Status of Metabolomic Measurement for Insights in Alzheimer's Disease Progression-What Is Missing?

Abstract

Alzheimer's disease (AD) is an aging-related neurodegenerative disease, leading to the progressive loss of memory and other cognitive functions. As there is still no cure for AD, the growth in the number of susceptible individuals represents a major emerging threat to public health. Currently, the pathogenesis and etiology of AD remain poorly understood, while no efficient treatments are available to slow down the degenerative effects of AD. Metabolomics allows the study of biochemical alterations in pathological processes which may be involved in AD progression and to discover new therapeutic targets. In this review, we summarized and analyzed the results from studies on metabolomics analysis performed in biological samples of AD subjects and AD animal models. Then this information was analyzed by using MetaboAnalyst to find the disturbed pathways among different sample types in human and animal models at different disease stages. We discuss the underlying biochemical mechanisms involved, and the extent to which they could impact the specific hallmarks of AD. Then we identify gaps and challenges and provide recommendations for future metabolomics approaches to better understand AD pathogenesis.

Keywords: Alzheimer’s disease; animal; biomarkers; human; lipidomics; metabolomics; pathways.

Figure 1

Metabolic pathway analysis in biological samples (CSF, brain, and plasma) of 43 human AD studies. The size of the circle corresponds to the pathway impact score and was correlated with the centrality of the involved metabolites. Darker circle colors indicated more significant changes in metabolites in the corresponding pathway.

Figure 2

Disturbed metabolic pathways analysis in humans, comparing different disease stages with healthy controls: (A) Intersection analysis of metabolic pathways among MCI and AD groups in plasma samples. Yellow circles are all the disturbed pathways in MCI plasma samples, blue circles are all the disturbed pathways in AD plasma samples, and the middle intersection is pathways in common among MCI and AD in plasma samples. (B) Intersection analysis of metabolic pathways among MCI and AD groups in CSF samples. Yellow circles are all the disturbed pathways in MCI CSF samples, blue circles are all the disturbed pathways in AD CSF samples. All the MCI pathways overlapped with AD pathways in CSF samples. (C) Intersection analysis of metabolic pathways among plasma and CSF samples. Yellow circles are all the disturbed pathways in plasma samples, blue circles are all the disturbed pathways in CSF samples, and the middle intersection is pathways in common among plasma and CSF samples.

Figure 3

Metabolic pathway analysis in biological samples (brain and plasma) of 42 mouse studies. The size of the circle corresponds to the pathway impact score and was correlated with the centrality of the involved metabolites. Darker circle colors indicated more significant changes in metabolites in the corresponding pathway.

Figure 4

Altered metabolic pathways in mouse plasma and brain samples, comparing AD and control animals. (A) Heatmap of the changes of significantly altered metabolic pathways at different ages of AD mouse in brain and plasma samples. The impact value is calculated as the sum of the importance measures of matched metabolites normalized by the sum of the importance measures of all metabolites in each pathway. (B) Altered pathways in AD mouse plasma and brain samples combining all age groups. Yellow circles are all the disturbed pathways in mouse plasma samples, blue circles are all the disturbed pathways in mouse brain samples, and the middle intersection is pathways in common among plasma and brain samples in mouse research.

Figure 5

Arginine metabolic pathways. L-arginine can be metabolized by phosphatidic acid (PA), nitric oxide synthase (NOS), arginase, and arginine decarboxylase (ADC) to form several bioactive molecules. (ADC, Arginine decarboxylase; ADMA, NG-dimethyl-L-arginine; DDAH, dimethylarginine dimethylaminohydrolase; GABA, γ-aminobutyric acid; ODC, ornithine decarboxylase;).