• Low-dose lithium supplementation influences GSK3β activity in the brains of an early, diet-induced sporadic Alzheimer’s disease mouse model

      Fenech, Rachel; Applied Health Sciences Program
      Alzheimer’s disease (AD) is a neurodegenerative disease characterized by neurofibrillary tangles, amyloid-beta plaques, and cognitive decline. Research supports that key highlights of Type-2 Diabetes Mellitus (T2DM; i.e. obesity and insulin resistance) are significant risk factors for AD. At the forefront of both AD and T2DM pathologies is increased glycogen synthase kinase 3-β (GSK3β) activity. Targeting the inhibition of GSK3β has thus been suggested as an AD prophylactic. Lithium (Li), is a well-known natural GSK3β inhibitor, but is associated with dose-dependent adverse side effects. I thus aimed to examine the effects of low-dose Li supplementation on brain GSK3β activity, the development of AD pathologies, and markers of insulin signaling in a diet-induced insulin resistant mouse model. Male C57BL/6J mice were divided into either a 6-week (n = 24) or 12-week study (n = 72). In the 6-week study, mice were fed a chow diet (CON; n = 12) or a chow diet with Li-supplemented drinking water (Li; 10 mg / kg / day; n = 12) for 6 weeks. Alternatively, in the 12-week study, mice were fed a chow diet (CON; n = 24), a high-fat diet (HFD; 60% fat; n = 24), or a HFD with Li-supplemented drinking water (HFD+Li; n = 24) for 12 weeks. Prefrontal cortex and hippocampal tissues were collected for analysis. HFD and HFD+Li mice experienced significant weight gain and had impaired glucose and insulin tolerance compared to CON mice. Furthermore, HFD+Li mice had reduced caloric efficiency and rescued insulin degrading enzyme content compared to HFD mice. With respect to GSK3β activity, increases in inhibitory p-GSK3β Ser9 were not observed until 12 weeks in the HFD+Li compared to CON mice, however actual activity was reduced after only 6 weeks in the Li compared to CON mice. Collectively, these data provides evidence for low-dose Li supplementation to improve diet-induced impairments that can otherwise contribute to AD. Moreover, these results indicate that GSK3β activity can be inhibited despite any changes in phosphorylation. These findings contribute to an overall greater understanding of low-dose Li’s ability to influence GSK3β activity in the brain and its potential as an AD prophylactic.