Wilson E N, Do Carmo S, Iulita M F, Hall H, Ducatenzeiler A, Marks A R, Allard S, Jia D T, Windheim J, Cuello A C
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Transl Psychiatry. 2017 Aug 1;7(8):e1190. doi: 10.1038/tp.2017.169.
Lithium is first-line therapy for bipolar affective disorder and has recently been shown to have protective effects in populations at risk for Alzheimer's disease (AD). However, the mechanism underlying this protection is poorly understood and consequently limits its possible therapeutic application in AD. Moreover, conventional lithium formulations have a narrow therapeutic window and are associated with a severe side effect profile. Here we evaluated a novel microdose formulation of lithium, coded NP03, in a well-characterized rat model of progressive AD-like amyloid pathology. This formulation allows microdose lithium delivery to the brain in the absence of negative side effects. We found that NP03 rescued key initiating components of AD pathology, including inactivating GSK-3β, reducing BACE1 expression and activity, and reducing amyloid levels. Notably, NP03 rescued memory loss, impaired CRTC1 promoter binding of synaptic plasticity genes and hippocampal neurogenesis. These results raise the possibility that NP03 be of therapeutic value in the early or preclinical stages of AD.
锂是双相情感障碍的一线治疗药物，最近已被证明对有患阿尔茨海默病（AD）风险的人群具有保护作用。然而，这种保护作用的潜在机制尚不清楚，因此限制了其在AD治疗中的可能应用。此外，传统的锂制剂治疗窗狭窄，且伴有严重的副作用。在此，我们在一个特征明确的进行性AD样淀粉样病理大鼠模型中评估了一种新型微剂量锂制剂NP03。这种制剂能够在无负面副作用的情况下将微剂量锂输送到大脑。我们发现NP03挽救了AD病理的关键起始成分，包括使糖原合成酶激酶-3β失活、降低β-分泌酶1（BACE1）的表达和活性以及降低淀粉样蛋白水平。值得注意的是，NP03挽救了记忆丧失、突触可塑性基因CRTC1启动子结合受损以及海马神经发生。这些结果增加了NP03在AD早期或临床前阶段具有治疗价值的可能性。
