Summary: Researchers report a theranostic approach that can detect and neutralize the earliest, preclinical signs of Alzheimer’s disease. Their method targets toxic soluble amyloid-β oligomers, offering potential to halt Alzheimer’s pathology before irreversible neuronal damage occurs.
Source: Bar-Ilan University
Alzheimer’s disease affected more than 55 million people worldwide in 2020, and that number is projected to rise substantially over coming decades. The global economic burden of dementia already exceeds $1.3 trillion annually and is expected to increase sharply by 2030.
Most drugs developed to date have failed because they focus on the wrong targets and are given after symptoms have appeared. By the time cognitive symptoms emerge, many neurons responsible for memory and cognition are already damaged and beyond repair. To address this challenge, Professor Shai Rahimipour and his team at Bar-Ilan University have developed a theranostic strategy designed to both detect and treat Alzheimer’s at its earliest, pre-symptomatic stages.
Alzheimer’s-related pathology begins when the small protein amyloid-β (Aβ) misfolds into intermediate assemblies that can grow into fibrils and insoluble plaques. For decades researchers targeted these visible plaques, investing heavily in molecules and antibodies to prevent plaque formation. Those efforts largely failed and often produced unacceptable side effects. Over time, the field concluded that plaques themselves are less toxic than earlier, soluble intermediates called oligomers, which now are widely considered the primary neurotoxic species in Alzheimer’s disease.
Recent antibody therapies that target oligomers have shown promise and led to regulatory approvals, but efficacy remains debated and adverse events such as microhemorrhages and brain swelling highlight the need for safer, more effective options. A key limitation of many antibody-based therapies is poor penetration across the blood–brain barrier (BBB), which restricts delivery of large proteins to the brain.
To overcome these barriers, Rahimipour’s group designed small, drug-like cyclic peptides that are abiotic—synthetic and non-immunogenic—and able to reach the brain more effectively than antibodies. In vitro, these cyclic peptides bind early Aβ species and completely blocked the formation of oligomers when mixed with amyloid-β, preventing further aggregation.
When human neurons were exposed to toxic Aβ oligomers together with the cyclic peptides, most cells survived. By contrast, neurons exposed to oligomers without the peptides experienced severe damage and cell death. These cell studies demonstrated the peptides’ protective effect against oligomer-induced toxicity.
The team then tested the peptides in animal models. In transgenic Caenorhabditis elegans engineered to develop Alzheimer’s-like symptoms, feeding the worms cyclic peptides dramatically increased lifespan and prevented disease manifestations by stopping the formation of early toxic oligomers. This suggests aggregation can be halted at very early stages, even before oligomers form.
To evaluate diagnosis and treatment in mammals, the researchers labeled the cyclic peptides with a radioisotope and used positron emission tomography (PET) imaging in transgenic mice. Remarkably, the radiolabeled peptides detected early Aβ oligomers in the thalamus of pre-symptomatic animals—before oligomers had spread to other regions and long before fibrils, plaques, or behavioral symptoms appeared. Compared with traditional PET tracers that bind fibrillar plaques, the (aza)peptide tracer provided superior contrast for early oligomeric species.
Following early detection, the pre-symptomatic mice received treatment with the cyclic peptides and were monitored over time for cognitive performance and brain oligomer levels. Molecular imaging showed that treated animals did not develop substantial oligomer burdens and showed no signs of Alzheimer’s-related deficits. The peptides cross the BBB effectively, are not immunogenic, and persist longer in the body than antibodies—potentially reducing dosing frequency. No toxicity was observed in these experimental models.
Professor Rahimipour’s research, published in Proceedings of the National Academy of Sciences (PNAS) and conducted in collaboration with researchers at Université de Sherbrooke and Université de Montréal, supports the use of cyclic (aza)peptides as both diagnostic tracers and early-stage therapeutics. The team is now advancing these molecules toward preclinical development and eventual clinical trials focused on early Alzheimer’s diagnosis and intervention.
About this Alzheimer’s disease research news
Author: Elana Oberlander
Source: Bar-Ilan University
Contact: Elana Oberlander – Bar-Ilan University
Image: The image is in the public domain
Original Research: Open access.
“Early diagnosis and treatment of Alzheimer’s disease by targeting toxic soluble Aβ oligomers” by Shai Rahimipour et al. PNAS
Abstract
Early diagnosis and treatment of Alzheimer’s disease by targeting toxic soluble Aβ oligomers
Transient soluble oligomers of amyloid-β (Aβ) are neurotoxic and accumulate early, before insoluble plaque formation and cognitive decline in Alzheimer’s disease (AD). The study introduces synthetic cyclic D,L-α-peptides (for example, peptide 1) that self-assemble into cross β-sheet nanotubes, react with early Aβ species (monomers to trimers), and inhibit Aβ aggregation and toxicity in vitro at stoichiometric concentrations.
By incorporating a semicarbazide as an aza-glycine residue to enhance hydrogen bonding, the modified peptide [azaGly6]-1 inhibits Aβ aggregation and toxicity at substoichiometric levels. High-resolution NMR showed dynamic binding between [azaGly6]-1 and Aβ42 residues F19 and F20, which are key to early dimerization and aggregation.
In an AD mouse model, PET imaging with stable 64Cu-labeled (aza)peptide tracers enabled unprecedented early detection of amyloid species in 44-day-old presymptomatic animals. Instead of cortical or hippocampal accumulation, intense PET signal appeared in the thalamus, a region that may serve as an initial hub from which Aβ oligomers spread.
Compared with the standard 11C-labeled Pittsburgh compound-B (PIB), which preferentially binds fibrillar plaques, the 64Cu-labeled (aza)peptide delivered superior contrast and correlated with oligomer levels in young brains. Peptide 1 and [azaGly6]-1 cross the blood–brain barrier effectively, lower Aβ oligomer levels, extend lifespan in AD transgenic C. elegans, and reduce memory and behavioral deficits in nematode and mouse models. These cyclic (aza)peptides therefore represent a promising new avenue for early Alzheimer’s diagnosis and therapy.