Late-onset Alzheimer’s disease is associated with inherent changes in bioenergetics profiles

Sonntag, Kai‐Christian; Ryu, Woo-In; Amirault, Kristopher M.; Healy, Ryan A; Siegel, Arthur J.; McPhie, Donna L.; Forester, Brent P.; Cohen, Bruce M.

doi:10.1038/s41598-017-14420-x

Cited by 118 publications

(130 citation statements)

References 52 publications

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“…Changes in mitochondrial function in AD fibroblasts also recapitulate metabolic alterations in energy pathways that we and others identified in the CSF and plasma from patients with MCI and AD [32,51,56]. These findings support the hypothesis that impairment of bioenergetics, mitochondrial dynamics and function, and cell metabolism occur throughout the body and contribute to the pathophysiology of AD providing a rationale for the analysis of mitochondrial bioenergetics in peripheral tissues as a promising strategy to develop new diagnostic methods for AD [33].…”

Section: Altered Energy Homeostasis and Mitochondrial Dysfunctionsupporting

confidence: 84%

“…Additional studies confirmed altered mitochondrial function in glucose and glutamine oxidation in fibroblasts from patients with sporadic AD [54]. Functional analysis conducted using an Extracellular Flux Analyzer in intact cells provided additional evidence that LOAD fibroblasts have increased glycolytic capacity, impaired mitochondrial metabolic potential associated with decreased nicotinamide adenine dinucleotide metabolites and reduced activity of the tricarboxylic acid cycle compared to control cells [33]. Lactate levels were higher in LOAD fibroblasts but not in healthy age‐matched and young fibroblasts suggesting that increased glycolysis was specific to the disease and not aging [33].…”

Section: Early Experimental Evidence To Support the Hypothesismentioning

confidence: 94%

“…Functional analysis conducted using an Extracellular Flux Analyzer in intact cells provided additional evidence that LOAD fibroblasts have increased glycolytic capacity, impaired mitochondrial metabolic potential associated with decreased nicotinamide adenine dinucleotide metabolites and reduced activity of the tricarboxylic acid cycle compared to control cells [33]. Lactate levels were higher in LOAD fibroblasts but not in healthy age‐matched and young fibroblasts suggesting that increased glycolysis was specific to the disease and not aging [33]. The authors concluded that the increase in glycolysis and the abnormal mitochondrial metabolic potential in LOAD fibroblasts appeared to be intrinsic further supporting the hypothesis that impairment in multiple components of bioenergetics may be a key mechanism contributing to the risk and pathophysiology of LOAD.…”

Section: Early Experimental Evidence To Support the Hypothesismentioning

confidence: 99%

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Alzheimer's disease mechanisms in peripheral cells: Promises and challenges

Trushina¹

2019

A&D Transl Res & Clin Interv

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Introduction Development of efficacious therapeutic interventions for Alzheimer's disease (AD) is hampered by the lack of understanding early disease mechanisms, biomarkers, and models that mimic complex pathophysiology of human disease. Methods This article aims to assess to what extent peripheral cells recapitulate molecular mechanisms altered in the brain and could be used as translational models for the development of individualized medicine for AD. Results Multiple studies suggest that AD is a systemic disorder with an active crosstalk between brain and periphery where multiple pathways altered in the brain cells are also affected in plasma, cerebrospinal fluid, and other peripheral cells of AD patients. Discussion Additional studies to validate molecular mechanisms in peripheral cells using advanced system biology techniques and well‐characterized cohorts of AD patients together with the development of standardized protocols should be considered to support the application of peripheral cells in AD research.

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Section: Altered Energy Homeostasis and Mitochondrial Dysfunctionsupporting

confidence: 84%

Section: Early Experimental Evidence To Support the Hypothesismentioning

confidence: 94%

Section: Early Experimental Evidence To Support the Hypothesismentioning

confidence: 99%

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Alzheimer's disease mechanisms in peripheral cells: Promises and challenges

Trushina¹

2019

A&D Transl Res & Clin Interv

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“…Moreover, it has been suggested that nutritional behavior is a key triggering factor in the pre-symptomatic stages of AD (Ríos et al 2014). Additional hypothesis emphasizing impairment of bioenergetic metabolism as a key contributing mechanism to the pathogenesis of AD has been proposed recently (Sonntag et al 2017). According to the authors, AD is characterized by a combination of several interrelating pathological events that include bio-energetic, metabolic, neurovascular, and inflammatory processes.…”

