Pyroglutamate Aβ cascade as drug target in Alzheimer's disease

Abstract

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 (Aβ_pE3) 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 Aβ_pE3-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 Aβ_pE, its biochemical properties, and the intervention points as a drug target in AD.

Fig. 1. Generation of pyroglutamated (pE) peptides involved in Alzheimer’s disease.

① The N-terminus of full-length Aβ is generated by BACE1 or meprin-β and secreted by neurons. ② Next, N-terminal amino acids are cleaved off by aminopeptidase A (APA), meprin-β or dipeptidyl peptidase 4 (DPP4). ③ Glutamate at position three of the N-terminus of Aβ is subsequently post-translationally modified into N-terminal pyroglutamate (pE) by dehydration catalyzed by glutaminyl cyclase (QC) activity. ④ The isoenzyme of QC, isoQC, predominantly converts the N-terminus of chemokine ligand 2 (CCL2) into pE-CCL2 ⑤ triggering monocyte recruitment into the central nervous system (CNS). The surface structure of DPP4 [84] and of QC [85] was taken from the Protein Data Bank (PDB). Created with BioRender.com.

Fig. 2. Pyroglutamate Aβ as a potential drug target against Alzheimer’s disease.

① Inhibition of DPP4 prevents N-terminal truncation of the first two amino acid residues of the full-length Aβ monomers (Aβ_1-x). ② Inhibition of QC activity prevents the conversion of Aβ_3-x into Aβ_pE3-x monomers. ③–⑤ Neutralizing antibodies react with different conformational and structural variants of Aβ_pE3-X. ③ Once Aβ_pE3-x monomers are generated, they adopt a pseudo β-hairpin structure at the N-terminus, which is specifically recognized by the TAPAS family of antibodies. The pseudo β-hairpin epitope is neutralized by the TAPAS vaccine and by TAPAS monoclonal antibodies. ④ Pan-Aβ_pE-X antibodies react with a range of conformations: soluble oligomers, protofibrils and fibrillar forms found in different plaque types. ⑤ Donanemab, a plaque-specific monoclonal antibody, reacts with Aβ_pE3-X aggregates found in the amyloid-plaque cores. The surface structure of DPP4 [84] and of QC [85] was taken from the Protein Data Bank (PDB). Created with BioRender.com.