Abstract Body

Pyroglutamate-3 Aβ protein (pGlu3 Aβ) is an N-terminally truncated and modified form of Aβ that plays a key role in AD pathogenesis. After degradation or cleavage of the first two N-terminal amino acids, the free glutamic acid at residue 3 is cyclized by glutaminyl cyclase to form pGlu3 Aβ, which resists degradation, drives rapid aggregation of pGlu3 and general Aβ into oligomers and fibrils, and is neurotoxic. Although relatively low in abundance in AD brain, pGlu3 Aβ appears in nearly all plaques and can act as a seed for plaque deposition. Nonclinical studies in Alzheimer’s-like mice indicate that removal of pGlu3 Aβ by anti-pGlu3 Aβ antibodies enhances plaque clearance and slows cognitive decline. Efficacy is influenced by the IgG isotype and CNS delivery is enhanced by low-frequency focused-ultrasound treatments that transiently disrupt the blood-brain-barrier. A recent Phase II clinical study using Eli Lilly's donanemab, a humanized anti-pGlu3 Aβ monoclonal antibody, demonstrated robust plaque lowering and significant slowing of cognitive and functional impairment in early-stage AD patients. A glutaminyl cyclase inhibitor, Vivoryon Therapeutics’ PQ912, which blocks the formation of pGlu3 Aβ, is currently being tested in Phase II clinical trials in Europe and the USA. Nonclinical studies in mice suggest that the combination of an anti-pGlu3 Aβ antibody and PQ912 has an additive effect on efficacy. Targeting pGlu3 Aβ early in the disease process appears promising and could potentially be used in combination with other therapies to maintain low levels of Aβ, reduce inflammation and tau pathology, and slow cognitive decline.