Linking lipids to Alzheimer's disease: cholesterol and beyond

Paolo, Gilbert Di; Kim, Tae‐Wan

doi:10.1038/nrn3012

Cited by 813 publications

(667 citation statements)

References 147 publications

(219 reference statements)

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“…In a broader context, altered lipid compositions are associated with a number of diseases such as cancer [31], obesity [32], Alzheimer's disease [33], liver disease [34] and type 2 diabetes [35]. Therefore, quantitative system models of cellular phospholipid homeostasis are critical to understanding these pathologies.…”

Section: Introductionmentioning

confidence: 99%

Mammalian phospholipid homeostasis: evidence that membrane curvature elastic stress drives homeoviscous adaptation in vivo

Dymond

2016

J. R. Soc. Interface.

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Several theories of phospholipid homeostasis have postulated that cells regulate the molecular composition of their bilayer membranes, such that a common biophysical membrane parameter is under homeostatic control. Two commonly cited theories are the intrinsic curvature hypothesis, which states that cells control membrane curvature elastic stress, and the theory of homeoviscous adaptation, which postulates cells control acyl chain packing order (membrane order). In this paper, we present evidence from datadriven modelling studies that these two theories correlate in vivo. We estimate the curvature elastic stress of mammalian cells to be 4-7 Â 10 212 N, a value high enough to suggest that in mammalian cells the preservation of membrane order arises through a mechanism where membrane curvature elastic stress is controlled. These results emerge from analysing the molecular contribution of individual phospholipids to both membrane order and curvature elastic stress in nearly 500 cellular compositionally diverse lipidomes. Our model suggests that the de novo synthesis of lipids is the dominant mechanism by which cells control curvature elastic stress and hence membrane order in vivo. These results also suggest that cells can increase membrane curvature elastic stress disproportionately to membrane order by incorporating polyunsaturated fatty acids into lipids.

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Section: Introductionmentioning

confidence: 99%

Mammalian phospholipid homeostasis: evidence that membrane curvature elastic stress drives homeoviscous adaptation in vivo

Dymond

2016

J. R. Soc. Interface.

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“…Estrogen has also been shown to act as a trophic factor promoting the growth and arborization of axons and dendrites in culture (17)(18)(19), as well as promoting synapse/spine formation (20 -26). In addition, estrogen also regulates the transcription of key enzymes involved in the synthesis and turnover of classic neurotransmitters including noradrenaline, dopamine, serotonin, and acetylcholine (27)(28)(29)(30), as well as the transcription of neurotrophins; neuropeptides, including vasopressin and insulin-like growth factor (31)(32)(33)(34); and cell surface receptors such as oxytocin receptor (35).…”

mentioning

confidence: 99%

Transcriptional Interaction of an Estrogen Receptor Splice Variant and ErbB4 Suggests Convergence in Gene Susceptibility Pathways in Schizophrenia