Section: Introductionmentioning

confidence: 99%

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

Polis

Srikanth

Elliott

et al. 2018

Preprint

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The urea cycle plays a role in the pathogenesis of Alzheimer's disease (AD). Arginase-I accumulation at sites of amyloid-beta deposition is associated with L-arginine deprivation and neurodegeneration. Moreover, a positive interaction between the arginase-II and mTOR-S6K1 pathways promote inflammation and oxidative stress. In this study, we treated 3xTg-AD mice exhibiting increased ribosomal protein S6 kinase beta-1 (S6K1) activity and wild-type (WT) mice with L-norvaline. The substance combines unique properties of arginase and S6K1 inhibition. The treated 3xTg-AD mice demonstrated significantly improved acquisition of spatial memory, associated with a substantial reduction of microgliosis and shift from activated to resting phenotype. Moreover, an increase of dendritic spines density and escalation of the expression rates of neuroplasticity related proteins were followed by a decline in the levels of amyloid-beta toxic oligomeric and fibrillar species in the hippocampus. Our findings associate local amyloid-beta-driven and immune-mediated response with altered L-arginine metabolism and suggest that arginase and S6K1 inhibition by L-norvaline can delay progression of AD.

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“…Interestingly, all three of the aforementioned major AD risk factors, i.e. age, APOE ε4 genotype, and sex, have a profound impact on metabolism (24)(25)(26)(27)(28)(29)(30), supporting the view of AD as a metabolic disease (31)(32)(33). In recent years, availability of high-throughput metabolomics techniques, which can measure hundreds of small biochemical molecules (metabolites) simultaneously, allows for the study of metabolic imprints of age, genetic variation, and sex very broadly, covering the entire metabolism: (i) Age-dependent differences were observed in levels of phosphatidylcholines (PCs), sphingomyelins (SMs), acylcarnitines, ceramides, and amino acids (29,34).…”

Section: Introductionmentioning

confidence: 95%

The Alzheimer’s Disease Metabolome: Effects of Sex andAPOEε4 genotype

Arnold¹,

Nho²,

Kueider‐Paisley³

et al. 2019

Preprint

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Research provides substantial evidence that late-onset Alzheimer's disease (AD), the major cause of dementia in the elderly, is a metabolic disease. Besides age, female sex and APOEε4 genotype represent strong risk factors for AD, and at the same time, give rise to large metabolic differences. Our systematic investigation of sex and APOE ε4 genotype differences in the link between metabolism and measures of pre-symptomatic AD using stratified analysis revealed several group-specific metabolic alterations that were not observed without sex and genotype stratification of the same cohort. Pathways linked to the observed metabolic alterations suggest females are more affected by impairment of mitochondrial energy production in AD than males, highlighting the importance of tailored treatment approaches towards a precision medicine approach. AbstractRecent studies have provided evidence that late-onset Alzheimer's disease (AD), the major cause of dementia in the elderly, can, at least in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD. At the same time, they both give rise to large metabolic differences, suggesting that metabolic aspects of AD pathogenesis may differ between males and females and APOE ε4 carriers and non-carriers, respectively. Here, we systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 140 metabolites measured in serum samples of 1,517 individuals from the AD neuroimaging initiative with AD biomarkers for Aβ and tau pathology, as well as neurodegeneration. We observed substantial sex differences in effects of 15 metabolites on AD biomarkers with partially overlapping differences for APOE ε4 status groups. These metabolites highlighted several group-specific alterations that were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification by both variables uncovered further subgroup-specific metabolic effects limited to the group with presumably highest AD risk, i.e. APOE ε4+ females. Pathways linked to the observed metabolic alterations suggest that females experience more expressed impairment of mitochondrial energy production in AD than males. These findings indicate that dissecting metabolic heterogeneity in AD pathogenesis may allow for grading the biomedical relevance of specific pathways for specific subgroups. Extending our approach beyond simple one or two-fold stratification may thus guide the way to personalized medicine. Alzheimer's Association; Alzheimer's Drug Fund and the Karen L. Wrenn Trust. PMD has served as an advisor to and or received grants from companies for other projects. PMD also owns shares or serves on the board of companies whose products are not discussed here. PMD is also a co-inventor on patents in this field through Duke University which are unlicensed.

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Late-onset Alzheimer’s disease is associated with inherent changes in bioenergetics profiles

Cited by 118 publications

References 52 publications

Alzheimer's disease mechanisms in peripheral cells: Promises and challenges

Alzheimer's disease mechanisms in peripheral cells: Promises and challenges

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

The Alzheimer’s Disease Metabolome: Effects of Sex andAPOEε4 genotype

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