Immunotherapy to improve cognition and reduce pathological species in an Alzheimer's disease mouse model

Background: Alzheimer's disease (AD) is characterized by physiologically endogenous proteins amyloid beta (A beta) and tau undergoing a conformational change and accumulating as soluble oligomers and insoluble aggregates. Tau and A beta soluble oligomers, which contain extensive beta-sheet secondary structure, are thought to be the most toxic forms. The objective of this study was to determine the ability of TWF9, an anti-beta-sheet conformation antibody (a beta ComAb), to selectively recognize pathological A beta and phosphorylated tau in AD human tissue compared with cognitively normal age-matched controls and to improve the performance of old 3xTg-AD mice with advanced pathology in behavioral testing after acute treatment with TWF9. Methods: In this study, we used immunohistochemistry, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA) to characterize TWF9 specificity. We further assessed cognitive performance in old (18-22 months) 3xTg-AD mice using both a Barnes maze and novel object recognition after intraperitoneal administration of TWF9 (4 mg/kg) biweekly for 2 weeks before the start of behavioral testing. Injections continued for the duration of the behavioral testing, which lasted 2 weeks. Results: Histological analysis of TWF9 in formalin-fixed paraffin-embedded human control and AD (ABC score: A3B3C3) brain tissue revealed preferential cytoplasmic immunoreactivity in neurons in the AD tissue compared with controls (p < 0.05). Furthermore, ELISA using oligomeric and monomeric A beta showed a preferential affinity for oligomeric A beta. Immunoprecipitation studies showed that TWF9 extracted both phosphorylated tau (p < 0.01) and A beta (p < 0.01) from fresh frozen brain tissues. Results show that treated old 3xTg-AD mice have an enhanced novel object recognition memory (p < 0.01) and Barnes maze performance (p = 0.05) compared with control animals. Overall plaque burden, neurofibrillary tangles, microgliosis, and astrocytosis remained unchanged. Soluble phosphorylated tau was significantly reduced in TWF9-treated mice (p < 0.05), and there was a trend for a reduction in soluble A beta levels in the brain homogenates of female 3xTg-AD mice (p = 0.06). Conclusions: This study shows that acute treatment with an a beta ComAb can effectively improve performance in behavioral testing without reduction of amyloid plaque burden, and that peripherally administered IgG can affect levels of pathological species in the brain.