Wong

Weickert

2009

Journal of Biological Chemistry

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Mounting evidence from clinical and basic research suggests that estrogen signaling may be altered in the brains of people with schizophrenia. Previously, we found that DNA sequence variation in the estrogen receptor (ER) ␣ gene, lower ER␣ mRNA levels, and/or blunted ER␣ signaling is associated with schizophrenia. In this study, we asked whether the naturally occurring truncated ER␣ isoform, ⌬7, which acts as a dominant negative, can attenuate gene expression induced by the wildtype (WT) receptor in an estrogen-dependent manner in neuronal (SHSY5Y) and non-neuronal (CHOK1 and HeLa) cells. In addition, we determined the extent to which ER␣ interacts with NRG1-ErbB4, a leading schizophrenia susceptibility pathway. Reductions in the transcriptionally active form of ErbB4 comprising the intracytoplasmic domain (ErbB4-ICD) have been found in schizophrenia, and we hypothesized that ER␣ and ErbB4 may converge to control gene expression. In the present study, we show that truncated ⌬7-ER␣ attenuates WT-ER␣-driven gene expression across a wide range of estrogen concentrations in cells that express functional ER␣ at base line or upon co-transfection of full-length ER␣. Furthermore, we find that ErbB4-ICD can potentiate the transcriptional activity of WT-ER␣ at EREs in two cell lines and that this potentiation effect is abolished by the presence of ⌬7-ER␣. Immunofluorescence microscopy revealed nuclear co-localization of WT-ER␣, ⌬7-ER␣, and ErbB4-ICD, whereas immunoprecipitation assays showed direct interaction. Our findings demonstrate convergence between ER␣ and ErbB4-ICD in the transcriptional control of ER␣-target gene expression and suggest that this may represent a convergent pathway that may be disrupted in schizophrenia.Schizophrenia is a devastating mental illness of unknown cause, afflicting 1% of the population worldwide. At present, the molecular processes underlying the development and progression of schizophrenia have not been clearly identified; however, we have recently found evidence to support the hypothesis that schizophrenia arises from a derailment of normal brain maturation during adolescence where the brain fails to respond to the developmental increase in sex steroids (testosterone and estrogen) (1). Testosterone is commonly converted into estrogen by the action of the enzyme aromatase whereby the converted hormone serves as a ligand for estrogen receptors. Schizophrenia affects both men and women occurring at a ratio of ϳ3:2, respectively (2). Males typically have an earlier age of onset and more severe symptoms and tend to be less treatment responsive than females with schizophrenia (3). However, women with schizophrenia can have symptom exacerbation at times of low estrogen: during post-partum and menopause (4 -6), and schizophrenic symptoms can be ameliorated with estrogen treatment (7-11).Estrogen affects the developing brain by influencing the genesis, development, migration, plasticity, and survival of neurons (12-16). Estrogen has also been shown to act as a trophic factor promoting the grow...

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“…There is evidence that changes in lipid parameters can affect AD pathology directly through complex interrelations with both plaque and neurofibrillary tangle formation [40,41]. Mapstone et al [42] discovered and validated a set of 10 lipids from peripheral blood that predicted a phenoconversion to either amnestic MCI or AD within a 2- to 3-year time frame with high accuracy.…”

Section: Circulating Biomarker Signaturementioning

confidence: 99%

“…A dysregulation of lipid pathways has been implicated in AD as well as in other neurodegenerative disorders [40]. There is evidence that changes in lipid parameters can affect AD pathology directly through complex interrelations with both plaque and neurofibrillary tangle formation [40,41].…”

Section: Circulating Biomarker Signaturementioning

confidence: 99%

Circulating Biomarker Panels in Alzheimer's Disease

et al. 2015

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The early diagnosis of diseases frequently represents an important unmet clinical need supporting in-time treatment of pathologies. This also applies to neurodegenerative diseases such as Alzheimer's disease (AD), the most common form of dementia, estimated to affect millions of individuals worldwide. The respective diagnostic and prognostic markers, especially for the preclinical stages of AD, are expected to improve patients' outcome significantly. In the last decades, many approaches to detecting AD have been developed, including markers to discover changes in amyloid-β levels [from cerebrospinal fluid (CSF) or using positron emission tomography] or other brain imaging technologies such as structural magnetic resonance imaging (MRI), functional-connectivity MRI or task-related functional MRI. A major challenge is the detection of AD using minimally or even noninvasive biomarkers from body fluids such as plasma or serum. Circulating biomarker candidates based on mRNAs or proteins measured from blood cells, plasma or serum have been proposed for various pathologies including AD. As for other diseases, there is a tendency to use marker signatures obtained by high-throughput approaches, which allow the generation of profiles of hundreds to thousands of biomarkers simultaneously [microarrays, mass spectrometry or next-generation sequencing (NGS)]. Beyond mRNAs and proteins, recent approaches have measured small noncoding RNA (so-called microRNA) profiles in AD patients' blood samples using NGS or array-based technologies. Generally, the development of marker panels is in its early stages and requires further, substantial clinical validation. In this review, we provide an overview of different circulating AD biomarkers, starting with a brief summary of CSF markers and focusing on novel biomarker signatures such as small noncoding RNA profiles.

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Linking lipids to Alzheimer's disease: cholesterol and beyond

Cited by 813 publications

References 147 publications

Mammalian phospholipid homeostasis: evidence that membrane curvature elastic stress drives homeoviscous adaptation in vivo

Mammalian phospholipid homeostasis: evidence that membrane curvature elastic stress drives homeoviscous adaptation in vivo

Transcriptional Interaction of an Estrogen Receptor Splice Variant and ErbB4 Suggests Convergence in Gene Susceptibility Pathways in Schizophrenia

Circulating Biomarker Panels in Alzheimer's Disease

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