P2‐458: NPT001 reduces Aβ plaque without altering brain interstitial fluid Aβ levels in aged Tg2576 mice

NeuroPhage is developing NPT001 (filamentous bacteriophage M13) for the treatment of AD. NPT001 binds Aß with high affinity and disaggregates Aß plaque in a concentration-dependent manner in vitro and in vivo. In aged Tg2576 mice, amyloid plaque is significantly reduced after intra hippocampal injection of NPT001. The current study was conducted to determine if NPT001-induced clearance of Aß alters brain interstitial fluid (ISF) Aß levels. Microdialysis was used to assess ISF Aß in the brains of awake Tg2576 mice following intra hippocampal injection of NPT001. This technique measures a specific pool of unbound Aß that diffuses across a 38kDa MWCO membrane on the microdialysis probe. Aged female B6; SJL-Tg(APPSWE)2576Kha (Tg2576) mice were implanted with a unilateral 38-kDa MWCO microdialysis/injection probe into the hippocampus. Following recovery, six 90-min samples of microdialysis perfusion buffer were obtained to establish basal ISF Aß levels in each mouse. After basal sampling, 2ul of NPT001 or vehicle was injected into the hippocampus via the injection port at the tip of the microdialysis probe. ISF Aß samples were obtained across 5 days at 90-min increments following injection. Microdialysis samples were analyzed for Aßx-40 and Aßx-42 by sandwich ELISA. Following sampling, hippocampal Aß plaque load was quantified. ISF Aßx-40 levels did not increase significantly in NPT001-injected mice (n = 6) compared to vehicle-injected controls (n = 5). Interestingly, a slight lowering of ISF Aßx-40 fluctuating levels in NPT001-injected mice was observed across days. In a subset of mice tested (n = 2), Aßx-42 levels also did not increase following NPT001 injection. Importantly, NPT001 significantly reduced Aß plaque load by 52.5 ± 7.5% (mean ± SEM) in the injected hemisphere compared to the contralateral hemisphere in the same mice. In contrast, vehicle-injected mice had similar plaque load in the ipsilateral and contralateral hemispheres. All six mice in the NPT001-injected group had a decline in plaque load. Results indicate that ISF Aß levels, as assessed by in vivo microdialysis, did not change as a result of NPT001 injection despite a 50% reduction in Aß plaque load. NPT001 reduces Aß plaque load by a mechanism or pathway that does not involve solubilization and/or release of Aß monomers into brain ISF.