.

Perspectives

Toward novel agents to diagnose early amyloid diseases for improved treatment, radiolabeled cyclic D,L-α-(aza)peptides offer unique potential as PET tracers for presymptomatic examination of the emergence and transformation of Aβ oligomer into plaque. Mitigations of oligomers and plaque formation and deficits in cognition, memory, and learning were achieved in transgenic animal models by early and prolonged treatment with cyclic D,L-α-(aza)peptides. Further studies are underway to refine understanding of cyclic (aza)peptide mode of action and probe benefits of early diagnosis and reduction of toxic oligomer levels to inhibit AD pathology and alleviate symptoms.

Prof. Shai Rahimipour
Bar-Ilan University

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This page is a summary of: Early diagnosis and treatment of Alzheimer’s disease by targeting toxic soluble Aβ oligomers, Proceedings of the National Academy of Sciences, November 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2210766119.
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