Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease

Rhinn, Hervé; Fujita, Reiko; Qiang, Liang; Cheng, Rong; Lee, Joseph H.; Abeliovich, Asa

doi:10.1038/nature12415

Cited by 146 publications

(140 citation statements)

References 56 publications

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“…RIF has been used to unravel the causal basis of Parkinson's (Rhinn et al, 2012) and Alzheimer's (Rhinn et al, 2013) diseases from brain transcriptome data, showing it generalises very well across species, tissues and data structure. This approach identified key roles for a number of TF relating to inflammation, fatty acid metabolism and production of fatty masses called liposarcoma.…”

Section: Marbling Physiology and Developmentmentioning

confidence: 99%

Longitudinal muscle gene expression patterns associated with differential intramuscular fat in cattle

Hudson

Reverter

Greenwood

et al. 2015

Animal

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Intramuscular fat (IMF) can improve meat product quality through its impact on flavour and juiciness. High marbling cuts can command premium prices in some countries and grading systems, but there is substantial cost involved in choosing to grain feed animals in an effort to deposit more IMF. There would be value in developing methods to predict predisposition to 'marble' well. Unfortunately, the biological mechanisms underpinning marbling remain a mystery: the key adipocyte cell populations have not been defined, there are no reliable DNA markers, no known (if any) causal mutations and gene expression analyses in the main have tended to characterise increases in expression of end-point fat metabolism proteins such as the fatty acid-binding proteins. To shed light on expression-based markers of marbling potential, we contrasted LD gene expression in high IMF Wagyu cross animals with a low IMF Piedmontese cross at various time points. The expected divergence in the fat metabolism genes FABP4, THRSP, CIDEC and ACACA between the breeds occurs surprisingly late in postnatal development at about 20 months. On the other hand, divergent expression of WISP2, RAI14 and CYP4F2 was discovered in animals at or before 12 months of age, suggesting these genes may have potential as earlier predictors of marbling potential. In line with other researchers, we found intriguing links between IMF development and connective tissue remodelling. WISP2 -a novel adipokine highly expressed and secreted by adipose precursor cells and an inhibitor of the pro-fibrotic connective tissue growth factor -emerges as a particularly attractive candidate. It is relatively upregulated in high marbling Wagyu before admission to feedlotting, somewhere between 7 and 12 months. This difference is subsequently maintained until 25 months, but not thereafter. RAI14, thought to play a role in porcine adipocyte differentiation and with links to retinoic acid metabolism, has an unusual expression profile. Its expression level increases monotonically with postnatal development, and is always higher in Wagyu than Piedmontese. Strong, sustained upregulation of the anti-inflammatory CYP4F2 in Piedmontese is consistent with Wagyu adiposity being a pro-inflammatory state. Application of regulatory impact factor analysis, a network method for identifying causal effector molecules, suggests marbling roles for transcription factors previously implicated in (1) the formation of liposarcoma (unconstrained fatty masses) (YEATS4, MDM2), (2) adipogenesis (CREBL2, SP1, STAT1) and (3) inflammation (ISGF3G, HOXB13, PML).

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Section: Marbling Physiology and Developmentmentioning

confidence: 99%

Longitudinal muscle gene expression patterns associated with differential intramuscular fat in cattle

Hudson

Reverter

Greenwood

et al. 2015

Animal

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“…For instance, predictions by the ARACNe, MINDy, PrePPI algorithms have been typically validated at a very high rate (~70%) by chromatin immunoprecipitation, gene expression profiling following silencing, coimmunoprecipitation and other relevant assays [12,19,24,25,34,35]. Other systems approaches have also been applied successfully in AD [36][37][38][39], and our focus here is to maintain clarity rather than review the entire literature. Each approach has a series of advantages and disadvantages.…”

