Lithium Enhances Hippocampal Glucose Metabolism in an In Vitro Mice Model of Alzheimer’s Disease

Abstract

Impaired cerebral glucose metabolism is an early event that contributes to the pathogenesis of Alzheimer’s disease (AD). Importantly, restoring glucose availability by pharmacological agents or genetic manipulation has been shown to protect against Aβ toxicity, ameliorate AD pathology, and increase lifespan. Lithium, a therapeutic agent widely used as a treatment for mood disorders, has been shown to attenuate AD pathology and promote glucose metabolism in skeletal muscle. However, despite its widespread use in neuropsychiatric disorders, lithium’s effects on the brain have been poorly characterized. Here we evaluated the effect of lithium on glucose metabolism in hippocampal neurons from wild-type (WT) and APPSwe/PS1ΔE9 (APP/PS1) mice. Our results showed that lithium significantly stimulates glucose uptake and replenishes ATP levels by preferential oxidation of glucose through glycolysis in neurons from WT mice. This increase was also accompanied by a strong increase in glucose transporter 3 (Glut3), the major carrier responsible for glucose uptake in neurons. Similarly, using hippocampal slices from APP-PS1 mice, we demonstrate that lithium increases glucose uptake, glycolytic rate, and the ATP:ADP ratio in a process that also involves the activation of AMPK. Together, our findings indicate that lithium stimulates glucose metabolism and can act as a potential therapeutic agent in AD.

Dietary lithium stimulates female fecundity in Drosophila melanogaster

“…However, the outcome on this matter was rather inconclusive. Lithium has previously shown to affect glycogen synthesis and glucose availability of peripheral tissues in mammalian models through inhibition of GSK‐3 61,74,90 . According to our results, however, no changes in GSK‐3‐dependent glycogen accumulation were observed in Drosophila oocytes in response to lithium.…”

“…Lithium has previously shown to affect glycogen synthesis and glucose availability of peripheral tissues in mammalian models through inhibition of GSK-3. 61,74,90 According to our results, however, no changes in GSK-3-dependent glycogen accumulation were observed in Drosophila oocytes in response to lithium. Likewise, we did not detect any significant impact of lithium on inhibitory phosphorylation of GSK-3 in the ovaries of lithium-treated females.…”

Alzheimer's Target and the Treatment Progression of Classic and New Clinical Drugs

“…16 In addition, another in vitro Animal study trials have shown that lithium also cause the affection of glucose metabolism on mouse's hippocampal when the mouse carry AD. 17 Furthermore, in a Meta-analysis included 3 randomized controlled studies (n=232), in this analysis, researchers assess the lithium effectiveness AD's patients and people who carry cognitive impairments. The feedback is, compare with the placebo, Lithium involved cognitive recoveries of patients gets a significant enhancement in AD and cognitive dysfunction (MD = -0.41, 95%CI = -0.81 to -0.02, P = 0.04, I2 = 47%).…”

Why Is Iron Deficiency/Anemia Linked to Alzheimer’s Disease and Its Comorbidities, and How Is It Prevented?

“…Recently, Ates et al [ 173 ] presented evidence that neuroprotection by lithium depends on GSK3ß phosphorylation along the Akt pathway. Under drug treatment, hippocampal glucose uptake is enhanced by a strong increase in Glut3 [ 174 ]. Although Akt signaling is the main pathway to increase glucose uptake, involvement of AMPK/insulin receptor signaling is very likely—at least in the transgenic AD mouse.…”