Conformation-specific antibodies to target amyloid β oligomers and their application to immunotherapy for Alzheimer’s disease

Murakami, Kazuma

doi:10.1080/09168451.2014.940275

Cited by 39 publications

(29 citation statements)

References 146 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Remarkably, the details of antibody binding seem to hinder Aβ aggregation and promote disaggregation in two ways. First, the antibody occludes half of the “hydrophobic core” sequence responsible for self-association and oligomerization5, residues Leu17 Aβ –Ala21 Aβ . Second, the hairpin turn is disrupted.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Structure of Crenezumab Complex with Aβ Shows Loss of β-Hairpin

Ultsch¹,

Li²,

Maurer³

et al. 2016

Sci Rep

109

View full text Add to dashboard Cite

Accumulation of amyloid-β (Aβ) peptides and amyloid plaque deposition in brain is postulated as a cause of Alzheimer’s disease (AD). The precise pathological species of Aβ remains elusive although evidence suggests soluble oligomers may be primarily responsible for neurotoxicity. Crenezumab is a humanized anti-Aβ monoclonal IgG4 that binds multiple forms of Aβ, with higher affinity for aggregated forms, and that blocks Aβ aggregation, and promotes disaggregation. To understand the structural basis for this binding profile and activity, we determined the crystal structure of crenezumab in complex with Aβ. The structure reveals a sequential epitope and conformational requirements for epitope recognition, which include a subtle but critical element that is likely the basis for crenezumab’s versatile binding profile. We find interactions consistent with high affinity for multiple forms of Aβ, particularly oligomers. Of note, crenezumab also sequesters the hydrophobic core of Aβ and breaks an essential salt-bridge characteristic of the β-hairpin conformation, eliminating features characteristic of the basic organization in Aβ oligomers and fibrils, and explains crenezumab’s inhibition of aggregation and promotion of disaggregation. These insights highlight crenezumab’s unique mechanism of action, particularly regarding Aβ oligomers, and provide a strong rationale for the evaluation of crenezumab as a potential AD therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

“…The accumulation and aggregation of Aβ peptides in brain takes many forms in addition to plaques, including soluble monomers and oligomers, and insoluble fibrils, with a large range of molecular weights from 10 to 1,000 KDa (see review ref. 5). In vitro and ex vivo evidence suggests that soluble oligomers, i.e.…”

mentioning

confidence: 99%

Structure of Crenezumab Complex with Aβ Shows Loss of β-Hairpin

Ultsch¹,

Li²,

Maurer³

et al. 2016

Sci Rep

109

View full text Add to dashboard Cite

show abstract

“…The value of AβOs as targets for immunotherapy and the status of clinical candidates have been recently reviewed [49, 124]. Although a caveat has suggested that antibodies bound to AβOs might activate microglia and potentiate AβO neurotoxicity [120], such toxicity is not in harmony with numerous reports of neuroprotection [49].…”

Section: Therapeuticsmentioning

confidence: 99%

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis

2015

View full text Add to dashboard Cite

Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson’s and Alzheimer’s. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble Aβ oligomers (AβOs), toxins now widely regarded as instigating neuron damage leading to Alzheimer’s dementia. Toxic AβOs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. Key experiments using fibril-free AβO solutions demonstrated that while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent. The AD-like cellular pathologies induced by AβOs suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of AβOs into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. AβO binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca2+ overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of AβOs have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of AβOs has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic AβOs appear early in the disease, they offer appealing targets for therapeutics and diagnostics. Promising therapeutic strategies include use of CNS insulin signaling enhancers to protect against the presence of toxins and elimination of the toxins through use of highly specific AβO antibodies. An AD-dependent accumulation of AβOs in CSF suggests their potential use as biomarkers and new AβO probes are opening the door to brain imaging. Overall, current evidence indicates that Aβ oligomers provide a substantive molecular basis for the cause, treatment and diagnosis of Alzheimer’s disease.

show abstract

“…Low concentrations of soluble oligomers and the lack of localized high concentrations of such small assemblies impede imaging applications. The wealth of non-overlapping, oligomer-specific monoclonal antibodies (Kayed, et al, 2010, Liu, et al, 2015, Murakami, 2014) indicates that multiple conformational states with different properties of these biologically potent assemblies exist and await ligand development.…”

Section: Probes Of Early Assembly Stages Of Misfolded Protein Patmentioning

confidence: 99%

What amyloid ligands can tell us about molecular polymorphism and disease

LeVine

Walker

2016

Neurobiology of Aging

View full text Add to dashboard Cite

Brain-penetrant PET imaging ligands selective for amyloid pathology in living subjects have sparked a revolution in presymptomatic biomarkers for Alzheimer’s disease progression. As additional chemical structures were investigated, the heterogeneity of ligand binding sites became apparent, as did discrepancies in binding of some ligands between human disease and animal models. These differences and their implications have received little attention. This review discusses the impact of different ligand binding sites and misfolded protein conformational polymorphism on the interpretation of imaging data acquired with different ligands. Investigation of the differences in binding in animal models may identify pathological processes informing improvements to these models for more faithful recapitulation of this uniquely human disease. The differential selectivity for binding of particular ligands to different conformational states could potentially be harnessed to better define disease progression and improve the prediction of clinical outcomes.

show abstract

Conformation-specific antibodies to target amyloid β oligomers and their application to immunotherapy for Alzheimer’s disease

Cited by 39 publications

References 146 publications

Structure of Crenezumab Complex with Aβ Shows Loss of β-Hairpin

Structure of Crenezumab Complex with Aβ Shows Loss of β-Hairpin

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis

What amyloid ligands can tell us about molecular polymorphism and disease

Contact Info

Product

Resources

About