Section: Creating the Assembly Manual Of The Alzheimer's Cellmentioning

confidence: 99%

A Systems Approach to Drug Discovery in Alzheimer's Disease

et al. 2015

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In the articles included in this volume, one feels a strong frustration among the writers with the slow course of therapeutics development for Alzheimer's disease and with the clinical failure of targeted therapeutic agents despite substantial progress in our understanding of the biology and biochemistry of the disease. Keywords Master regulator . Interactome . Human neuronsTo date, approaches to Alzheimer disease (AD) therapeutics have followed 2 main avenues. The first addresses neurotransmitter deficits in the early phases of the disease. This approach has led to the handful of AD drugs currently on the market that provide short-term symptomatic improvement but do not alter the course of the disease. The second approach has been directed at decreasing the burden of beta-amyloid (Aβ) in the brain by active or passive immunization or by inhibiting activity of β-or γ-secretases. To date, none of the approaches in this second class has been successful, although trials on β-or γ-secretase (BACE) inhibitors are ongoing.The lack of overt success has been even more frustrating because, in transgenic (Aβ-overproducing) mouse models of AD, Aβ-lowering approaches, as well as treatments with small molecules and biologics, have been successful in blocking memory loss, restoring memory function, reversing dendritic spine alterations, and reversing inhibition of longterm potentiation [1][2][3]. Indeed, as animal models only partially recapitulate the human AD phenotype and because human brain tissue is available only postmortem, translation of preclinical findings to the clinics has been fraught with difficulties.For instance, the characteristic intraneuronal neurofibrillary tangles and extensive neuronal loss observed in human AD are absent in mouse models of the disease. This dichotomy suggests that mouse models replicate only presymptomatic AD stages, while clinical manifestations appear only after neuronal loss becomes irreversible. This hypothesis is directly addressed by ongoing trials, where individuals with genetic mutations that predispose to early AD onset are being treated with Aβ-targeted therapies to assess whether presymptomatic treatment may block an otherwise certain disease progression. Beyond Aβ-targeted therapies, novel approaches are being developed based on inhibition of tau phosphorylation and aggregation, and on blockade of synaptic loss, leveraging "candidate" target approaches derived from human and animal data. Unfortunately, it has so far been impossible to discern whether "candidate genes" represent causal determinants of the disease process or are the downstream result of them.In this review, we will discuss the potential of adapting integrative systems biology approaches that have already proven extremely valuable in understanding multiple cancer related phenotypes to human neurodegenerative diseases.

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“…Mice deficient in SV2A develop seizures and die within 3 wk of birth (4). In addition to its well-established role as the target for the antiepileptic drug levetiracetam (5,6), dysfunction of SV2A has been implicated in other neurologic disorders such as Alzheimer's disease (7)(8)(9).…”

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confidence: 99%

Synthesis and Preclinical Evaluation of¹¹C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain

et al. 2016

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The synaptic vesicle glycoprotein 2A (SV2A) is found in secretory vesicles in neurons and endocrine cells. PET with a selective SV2A radiotracer will allow characterization of drugs that modulate SV2A (e.g., antiepileptic drugs) and potentially could be a biomarker of synaptic density (e.g., in neurodegenerative disorders). Here we describe the synthesis and characterization of the SV2A PET radiotracer 11 C-UCB-J ((R)-1-((3-( 11 C-methyl-11 C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) in nonhuman primates, including whole-body biodistribution. Methods: 11 C-UCB-J was prepared by C-11 C-methylation of the 3-pyridyl trifluoroborate precursor with 11 C-methyl iodide via the Suzuki-Miyaura cross-coupling method. Rhesus macaques underwent multiple scans including coinjection with unlabeled UCB-J (17, 50, and 150 μg/kg) or preblocking with the antiepileptic drug levetiracetam at 10 and 30 mg/kg. Scans were acquired for 2 h with arterial sampling and metabolite analysis to measure the input function. Regional volume of distribution (V T ) was estimated using the 1-tissue-compartment model. Target occupancy was assessed using the occupancy plot; the dissociation constant (K d ) was determined by fitting self-blocking occupancies to a 1-site model, and the maximum number of receptor binding sites (B max ) values were derived from baseline V T and from the estimated K d and the nondisplaceable distribution volume (V ND ). Results: 11 C-UCB-J was synthesized with greater than 98% purity. 11 C-UCB-J exhibited high free fraction (0.46 ± 0.02) and metabolized at a moderate rate (39% ± 5% and 24% ± 3% parent remaining at 30 and 90 min) in plasma. In the monkey brain, 11 C-UCB-J displayed high uptake and fast kinetics. V T was high (∼25-55 mL/cm 3 ) in all gray matter regions, consistent with the ubiquitous expression of SV2A. Preblocking with 10 and 30 mg/kg of levetiracetam resulted in approximately 60% and 90% occupancy, respectively. Analysis of the self-blocking scans yielded a K d estimate of 3.4 nM and B max of 125-350 nM, in good agreement with the in vitro inhibition constant (K i ) of 6.3 nM and regional B max in humans. Whole-body biodistribution revealed that the liver and the brain are the dose-limiting organs for males and females, respectively. Conclusion: 11 C-UCB-J exhibited excellent characteristics as an SV2A PET radiotracer in nonhuman primates. The radiotracer is currently undergoing first-in-human evaluation.

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Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease

Cited by 146 publications

References 56 publications

Longitudinal muscle gene expression patterns associated with differential intramuscular fat in cattle

Longitudinal muscle gene expression patterns associated with differential intramuscular fat in cattle

A Systems Approach to Drug Discovery in Alzheimer's Disease

Synthesis and Preclinical Evaluation of¹¹C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain

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Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease

Cited by 146 publications

References 56 publications

Longitudinal muscle gene expression patterns associated with differential intramuscular fat in cattle

Longitudinal muscle gene expression patterns associated with differential intramuscular fat in cattle

A Systems Approach to Drug Discovery in Alzheimer's Disease

Synthesis and Preclinical Evaluation of11C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain

Contact Info

Product

Resources

About

Synthesis and Preclinical Evaluation of¹¹C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain