O4‐06‐04: Immunization targeting a minor plaque constituent clears Aβ and rescues behavioral deficits in an Alzheimer's disease mouse model

Anti-human-Aβ immunotherapy has been shown to clear brain Aβ plaques in b-amyloid depositing mouse models and in human Alzheimer's disease (AD) brain. While immunotherapy targeting a minor constituent of peripheral amyloidoses has been shown to result in a broad amyloid clearance, targeting a minor brain plaque constituent leading to b-amyloid clearance has not been demonstrated. We showed that murine Aβ accumulates in multiple human amyloid precursor protein transgenic mouse lines, representing ∼2-8% of the total Aβ in the brain. We also determined that murine Aβ co-localizes and interacts with the human Aβ by co-immunolabeling of and co-immunoprecipitation from brain tissue. Given that endogenous murine Aβ is a minor b-amyloid plaque component in these mouse models, we undertook an anti-murine-Aβ passive immunization by intraperitoneal injection for eight weeks in Tg2576 mice to determine whether this immunotherapy reduces brain plaque pathology while improving performance in behavioral assays in these mice. This immunization resulted in the clearance of more than one-half of the b-amyloid plaque pathology - including both the endogenous murine Aβ and the human Aβ components - following two months of treatment. The immunized mice additionally showed improvements in two behavioral assays, odor habituation and nesting behavior. Given the interactions we showed between the two Aβ species, our results argue that anti-murine-Aβ immunization clears human Aβ with murine Aβ as a complex while improving behavioral deficits which suggests that this immunization strategy may effectively clear oligomeric Aβ. We conclude that passive anti-murine-Aβ immunization clears Aβ plaque pathology - including the major human Aβ component - and decreases behavioral deficits, arguing that targeting minor, endogenous brain plaque constituents can be beneficial, broadening the range of plaque-associated targets for AD therapeutics.