Assessment of Oral LISPRO Treatment in Ameliorating Amyloid and Tau Pathology in Transgenic Alzheimer’s Mice Model
Lithium is used primarily as a mood stabilizer for bipolar disorder and has been used to treat mania, depression and suicidal thoughts for a long time. In addition, it has also been shown to prevent cognitive decline which indicated that lithium has a potential therapeutic effect in Alzheimer’s disease (AD). However, one of the main problems that exist in the currently FDA-approved lithium pharmaceutics (carbonate and citrate) is that it has narrow therapeutic index and lithium plasma level change drastically which can cause adverse side effects. Here we investigated the safety, pharmacokinetics and therapeutic efficacies of LISPRO (ionic co-crystals of lithium salicylate with organic l-proline), lithium salicylate, Li2CO3 (currently used) and placebo. We found that LISPRO attenuate β-amyloid plaques and phosphorylation of tau through modulation of inflammation and GSK3β inactivation. Cytokine profiles in the brain, plasma and splenocyte suggest that LISPRO (8-weeks) down-regulates pro-inflammatory, up-regulates anti-inflammatory and suppresses renal COX2 expression in Tg2576 mice. Plasma and brain pharmacokinetics of lithium indicated that LISPRO showed significantly higher brain and steady plasma lithium levels on C57BL/6J (2-weeks) and Tg2576 (8-weeks) mice. Interestingly, chronic (20-weeks) administration of LISPRO produces a slightly higher, but non-significant brain to plasma lithium levels and reduces β-amyloid plaques, and tau-phosphorylation through modulation of presynaptic (synaptophysin) and post-synaptic protein (PSD95) expression in 3xTg-AD mice.