Molecular basis for mid-region amyloid-β capture by leading Alzheimer's disease immunotherapies

Crespi, Gabriela A. N.; Hermans, S.J.; Parker, Michael W.; Miles, Luke A.

doi:10.1038/srep09649

Cited by 82 publications

(85 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Despite certain sequence homology in their respective CDRs (Figure S4), they exhibited vastly different specificity for various oligomeric forms of Aβ. This long-standing puzzle was unresolved even after examining the published crystal structure of the solanezumab/Aβ complex25. Here, we present a key finding by comparing the two structures.…”

Section: Discussionmentioning

confidence: 87%

“…Coarse epitope classification of the antibodies does not correlate with their binding profiles. Not surprisingly, high-resolution X-ray crystal structures of antibody/Aβ complexes reported in recent years have revealed diverse epitopes2122232425. It is also important to understand the Aβ peptide structure, especially in aggregates, where Aβ oligomerization can produce various products2627282930.…”

mentioning

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: 87%

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

“…Detailed structural studies of how different antibodies interact with specific epitopes in the Aβ molecule are now underway [101] and help inform antibody design and epitope-targeting in the future. An alternative method of improving the clearance of toxic misfolded species is to harness endogenous mechanisms of protein clearance into the extracellular space.…”

Section: Therapeutic Targetsmentioning

confidence: 99%

Protein misfolding in neurodegenerative diseases: implications and strategies

Sweeney

Park²,

Baumann

et al. 2017

Transl Neurodegener

485

307

View full text Add to dashboard Cite

A hallmark of neurodegenerative proteinopathies is the formation of misfolded protein aggregates that cause cellular toxicity and contribute to cellular proteostatic collapse. Therapeutic options are currently being explored that target different steps in the production and processing of proteins implicated in neurodegenerative disease, including synthesis, chaperone-assisted folding and trafficking, and degradation via the proteasome and autophagy pathways. Other therapies, like mTOR inhibitors and activators of the heat shock response, can rebalance the entire proteostatic network. However, there are major challenges that impact the development of novel therapies, including incomplete knowledge of druggable disease targets and their mechanism of action as well as a lack of biomarkers to monitor disease progression and therapeutic response. A notable development is the creation of collaborative ecosystems that include patients, clinicians, basic and translational researchers, foundations and regulatory agencies to promote scientific rigor and clinical data to accelerate the development of therapies that prevent, reverse or delay the progression of neurodegenerative proteinopathies.

show abstract

“…Anti-Aβ antibodies (solanezumab, gantenerumab, crenezumab, IVIG), which can bind soluble Aβ and improve cognitive performance, are currently in clinical trials [165,284,285] . Solanezumab accommodates a large Aβ epitope (960 Å 2 buried interface over residues 16 to 26) that forms extensive contacts and hydrogen bonds to the antibody, largely via main-chain Aβ atoms and a deeply buried Phe19-Phe20 dipeptide core Solanezumab and crenezumab both share identity with the Aβ KLVFF epitope [286] . The human anti-Aβ monoclonal antibody, gantenerumab, binds Aβ plaques and targets the N-terminus and central portion of Aβ [287] .…”

Section: Immunotherapeutic Approachmentioning

confidence: 99%

Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

View full text Add to dashboard Cite

Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β-and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ; inhibitors or modulators of β-and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

show abstract

Molecular basis for mid-region amyloid-β capture by leading Alzheimer's disease immunotherapies

Cited by 82 publications

References 34 publications

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

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

Protein misfolding in neurodegenerative diseases: implications and strategies

Amyloid beta: structure, biology and structure-based therapeutic development

Contact Info

Product

Resources

About