An anti-pyroglutamate-3 Aβ vaccine reduces plaques and improves cognition in APPswe/PS1ΔE9 mice

Abstract

Pyroglutamate-3 amyloid-beta (pGlu-3 Aβ) is an N-terminally truncated Aβ isoform likely playing a decisive role in Alzheimer's disease (AD) pathogenesis. Here, we describe a prophylactic passive immunization study in APPswe/PS1ΔE9 mice using a novel pGlu-3 Aβ IgG1 monoclonal antibody (mAb), 07/1 (150 and 500μg i.p. weekly), and compare its efficacy with a general Aβ IgG1 mAb, 3A1 (200μg i.p. weekly) as a positive control. After 28 weeks of treatment, plaque burden was reduced and cognitive performance of 07/1-immunized Tg mice, especially at the higher dose, was normalized to wild-type (Wt) levels in two hippocampal-dependent tests and partially spared compared to PBS-treated Tg mice. Mice that received 3A1 had reduced plaque burden but showed no cognitive benefit. In contrast to 3A1, treatment with 07/1 did not increase the concentration of Aβ in plasma, suggesting different modes of Aβ plaque clearance. In conclusion, early selective targeting of pGlu-3 Aβ by immunotherapy may be effective in lowering cerebral Aβ plaque burden and preventing cognitive decline in the clinical setting. Targeting this pathologically-modified form of Aβ thereby is unlikely to interfere with potential physiologic function(s) of Aβ that have been proposed.

Longitudinal measures of cognition in the Ts65Dn mouse: Refining windows and defining modalities for therapeutic intervention in Down syndrome

“…The platform is a 5 cm x 5 cm square made from Plexiglas and was submerged during the experiments. A recent study has been published using this behavioral paradigm (Frost et al, 2015). Mice were given 10 trials per day with an inter-trial interval (ITI) of approximately 5–8 min.…”

Flexible N‐Termini of Amyloid β‐Protein Oligomers: A Link between Structure and Activity?

“…Another study revealed that unlike the non‐pyroglutamated Aβ load, the Aβ 3(pE) load correlates with both AD severity and the amount of hyperphosphorylated tau, suggesting that Aβ 3(pE) may represent a missing link between Aβ and tau pathologies . Passive immunotherapy with a monoclonal antibody designed to specifically target Aβ 3(pE) , effectively lowered not only cerebral Aβ plaque burden but also reversed cognitive decline in a Tg mouse model . Thus, N‐terminally truncated and pyroglutamated Aβ, in particular Aβ 3(pE)–42 , may not be just a byproduct of Aβ deposition into plaques but may actually play a central role in AD pathology.…”

A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

“…pGlu-A␤ exhibits increased aggregation propensity and increased cellular toxicity and disrupts long term potentiation to a greater extent than A␤1-X species (39 -41). In addition, recent work has proposed pGlu-A␤ as the predominant A␤ species within the brains of AD patients (42), and efforts to design therapeutics specifically targeting this A␤ species have proved successful in mouse models (43). However, evidence for direct proteolysis of APP between Ala 673 -Glu 674 by cathepsin B remains to be provided.…”