Multi-Omics, an Integrated Approach to Identify Novel Blood Biomarkers of Alzheimer’s Disease

François, Maxime; Karpe, Avinash V.; Liu, Jianwei; Beale, David J.; Hor, Maryam; Hecker, Jane; Faunt, Jeff; Maddison, John; Johns, Sally; Doecke, James D.; Rose, Stephen; Leifert, Wayne R.

doi:10.3390/metabo12100949

Cited by 17 publications

(6 citation statements)

References 66 publications

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“…As the worms aged, there was a further increase in metabolite alterations associated with energy and lipid metabolism in the c strain, which are changes observed in AD [35][36][37][38][39][40] . These findings suggest that the expression of Tau and Aβ leads to disruptions in energy metabolism, lipid metabolism, and mitochondrial function, which may contribute to the observed changes in the proteome, metabolome and phenotypes associated with the Tau;Aβ strain.…”

Section: Discussionmentioning

confidence: 82%

Neuronal expression of human amyloid-β and Tau drives global phenotypic and multi-omic changes inC. elegans

Holcom

Fuentealba

Sivapatham

et al. 2023

Preprint

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Alzheimer's disease (AD) and Alzheimer's related diseases (ADRD) represent prevalent age-related neurodegenerative disorders characterized by the accumulation of amyloid-β (Aβ) plaques and Tau neurofibrillary tangles. The intricate interplay between Aβ and Tau proteins requires further investigation to better understand the precise mechanisms underlying disease pathology. The nematodeCaenorhabditis elegansserves as an invaluable model organism for studying aging and neurodegenerative diseases. Here we performed an unbiased systems analysis of aC. elegansstrain expressing both Aβ and Tau proteins within neurons. Intriguingly, even at an early stage of adulthood, we observed reproductive impairments and mitochondrial dysfunction consistent with substantial disruptions in mRNA transcript abundance, protein solubility, and metabolite levels. Notably, the simultaneous expression of these two neurotoxic proteins exhibited a synergistic effect, leading to accelerated aging in the model organism. Our comprehensive findings shed light on the intricate relationship between normal aging processes and the etiology of ADRD. Specifically, we demonstrate the alterations to metabolic functions precede age-related neurotoxicity, offering critical insights into potential therapeutic strategies.

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Section: Discussionmentioning

confidence: 82%

Neuronal expression of human amyloid-β and Tau drives global phenotypic and multi-omic changes inC. elegans

Holcom

Fuentealba

Sivapatham

et al. 2023

Preprint

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“…Contrary to the fact that increased expression of CD206 is considered a marker of alternative (anti-inflammatory) metabolic polarization of macrophages [34], it has a special role in the assessment of polarized activation of microglia. It is known that mannose-binding lectins, including mannose receptors, are able to bind to A, which causes a pro-inflammatory metabolic shift of cells of the immune system, including microglia [35,36]. In animals with A1-40-induced AD, the quantitative indicators of CD206+ cells were 3.5 times higher, and the expression level was 5 times higher as compared to the groups of control animals.…”

