Identification of a novel Aβ(pGlu3-x) targeting pathway in Alzheimer’s disease

The pyroglutamate-3-modified form of the amyloid-β (Aβ) peptide (Aβ(pGlu3-x)) is enriched in brains of Alzheimer’s disease (AD) patients and is highly neurotoxic, aggregation-prone, resistant to proteolytic degradation and acts as a seed for the co-aggregation of unmodified Aβ. Therefore, it became a pharmacologic target for AD therapy either by inhibition of its synthesizing enzyme, glutaminyl cyclase, or by passive immunization with antibodies targeting the Aβ(pGlu3-x) neoepitope. Here, we present a novel, antibody-independent approach targeting existing Aβ(pGlu3-x) by proteolytic degradation with the physiological enzyme pyroglutamyl-peptidase 1 (PGP-1). We demonstrate degradation of Aβ(pGlu3-x) in post mortem brain sections of transgenic mice and AD subjects, along with increased formation of Aβ(4-x). The resulting Aβ(4-x), generated after removal of the pGlu-blocking group, displays slower aggregation kinetics and improved proteolytic degradation by aminopeptidases. In a transgenic mouse model of AD, intracortical PGP-1 injection reduced the Aβ(pGlu3-x) load. Our results strongly support the exploration of in vivo PGP-1 delivery routes for therapeutic targeting of Aβ(pGlu3-x) in AD and of other pGlu-modified pathogenic peptides in different neurodegenerative diseases.