Discovery of a novel pseudo β-hairpin structure of N-truncated amyloid-β for use as a vaccine against Alzheimer’s disease

Bakrania, Preeti; Hall, G. G.; Bouter, Yvonne; Bouter, Caroline; Beindorff, Nicola; Cowan, Richard; Davies, Sarah L.; Price, Jemma; Mpamhanga, Chido; Love, Elizabeth A.; Matthews, David J.; Carr, Mark D.; Bayer, Thomas A.

doi:10.1038/s41380-021-01385-7

Cited by 19 publications

(28 citation statements)

References 53 publications

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“…For example, post-translational modifications involving N-terminal residues may play a role in fibril formation. 95 Recently, a novel β-hairpin fold of the N-terminus of Aβ has been used to generate antibodies that reduce the level of plaque formation in mouse of AD, 96 which may be similar to the target of aducanumab, an antibody that targets monomers and aggregated forms of Aβ. 97 …”

Section: Discussionmentioning

confidence: 99%

Insights into Cerebral Amyloid Angiopathy Type 1 and Type 2 from Comparisons of the Fibrillar Assembly and Stability of the Aβ40-Iowa and Aβ40-Dutch Peptides

et al. 2022

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Two distinct diseases are associated with the deposition of fibrillar amyloid-β (Aβ) peptides in the human brain in an age-dependent fashion. Alzheimer’s disease is primarily associated with parenchymal plaque deposition of Aβ42, while cerebral amyloid angiopathy (CAA) is associated with amyloid formation of predominantly Aβ40 in the cerebral vasculature. In addition, familial mutations at positions 22 and 23 of the Aβ sequence can enhance vascular deposition in the two major subtypes of CAA. The E22Q (Dutch) mutation is associated with CAA type 2, while the D23N (Iowa) mutation is associated with CAA type 1. Here we investigate differences in the formation and structure of fibrils of these mutant Aβ peptides in vitro to gain insights into their biochemical and physiological differences in the brain. Using Fourier transform infrared and nuclear magnetic resonance spectroscopy, we measure the relative propensities of Aβ40-Dutch and Aβ40-Iowa to form antiparallel structure and compare these propensities to those of the wild-type Aβ40 and Aβ42 isoforms. We find that both Aβ40-Dutch and Aβ40-Iowa have strong propensities to form antiparallel β-hairpins in the first step of the fibrillization process. However, there is a marked difference in the ability of these peptides to form elongated antiparallel structures. Importantly, we find marked differences in the stability of the protofibril or fibril states formed by the four Aβ peptides. We discuss these differences with respect to the mechanisms of Aβ fibril formation in CAA.

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Section: Discussionmentioning

confidence: 99%

Insights into Cerebral Amyloid Angiopathy Type 1 and Type 2 from Comparisons of the Fibrillar Assembly and Stability of the Aβ40-Iowa and Aβ40-Dutch Peptides

et al. 2022

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“…Both, active immunization with the TAPAS vaccine and passive immunization with the humanized TAPAS version of the murine precursor antibody [61,62] had similar treatment effects. Of note the TAPAS binding motif is not found in amyloid plaques [60,63].…”

Section: Drug Target Pyroglutamate Aβmentioning

confidence: 94%

“…Therefore, it is of upmost interest that the N-terminus of Aβ pE3-X monomers adopt a unique pseudo β-hairpin structure, which is recognized by the TAPAS family antibodies (murine and humanized variants) [60]. A stabilized cyclic form of Aβ 1-14 (Ntruncated amyloid peptide antibodies, the "TAPAS" vaccine) was engineered and shown that the vaccine adopted the same conformation as the native sequence when bound to TAPAS antibodies.…”

Section: Drug Target Pyroglutamate Aβmentioning

confidence: 99%

Pyroglutamate Aβ cascade as drug target in Alzheimer’s disease

Bayer

2021

Mol Psychiatry

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One of the central aims in Alzheimer’s disease (AD) research is the identification of clinically relevant drug targets. A plethora of potential molecular targets work very well in preclinical model systems both in vitro and in vivo in AD mouse models. However, the lack of translation into clinical settings in the AD field is a challenging endeavor. Although it is long known that N-terminally truncated and pyroglutamate-modified Abeta (AβpE3) peptides are abundantly present in the brain of AD patients, form stable and soluble low-molecular weight oligomers, and induce neurodegeneration in AD mouse models, their potential as drug target has not been generally accepted in the past. This situation has dramatically changed with the report that passive immunization with donanemab, an AβpE3-specific antibody, cleared aymloid plaques and stabilized cognitive deficits in a group of patients with mild AD in a phase II trial. This review summarizes the current knowledge on the molecular mechanisms of generation of AβpE, its biochemical properties, and the intervention points as a drug target in AD.

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“…Therefore, clearance of Aβ plaque rather than Aβ oligomers might have limited effects on ameliorating the cognitive impairment in AD patients. In addition to Aβ 1-40 and Aβ 1-42 , pyroglutamate Aβ 3-42 and Aβ 4-42 have also been identified as major Aβ isoforms that play significant roles in AD neurodegeneration, with no obvious differences between familial and sporadic AD patients, indicating that these two isoforms can be potential immunotherapeutic targets [ 110 ]. Recently, a novel, pseudo β-hairpin conformation of the N-terminal region of pyroglutamate Aβ monomers has been reported, which provides novel insights into both active and passive immunization against AD [ 111 ].…”

Section: Challenges and Perspectives Of Immunotherapy For Admentioning

confidence: 99%

Immunotherapy for Alzheimer’s disease: targeting β-amyloid and beyond

Song

Shi

Zhang

et al. 2022

Transl Neurodegener

118

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Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly worldwide. However, the complexity of AD pathogenesis leads to discrepancies in the understanding of this disease, and may be the main reason for the failure of AD drug development. Fortunately, many ongoing preclinical and clinical studies will continually open up avenues to unravel disease mechanisms and guide strategies for AD diagnosis and drug development. For example, immunotherapeutic strategies targeting amyloid-β (Aβ) and tau proteins were once deemed almost certainly effective in clinical treatment due to the excellent preclinical results. However, the repeated failures of clinical trials on vaccines and humanized anti-Aβ and anti-tau monoclonal antibodies have resulted in doubts on this strategy. Recently, a new anti-Aβ monoclonal antibody (Aducanumab) has been approved by the US Food and Drug Administration, which brings us back to the realization that immunotherapy strategies targeting Aβ may be still promising. Meanwhile, immunotherapies based on other targets such as tau, microglia and gut-brain axis are also under development. Further research is still needed to clarify the forms and epitopes of targeted proteins to improve the accuracy and effectiveness of immunotherapeutic drugs. In this review, we focus on the immunotherapies based on Aβ, tau and microglia and their mechanisms of action in AD. In addition, we present up-to-date advances and future perspectives on immunotherapeutic strategies for AD.

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Discovery of a novel pseudo β-hairpin structure of N-truncated amyloid-β for use as a vaccine against Alzheimer’s disease

Cited by 19 publications

References 53 publications

Insights into Cerebral Amyloid Angiopathy Type 1 and Type 2 from Comparisons of the Fibrillar Assembly and Stability of the Aβ40-Iowa and Aβ40-Dutch Peptides

Insights into Cerebral Amyloid Angiopathy Type 1 and Type 2 from Comparisons of the Fibrillar Assembly and Stability of the Aβ40-Iowa and Aβ40-Dutch Peptides

Pyroglutamate Aβ cascade as drug target in Alzheimer’s disease

Immunotherapy for Alzheimer’s disease: targeting β-amyloid and beyond

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