Amyloid-β peptide-specific DARPins as a novel class of potential therapeutics for Alzheimer disease (original) (raw)
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Passive immunization with anti-amyloid-beta peptide (Abeta) antibodies is effective in animal models of Alzheimer disease. With the advent of efficient in vitro selection technologies, the novel class of designed ankyrin repeat proteins (DARPins) presents an attractive alternative to the immunoglobulin scaffold. DARPins are small and highly stable proteins with a compact modular architecture ideal for high affinity protein-protein interactions. In this report, we describe the selection, binding profile, and epitope analysis of Abeta-specific DARPins. We further showed their ability to delay Abeta aggregation and prevent Abeta-mediated neurotoxicity in vitro. To demonstrate their therapeutic potential in vivo, mono- and trivalent Abeta-specific DARPins (D23 and 3xD23) were infused intracerebroventricularly into the brains of 11-month-old Tg2576 mice over 4 weeks. Both D23 and 3xD23 treatments were shown to result in improved cognitive performance and reduced soluble Abeta levels. These findings demonstrate the therapeutic potential of Abeta-specific DARPins for the treatment of Alzheimer disease.
Progress toward Alzheimer's disease treatment: Leveraging the Achilles' heel of Aβ oligomers?
Protein Science, 2020
After three decades of false hopes and failures, a pipeline of therapeutic drugs that target the actual root cause of Alzheimer's disease (AD) is now available. Challenging the old paradigm that focused on β‐amyloid peptide (Aβ) aggregation in amyloid plaques, these compounds are designed to prevent the neurotoxicity of Aβ oligomers that form Ca2+ permeable pores in the membranes of brain cells. By triggering an intracellular Ca2+ overdose, Aβ oligomers induce a cascade of neurotoxic events including oxidative stress, tau hyperphosphorylation, and neuronal loss. Targeting any post‐Ca2+ entry steps (e.g., tau) will not address the root cause of the disease. Thus, preventing Aβ oligomers formation and/or blocking their toxicity is by essence the best approach to stop any progression of AD. Three categories of anti‐oligomer compounds are already available: antibodies, synthetic peptides, and small drugs. Independent in silico‐based designs of a peptide (AmyP53) and a monoclonal ant...
Journal of Alzheimer's disease : JAD, 2012
The amyloid-β lowering capacity of anti-Aβ antibodies has been demonstrated in transgenic models of Alzheimer's disease (AD) and in AD patients. While the mechanism of immunotherapeutic amyloid-β removal is controversial, antibody-mediated sequestration of peripheral Aβ versus microglial phagocytic activity and disassembly of cerebral amyloid (or a combination thereof) has been proposed. For successful Aβ immunotherapy, we hypothesized that high affinity antibody binding to amyloid-β plaques and recruitment of brain effector cells is required for most efficient amyloid clearance. Here we report the generation of a novel fully human anti-Aβ antibody, gantenerumab, optimized in vitro for binding with sub-nanomolar affinity to a conformational epitope expressed on amyloid-β fibrils using HuCAL(®) phage display technologies. In peptide maps, both N-terminal and central portions of Aβ were recognized by gantenerumab. Remarkably, a novel orientation of N-terminal Aβ bound to the compl...
An in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer's disease
Nature communications, 2018
Although the amyloid β-protein (Aβ) is believed to play an initiating role in Alzheimer's disease (AD), the molecular characteristics of the key pathogenic Aβ forms are not well understood. As a result, it has proved difficult to identify optimal agents that target disease-relevant forms of Aβ. Here, we combined the use of Aβ-rich aqueous extracts of brain samples from AD patients as a source of human Aβ and live-cell imaging of iPSC-derived human neurons to develop a bioassay capable of quantifying the relative protective effects of multiple anti-Aβ antibodies. We report the characterization of 1C22, an aggregate-preferring murine anti-Aβ antibody, which better protects against forms of Aβ oligomers that are toxic to neurites than do the murine precursors of the clinical immunotherapeutics, bapineuzumab and solanezumab. These results suggest further examination of 1C22 is warranted, and that this bioassay maybe useful as a primary screen to identify yet more potent anti-Aβ ther...
2021
Improvements have been made in the diagnosis of Alzheimer’s disease (AD), manifesting mostly in the development of in vivo imaging methods that allow for the detection of pathological changes in AD by MRI and PET scans. Many of these imaging methods, however, use agents that probe amyloid fibrils and plaques - species that do not correlate well with disease progression and are not present at the earliest stages of the disease. Amyloid β oligomers (AβOs), rather, are now widely accepted as the Aβ species most germane to AD onset and progression. Here we report evidence further supporting the role of AβOs as pathological instigators of AD and introduce promising anti-AβO diagnostic probes capable of distinguishing the 5xFAD mouse model from wild type mice by PET and MRI. In a developmental study, Aβ oligomers in 5xFAD mice were found to appear at 3 months of age, just prior to the onset of memory dysfunction, and spread as memory worsened. The increase of AβOs is prominent in the subi...
2020
Alzheimer’s disease is the most common irreversible neurodegenerative disorder. To date, there is no cure for Alzheimer’s disease. While multiple pathological mechanisms have been proposed for the onset and progression of Alzheimer’s disease, the hypothesis that attracted much attention is the amyloid hypothesis. The senile plaques that accumulate in the brain of Alzheimer’s disease patients are predominantly composed of beta amyloid (Aβ). Aβ deposition in the brain is thought to occur years before the emergence of clinical symptoms. The overproduction, aggregation, and fibrillation of Aβ, combined with reduced clearance, eventually lead to amyloid plaque formation and subsequent neurotoxicity. Hence, inhibition of Aβ aggregation and the promotion of Aβ clearance have been actively explored as therapeutic strategies for Alzheimer’s disease. This chapter provides an overview of the current knowledge on one such strategy, Aβ-targeted inhibitory peptides.
Scientific Reports, 2020
Bicyclic peptides have great therapeutic potential since they can bridge the gap between small molecules and antibodies by combining a low molecular weight of about 2 kDa with an antibody-like binding specificity. Here we apply a recently developed in silico rational design strategy to produce a bicyclic peptide to target the C-terminal region (residues 31–42) of the 42-residue form of the amyloid β peptide (Aβ42), a protein fragment whose aggregation into amyloid plaques is linked with Alzheimer’s disease. We show that this bicyclic peptide is able to remodel the aggregation process of Aβ42 in vitro and to reduce its associated toxicity in vivo in a C. elegans worm model expressing Aβ42. These results provide an initial example of a computational approach to design bicyclic peptides to target specific epitopes on disordered proteins.
2021
The primary pathological hallmarks of Alzheimer's disease are extracellular amyloid plaques and intraneuronal tangles of hyperphosphorylated tau (Masters et al., 1985). It is well known, however, that amyloid plaques do not correlate well with cognitive decline in AD (Terry et al., 1991; Hsia et al., 1999) and are not present in the earliest stages of the disease (Nyborg et al., 2013). Research from the previous two decades strongly indicates that soluble AβOs, not plaques, are the more appropriate amyloid beta species to target in AD (Ashe, 2020; Hampel et al., 2021). Amyloid β oligomers are potent neurotoxins that show ADdependent accumulation in the brain of AD patients (