NP03 INHIBITS BACE1 AND GSK-3B FOR THE PREVENTION OF EARLY ALZHEIMER’S-LIKE AMYLOID NEUROPATHOLOGY IN TRANSGENIC RATS

The inhibition of GSK-3β represents a major therapeutic target in AD research and in drug development. Lithium has been shown to inhibit GSK-3β through direct and indirect mechanisms and lithium treatment has shown therapeutic effects in human patients with AD and in AD animal models. Importantly, however, the standard formulation of lithium has a low therapeutic window and provokes severe side effects, making it inappropriate for long-term treatment in elderly populations. Here we use a novel lipidic nano-particle formulation of lithium (NP03) that when deposited on the mucosa is expected to facilitate the passage through the blood brain barrier. As a result of this formulation, significantly lower amounts of lithium can be administered thereby avoiding adverse effects without loss of therapeutic efficacy. We evaluated this new formulation of lithium (coded NP03) using a rat model of Alzheimer-like amyloidosis. McGill-R-Thy1-APP transgenic rats at the pre-plaque stage and wild-type controls were treated with NP03 for 8 weeks. We measured cognition, Aβ peptide production, BACE1 activity, and GSK-3α/β, as well as markers of CNS inflammation. Compared to the vehicle treated AD rats, NP03 prevented BACE1 hyperactivity, leading to a significant reduction in the ratio of soluble human Aβ42/Aβ40. NP03 restored GSK-3β phosphorylation to control levels. NP03 reduced expression of pro-inflammatory cytokines. These changes occurred with significant improvements in cognition as assessed using standard rodent tasks. The NP03-mediated protective effects toward BACE1 hyperactivity, GSK-3β, and the Aβ42/Aβ40 ratio support the evaluation of this new formulation of lithium in the early stages of Alzheimer’s disease.