Studies on diagnostic biomarkers and therapeutic mechanism of Alzheimer's disease through metabolomics and hippocampal proteomics

Lin, Weiwei; Zhang, Jianmei; Liu, Yanmeng; Wu, Ruijun; Yang, Haisong; Hu, Xiaobo; Ling, Xiaomei

doi:10.1016/j.ejps.2017.05.003

Cited by 42 publications

(26 citation statements)

References 29 publications

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“…The observed decreased level in multiple LysoPC species with saturated FACs may contradict an inflammatory role; however, we cannot conclude on the fate of these species as the rates of synthesis and clearance ultimately determine circulating levels. Of note, decreased LysoPC levels were also reported in other inflammatory states, including obesity and Alzheimer’s disease [47,48,49,50,51].…”

Section: Discussionmentioning

confidence: 93%

Dysregulated Choline, Methionine, and Aromatic Amino Acid Metabolism in Patients with Wilson Disease: Exploratory Metabolomic Profiling and Implications for Hepatic and Neurologic Phenotypes

Mazi

Sarode

Członkowska

et al. 2019

IJMS

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Wilson disease (WD) is a genetic copper overload condition characterized by hepatic and neuropsychiatric symptoms with a not well-understood pathogenesis. Dysregulated methionine cycle is reported in animal models of WD, though not verified in humans. Choline is essential for lipid and methionine metabolism. Defects in neurotransmitters as acetylcholine, and biogenic amines are reported in WD; however, less is known about their circulating precursors. We aimed to study choline, methionine, aromatic amino acids, and phospholipids in serum of WD subjects. Hydrophilic interaction chromatography-quadrupole time-of-flight mass spectrometry was employed to profile serum of WD subjects categorized as hepatic, neurologic, and pre-clinical. Hepatic transcript levels of genes related to choline and methionine metabolism were verified in the Jackson Laboratory toxic milk mouse model of WD (tx-j). Compared to healthy subjects, choline, methionine, ornithine, proline, phenylalanine, tyrosine, and histidine were significantly elevated in WD, with marked alterations in phosphatidylcholines and reductions in sphingosine-1-phosphate, sphingomyelins, and acylcarnitines. In tx-j mice, choline, methionine, and phosphatidylcholine were similarly dysregulated. Elevated choline is a hallmark dysregulation in WD interconnected with alterations in methionine and phospholipid metabolism, which are relevant to hepatic steatosis. The elevated phenylalanine, tyrosine, and histidine carry implications for neurologic manifestations and are worth further investigation.

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Section: Discussionmentioning

confidence: 93%

Dysregulated Choline, Methionine, and Aromatic Amino Acid Metabolism in Patients with Wilson Disease: Exploratory Metabolomic Profiling and Implications for Hepatic and Neurologic Phenotypes

Mazi

Sarode

Członkowska

et al. 2019

IJMS

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“…In one study, LPC levels were significantly increased in patients with repetitive mild traumatic brain injury [82]. However, other studies have shown that plasma levels of LPC were decreased in patients with Alzheimer’s disease [54,55] and that the LPC-to-PC ratio was also decreased either in plasma or in cerebrospinal fluid from patients with Alzheimer’s disease [56,77].…”

Section: Lysophosphatidylcholine and Human Diseasesmentioning

confidence: 99%

“…For example, plasma LPCs showed an inverse relationship with cardiovascular diseases [51,52,53]. In other studies, the LPC:PC ratio decreased either in plasma or cerebrospinal fluid from patients with Alzheimer’s disease [54,55,56]. To help clarify the controversy and delineate the role of LPC in these diseases, we have provided a timely and important updated review on LPC homeostasis.…”

