Wnt‐induced activation of glucose metabolism mediates the in vivo neuroprotective roles of Wnt signaling in Alzheimer disease

Abstract

Dysregulated Wnt signaling is linked to major neurodegenerative diseases, including Alzheimer disease (AD). In mouse models of AD, activation of the canonical Wnt signaling pathway improves learning/memory, but the mechanism for this remains unclear. The decline in brain function in AD patients correlates with reduced glucose utilization by neurons. Here, we test whether improvements in glucose metabolism mediate the neuroprotective effects of Wnt in AD mouse model. APPswe/PS1dE9 transgenic mice were used to model AD, Andrographolide or Lithium was used to activate Wnt signaling, and cytochalasin B was used to block glucose uptake. Cognitive function was assessed by novel object recognition and memory flexibility tests. Glucose uptake and the glycolytic rate were determined using radiotracer glucose. The activities of key enzymes of glycolysis such as hexokinase and phosphofructokinase, Adenosine triphosphate (ATP)/Adenosine diphosphate (ADP) levels and the pentose phosphate pathway and activity of glucose‐6 phosphate dehydrogenase were measured. Wnt activators significantly improved brain glucose utilization and cognitive performance in transgenic mice. Wnt signaling enhanced glucose metabolism by increasing the expression and/or activity of hexokinase, phosphofructokinase and AMP‐activated protein kinase. Inhibiting glucose uptake partially abolished the beneficial effects of Wnt signaling on learning/memory. Wnt activation also enhanced glucose metabolism in cortical and hippocampal neurons, as well as brain slices derived from APPswe/PS1E9 transgenic mice. Combined, these data provide evidence that the neuroprotective effects of Wnt signaling in AD mouse models result, at least in part, from Wnt‐mediated improvements in neuronal glucose metabolism.

Metabolic Dysregulation Contributes to the Progression of Alzheimer’s Disease

“…Considerable research has examined the associations between AD and the enzymes intimately linked to glycolysis (i.e., hexokinase, glyceraldehyde 3-phosphate dehydrogenase [GAPDH], and pyruvate kinase [PK]) (Vallee et al, 2018b;Wu et al, 2018;Butterfield and Halliwell, 2019). Cisternas et al (2019) reported that Wnt signaling promotes glucose metabolism by increasing the expression of hexokinase and PFK, which causes neuroprotective effects. However, decreased hexokinase and PFK expression and dysregulated Wnt signaling are observed in AD.…”

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

“…Wnt signaling is known to be impaired in AD [109][110][111], and activation of the Wnt/β-catenin signaling pathway represses BACE-1 expression [112]. Activation of Wnt signaling has been shown to rescue memory loss and improves synaptic dysfunction in APP/PS1 AD transgenic mice [113,114]. In the well-known canonical Wnt signaling pathway, Wnt's binding to its receptor Frizzled and the downstream processes leading to the stabilization of β-catenin involves the inhibition of GSK-3β [115].…”

The Wnt/β-catenin signaling pathway affects the distribution of cytoskeletal proteins in Aβ treated PC12 cells

“…Hyperphosphorylated Tau accumulates in paired helical filaments (PHF) and leads to the formation of neurofibrillary tangles as well as neuronal degeneration in AD (Alonso et al, 1996). Several studies point to a possible role for Wnt in AD (Cisternas et al, 2019;Hu et al, 2019;Huang et al, 2018).…”