Section: Resultsmentioning

confidence: 97%

Microglial Phagocytosis in Rats With Different Models of Alzheimer's Disease

Nefedova

2023

Biotechnol. acta

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Neuroinflammation is a key feature of Alzheimer's disease (AD), a progressive neurodegenerative disorder. Microglia, the resident immune cells of the central nervous system, play a crucial role in the pathogenesis of AD and are active participants in neuroinflammation. Adequate reproduction of neuroinflammation in animal models is one of the main methodological approaches for studying AD pathogenesis and pathophysiology. The aim of the study was to conduct a comparative assessment of the phagocytic activity of microglia in rats with AD induced by intrahippocampal administration of beta-amyloid (Aβ) 1-40 and Aβ25-35. Materials and methods. Wistar male rats were used in the study. Intact and sham-operated animals were used as controls. The development of the disease was confirmed by the assessment of cognitive impairment in the Barnes maze behavioral test, as well as by the level of dopaminergic neurons (DN). The phagocytic activity of microglia, as well as oxidative metabolism and the expression of phenotypic markers CD80 and CD206 were determined by flow cytometry. Results. In animals with Aβ 1-40-induced AD, significant impairment of cognitive activity and loss of DN were registered, microglial cells were characterized by an increase in the proportion of phagocytic cells and an increase in their endocytic activity, augmented oxidative metabolism and overexpression of CD86 and CD206. In animals with Aβ 25-35-induced AD, moderate impairment of cognitive activity was observed, microglial cells were characterized only by an increase in the number of phagocytizing cells without changes in their endocytic activity, oxidative metabolism, and expression of phenotypic markers. Conclusion. Thus, in animals with Aβ1–40-induced AD, the pro-inflammatory functional profile of microglia, which is characteristic for neuroinflammation in the clinical course of the disease, is more adequately reproduced.

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“…We found that those with the lowest choline levels corresponded to lower MMA. Metabolomic studies have found that MMA is decreased in patients with MCI and AD compared to healthy controls [ 19 ]. This supports our findings as the AD Sev group had the lowest choline levels.…”

Section: Discussionmentioning

confidence: 99%

Inflammation and the pathological progression of Alzheimer’s disease are associated with low circulating choline levels

Judd,

Jasbi,

Winslow

et al. 2023

Acta Neuropathol

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Deficiency of dietary choline, an essential nutrient, is observed worldwide, with ~ 90% of Americans being deficient. Previous work highlights a relationship between decreased choline intake and an increased risk for cognitive decline and Alzheimer’s disease (AD). The associations between blood circulating choline and the pathological progression in both mild cognitive impairment (MCI) and AD remain unknown. Here, we examined these associations in a cohort of patients with MCI with presence of either sparse or high neuritic plaque density and Braak stage and a second cohort with either moderate AD (moderate to frequent neuritic plaques, Braak stage = IV) or severe AD (frequent neuritic plaques, Braak stage = VI), compared to age-matched controls. Metabolomic analysis was performed on serum from the AD cohort. We then assessed the effects of dietary choline deficiency (Ch−) in 3xTg-AD mice and choline supplementation (Ch+) in APP/PS1 mice, two rodent models of AD. The levels of circulating choline were reduced while pro-inflammatory cytokine TNFα was elevated in serum of both MCI sparse and high pathology cases. Reduced choline and elevated TNFα correlated with higher neuritic plaque density and Braak stage. In AD patients, we found reductions in choline, its derivative acetylcholine (ACh), and elevated TNFα. Choline and ACh levels were negatively correlated with neuritic plaque load, Braak stage, and TNFα, but positively correlated with MMSE, and brain weight. Metabolites L-Valine, 4-Hydroxyphenylpyruvic, Methylmalonic, and Ferulic acids were significantly associated with circuiting choline levels. In 3xTg-AD mice, the Ch− diet increased amyloid-β levels and tau phosphorylation in cortical tissue, and TNFα in both blood and cortical tissue, paralleling the severe human-AD profile. Conversely, the Ch+ diet increased choline and ACh while reducing amyloid-β and TNFα levels in brains of APP/PS1 mice. Collectively, low circulating choline is associated with AD-neuropathological progression, illustrating the importance of adequate dietary choline intake to offset disease.

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Multi-Omics, an Integrated Approach to Identify Novel Blood Biomarkers of Alzheimer’s Disease

Cited by 17 publications

References 66 publications

Neuronal expression of human amyloid-β and Tau drives global phenotypic and multi-omic changes inC. elegans

Neuronal expression of human amyloid-β and Tau drives global phenotypic and multi-omic changes inC. elegans

Microglial Phagocytosis in Rats With Different Models of Alzheimer's Disease

Inflammation and the pathological progression of Alzheimer’s disease are associated with low circulating choline levels

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