Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer’s Disease

Abstract

Post-translationally modified N-terminally truncated amyloid beta peptide with a cyclized form of glutamate at position 3 (pE3Aβ) is a highly pathogenic molecule with increased neurotoxicity and propensity for aggregation. In the brains of Alzheimer’s Disease (AD) cases, pE3Aβ represents a major constituent of the amyloid plaque. The data show that pE3Aβ formation is increased at early pre-symptomatic disease stages, while tau phosphorylation and aggregation mostly occur at later stages of the disease. This suggests that pE3Aβ accumulation may be an early event in the disease pathogenesis and can be prophylactically targeted to prevent the onset of AD. The vaccine (AV-1986R/A) was generated by chemically conjugating the pE3Aβ3-11 fragment to our universal immunogenic vaccine platform MultiTEP, then formulated in AdvaxCpG adjuvant. AV-1986R/A showed high immunogenicity and selectivity, with endpoint titers in the range of 105–106 against pE3Aβ and 103–104 against the full-sized peptide in the 5XFAD AD mouse model. The vaccination showed efficient clearance of the pathology, including non-pyroglutamate-modified plaques, from the mice brains. AV-1986R/A is a novel promising candidate for the immunoprevention of AD. It is the first late preclinical candidate which selectively targets a pathology-specific form of amyloid with minimal immunoreactivity against the full-size peptide. Successful translation into clinic may offer a new avenue for the prevention of AD via vaccination of cognitively unimpaired individuals at risk of disease.

A case for seeking sex-specific treatments in Alzheimer’s disease

“…Targeting pyroglutamate-modified pE 3 Aβ in the 5XFAD mouse model of AD reduced pyroglutamated and non-pyroglutamated Aβ plaques in male and female mice. Highlighting a sexual dimorphism, soluble Aβ was decreased only in male mice whereas insoluble Aβ was decreased only in female mice ( Zagorski et al, 2023 ). Of course, there is no guarantee that the sex differences identified in mice will translate into humans, but the fact that there are indications of sex-related responses to lecanemab and solanezumab presents a forceful argument for stratification by sex in all clinical trials.…”

Current Anti-Amyloid-β Therapy for Alzheimer’s Disease Treatment: From Clinical Research to Nanomedicine

“…This vaccine successfully reduced both pE3-Aβ and full-length Aβ in 5×FAD mice. 89 FDA approval of the aducanumab has greatly promoted the research and development of other AD immunotherapies. Efforts still needed to be made to overcome the obstacles, including side effect events, target selection, and delivery platform, with the aim of developing more effective, even customized immunotherapies.…”