Dysfunctional Glucose Metabolism in Alzheimer's Disease Onset and Potential Pharmacological Interventions

Abstract

Alzheimer's disease (AD) is the most common age-related dementia. The alteration in metabolic characteristics determines the prognosis. Patients at risk show reduced glucose uptake in the brain. Additionally, type 2 diabetes mellitus increases the risk of AD with increasing age. Therefore, changes in glucose uptake in the cerebral cortex may predict the histopathological diagnosis of AD. The shifts in glucose uptake and metabolism, insulin resistance, oxidative stress, and abnormal autophagy advance the pathogenesis of AD syndrome. Here, we summarize the role of altered glucose metabolism in type 2 diabetes for AD prognosis. Additionally, we discuss diagnosis and potential pharmacological interventions for glucose metabolism defects in AD to encourage the development of novel therapeutic methods.

Keywords: Alzheimer’s disease; ROS; diabetes; genetic mutation; glycolysis; therapy.

Figure 1

Dysfunctional cerebral glucose metabolism is a crucial factor in AD development. Glucose catabolism in AD is directly connected to further negative consequences in AD syndrome development. (A) Schematic representation of defective glucose metabolism in AD and various outcomes. ↑ arrows indicate upregulation and ↓ arrows indicate downregulation. (B) Glucose metabolism forms the bridge between neurotoxicity and cognitive dysfunction in AD. This interconnected Venn diagram describes the scenarios in which AD-related toxicity and cognitive dysfunction appear during AD onset and progression.

Figure 2

Overview of 18F-FDG PET working mechanism. The radioactive FDG is converted to FDG6P, which can be measured and quantified by PET imaging. In AD, the glucose uptake is vastly reduced due to insulin resistance. Thus, the radioactive tracer does not show up in AD brain imaging.

Figure 3

Dysregulated proteostasis network leads to neurotoxicity in AD brains. The UPR system usually ceases, and the buildup of aggregated Aβ plaques and additional misfolded proteins often induces cell death signals in the neurons. ↑ arrows indicate upregulation.

Figure 4

The early onset of AD at a younger age is due to the mutations in lysosomal membrane proteins. In these conditions, standard autophagy clearance is hampered. Primary research identified various other signaling mechanisms in FAD patients. ↑ arrows indicate upregulation and ↓ arrows indicate downregulation process.

Figure 5

Proteolytic cleavage of APP. In the non-amyloidogenic pathway, the extracellular domain cleavages by α-secretase and releases the soluble peptide sAPPα. In contrast, the amyloidogenic pathway releases Aβ42, a significant component of Aβ plaques.

Figure 6

(A) The inhibition in the oxidative defense system potentiates Aβ oligomerization and Tau phosphorylation in the diabetic brain. ↓ arrows indicate downregulation. (B) Tau phosphorylation and NFT formation. In a healthy cell, phosphorylated tau protein binds with microtubules (MT) and maintains stability. However, hyperphosphorylation tau aggregates into the NFTs which leads to MT instability. This figure was drawn using BioRender application (https://biorender.com (accessed on 21 June 2022)).