Metabolic Profile of Alzheimer's Disease: Is 10-Hydroxy-2-decenoic Acid a Pertinent Metabolic Adjuster?

Abstract

Alzheimer's disease (AD) represents a significant public health concern in modern society. Metabolic syndrome (MetS), which includes diabetes mellitus (DM) and obesity, represents a modifiable risk factor for AD. MetS and AD are interconnected through various mechanisms, such as mitochondrial dysfunction, oxidative stress, insulin resistance (IR), vascular impairment, inflammation, and endoplasmic reticulum (ER) stress. Therefore, it is necessary to seek a multi-targeted and safer approach to intervention. Thus, 10-hydroxy-2-decenoic acid (10-HDA), a unique hydroxy fatty acid in royal jelly, has shown promising anti-neuroinflammatory, blood-brain barrier (BBB)-preserving, and neurogenesis-promoting properties. In this paper, we provide a summary of the relationship between MetS and AD, together with an introduction to 10-HDA as a potential intervention nutrient. In addition, molecular docking is performed to explore the metabolic tuning properties of 10-HDA with associated macromolecules such as GLP-1R, PPARs, GSK-3, and TREM2. In conclusion, there is a close relationship between AD and MetS, and 10-HDA shows potential as a beneficial nutritional intervention for both AD and MetS.

Keywords: 10-HDA; Alzheimer’s disease; diabetes mellitus; molecular docking; obesity.

Figure 1

A summary of the pathogenesis of MetS-related AD. First, under low-grade inflammation in adipose tissue caused by MetS, IR is formed in the adipose tissue, liver, and muscles due to impaired tyrosine phosphorylation. Afterwards, IR induces hyperglycemia, which causes the formation of more AGEs. IR also leads to energy metabolism dysfunction in mitochondria, which causes more ROS production. Released inflammatory cytokines, AGEs, and ROS damage the BBB; then, they enter the brain matter via the impaired BBB. After entering, they directly hamper neurons or activate microglia cells to damage neurons.

Figure 2

Docking results between 10-HDA and GLP-1R: (a) A gross view of the optimal conformation between GLP-1R and 10-HDA after molecular docking. (b) Details of the binding site be-tween GLP-1R and 10-HDA. Here, 10-HDA is represented as orange sticks, while GLP-1R is represented as a grey surface. And amino acid residues are represented as blue sticks, while hydrogen bonds are represented as dashed yellow sticks. Four hydrogen bonds are shown in the image, and 10-HDA is rooted in the binding pocket of GLP-1R.

Figure 3

Docking results between 10-HDA and PPAR-γ: (a) A gross view of the optimal conformation between PPAR-γ and 10-HDA after molecular docking. (b) Details of the binding site be-tween PPAR-γ and 10-HDA. Here, 10-HDA is represented as orange sticks, while PPAR-γ is represented as a grey surface. And amino acid residues are represented as blue sticks, while hydrogen bonds are represented as dashed yellow sticks. Four hydrogen bonds are shown in the image, and 10-HDA is rooted in the binding pocket of PPAR-γ.

Figure 4

Docking results between 10-HDA and PPAR-α: (a) A gross view of the optimal conformation between PPAR-α and 10-HDA after molecular docking. (b) Details of the binding site be-tween PPAR-α and 10-HDA. Here, 10-HDA is represented as orange sticks, while PPAR-α is represented as a grey surface. And amino acid residues are represented as blue sticks, while hydrogen bonds are represented as dashed yellow sticks. Six hydrogen bonds are shown in the image, and 10-HDA is rooted in the binding pocket of PPAR-α.

Figure 5

Docking results between 10-HDA and GSK-3: (a) A gross view of the optimal conformation between GSK-3 and 10-HDA after molecular docking. (b) Details of the binding site between GSK-3 and 10-HDA. Here, 10-HDA is represented as orange sticks, while GSK-3 is represented as a grey surface. And amino acid residues are represented as blue sticks, while hydrogen bonds are represented as dashed yellow sticks. Four hydrogen bonds are shown in the image, and 10-HDA is rooted in the binding pocket of GSK-3.

Figure 6

Docking results between 10-HDA and TREM2: (a) A gross view of the optimal conformation between TREM2 and 10-HDA after molecular docking. (b) Details of the binding site be-tween TREM2 and 10-HDA. Here, 10-HDA is represented as orange sticks, while TREM2 is represented as a grey surface. And amino acid residues are represented as blue sticks, while hydrogen bonds are represented as dashed yellow sticks. Five hydrogen bonds are shown in the image, and 10-HDA is rooted in the binding pocket of TREM2.