Section: Introductionmentioning

confidence: 99%

An Updated Review of Lysophosphatidylcholine Metabolism in Human Diseases

Law

Chan

Marathe

et al. 2019

IJMS

533

379

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Lysophosphatidylcholine (LPC) is increasingly recognized as a key marker/factor positively associated with cardiovascular and neurodegenerative diseases. However, findings from recent clinical lipidomic studies of LPC have been controversial. A key issue is the complexity of the enzymatic cascade involved in LPC metabolism. Here, we address the coordination of these enzymes and the derangement that may disrupt LPC homeostasis, leading to metabolic disorders. LPC is mainly derived from the turnover of phosphatidylcholine (PC) in the circulation by phospholipase A2 (PLA2). In the presence of Acyl-CoA, lysophosphatidylcholine acyltransferase (LPCAT) converts LPC to PC, which rapidly gets recycled by the Lands cycle. However, overexpression or enhanced activity of PLA2 increases the LPC content in modified low-density lipoprotein (LDL) and oxidized LDL, which play significant roles in the development of atherosclerotic plaques and endothelial dysfunction. The intracellular enzyme LPCAT cannot directly remove LPC from circulation. Hydrolysis of LPC by autotaxin, an enzyme with lysophospholipase D activity, generates lysophosphatidic acid, which is highly associated with cancers. Although enzymes with lysophospholipase A1 activity could theoretically degrade LPC into harmless metabolites, they have not been found in the circulation. In conclusion, understanding enzyme kinetics and LPC metabolism may help identify novel therapeutic targets in LPC-associated diseases.

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“…Several groups have used proteomics approaches to discover biomarkers for AD [4–6]. Russell et al combined tissue and fluid proteomics with tandem mass tags (TMT) for detection of low-abundance peptides in biological fluids [7].…”

Section: Introductionmentioning

confidence: 99%

Quantitative Proteomic Profiling of Cerebrospinal Fluid to Identify Candidate Biomarkers for Alzheimer's Disease

Sathe

Renuse

et al. 2019

Proteomics Clinical Apps

107

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Purpose Development of novel biomarkers for AD is important for early diagnosis, monitoring disease progression and therapeutic response. The aim of this study was to identify the potential CSF biomarkers for Alzheimer's disease (AD) and evaluate these markers on independent CSF samples using a parallel reaction monitoring mass spectrometry (PRM-MS) assay. Experimental design In this study, we employed high-resolution mass spectrometry and tandem mass tag (TMT) multiplexing technology to identify proteins that might serve as candidate biomarkers for Alzheimer’s disease. Identified potential biomarkers were validated using a parallel reaction monitoring mass spectrometry (PRM-MS) assay. Results We identified 2,327 proteins in the cerebrospinal fluid (CSF) of which 139 were observed to be significantly different in their abundance in the CSF of AD patients versus controls. The proteins whose abundance was altered in AD included a number of known AD marker proteins such as MAPT, NPTX2, SCG2, VGF, GFAP, SST and NCAM1 as well as novel biomarkers such as GSN, PKM and YWHAG. We then sought to validate these findings in a separate set of CSF specimens from AD dementia patients and controls. For the AD group, significant increases were found for YWHAG and PKM, and a significant decrease was observed for VGF by multiplexed targeted parallel reaction monitoring (PRM) experiments. NPTX2 in combination with PKM or with YWHAG led to the best results with AUCs of 0.935 and 0.933, respectively. Conclusions and clinical relevance The identified altered CSF proteins in AD CSF samples will be useful to understand AD pathogenesis.

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Studies on diagnostic biomarkers and therapeutic mechanism of Alzheimer's disease through metabolomics and hippocampal proteomics

Cited by 42 publications

References 29 publications

Dysregulated Choline, Methionine, and Aromatic Amino Acid Metabolism in Patients with Wilson Disease: Exploratory Metabolomic Profiling and Implications for Hepatic and Neurologic Phenotypes

Dysregulated Choline, Methionine, and Aromatic Amino Acid Metabolism in Patients with Wilson Disease: Exploratory Metabolomic Profiling and Implications for Hepatic and Neurologic Phenotypes

An Updated Review of Lysophosphatidylcholine Metabolism in Human Diseases

Quantitative Proteomic Profiling of Cerebrospinal Fluid to Identify Candidate Biomarkers for Alzheimer's Disease

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