Changes in brain oxysterols at different stages of Alzheimer's disease: Their involvement in neuroinflammation

Redox Biology, Год журнала: 2016, Номер 10, С. 24 - 33

Опубликована: Сен. 17, 2016

Alzheimer's disease (AD) is a gradually debilitating that leads to dementia. The molecular mechanisms underlying AD are still not clear, and at present no reliable biomarkers available for the early diagnosis. In last several years, together with oxidative stress neuroinflammation, altered cholesterol metabolism in brain has become increasingly implicated progression. A significant body of evidence indicates oxidized cholesterol, form oxysterols, one main triggers AD. oxysterols potentially most closely involved pathogenesis 24-hydroxycholesterol 27-hydroxycholesterol, respectively deriving from oxidation by enzymes CYP46A1 CYP27A1. However, possible involvement resulting autooxidation, including 7-ketocholesterol 7β-hydroxycholesterol, now emerging. systematic analysis post-mortem human brains, classified Braak staging system neurofibrillary pathology, alongside two enzymatic origin, variety autoxidation were identified; these included 7-ketocholesterol, 7α-hydroxycholesterol, 4β-hydroxycholesterol, 5α,6α-epoxycholesterol, 5β,6β-epoxycholesterol. Their levels quantified compared across stages. Some inflammatory mediators, proteolytic enzyme matrix metalloprotease-9, also found be enhanced depending on This highlights pathogenic association between trends molecules oxysterol during evolution Conversely, sirtuin 1, an regulates pathways anti-inflammatory response, was reduced markedly progression AD, supporting hypothesis loss 1 might play key role Taken together, results strongly support changes

Язык: Английский

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Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: a systematic review

Ageing Research Reviews, Год журнала: 2021, Номер 72, С. 101496 - 101496

Опубликована: Окт. 22, 2021

Alzheimer's disease (AD) is the most prevalent neurodegenerative in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD still puzzling, and new drugs development clinical trials have high failure rates. Urgent outline an integral (multi-target) effective treatment needed. Accumulation amyloid-β (Aβ) peptides considered one fundamental neuropathological pillars disease, its dyshomeostasis has shown a crucial role onset. Therefore, many amyloid-targeted therapies been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up studies focused on anti-amyloid strategies to summarize analyze their current potential. Combination anti-Aβ with developing early detection biomarkers other therapeutic agents acting functional changes be highlighted this review. Near-term approval seems likely for several against Aβ, FDA monoclonal oligomers antibody –aducanumab– raising hopes controversies. We conclude that, oligomer-epitope specific Aβ implementation multiple improved risk prediction methods allowing detection, together factors such as hyperexcitability AD, could key slowing global pandemic.

Язык: Английский

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Transcriptional control of microglia phenotypes in health and disease

Journal of Clinical Investigation, Год журнала: 2017, Номер 127(9), С. 3220 - 3229

Опубликована: Июль 30, 2017

Microglia are the main resident macrophage population of CNS and perform numerous functions required for development, homeostasis, immunity, repair. Many lines evidence also indicate that dysregulation microglia contributes to pathogenesis neurodegenerative behavioral diseases. These observations provide a compelling argument more clearly define mechanisms control identity function in health disease. In this Review, we present conceptual framework how different classes transcription factors interact select activate regulatory elements development their responses internal external signals. We then describe specific normal pathological contexts conclude with consideration open questions be addressed future.

Язык: Английский

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X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

International Journal of Developmental Neuroscience, Год журнала: 2020, Номер 80(1), С. 52 - 72

Опубликована: Янв. 13, 2020

Abstract Adrenoleukodystrophy (ALD) is a rare X‐linked disease caused by mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding pathogenic cell‐ and tissue‐specific roles lipid species in context experimental therapeutic strategies provides an overview critical historical developments, trials advent newborn screening USA. In ALD, very long‐chain fatty acid (VLCFA) chain length‐dependent dysregulation endoplasmic reticulum stress mitochondrial radical generating systems inducing cell death pathways has been shown, providing rationale for moiety‐specific VLCFA reduction antioxidant strategies. The continuing increase programs promising results from ongoing recent investigations provide hope ALD.

Язык: Английский

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The Alzheimer's disease‐associated C99 fragment of APP regulates cellular cholesterol trafficking

The EMBO Journal, Год журнала: 2020, Номер 39(20)

Опубликована: Авг. 31, 2020

Article31 August 2020Open Access Source DataTransparent process The Alzheimer's disease-associated C99 fragment of APP regulates cellular cholesterol trafficking Jorge Montesinos Department Neurology, Columbia University Irving Medical Center, New York, NY, USA Search for more papers by this author Marta Pera Delfina Larrea Cristina Guardia-Laguarta Rishi R Agrawal orcid.org/0000-0002-5851-9978 Institute Human Nutrition, Kevin Velasco Taekyung D Yun Irina G Stavrovskaya Yimeng Xu Biomarkers Core Laboratory, So Yeon Koo Taub Research on Disease and the Aging Brain, Amanda M Snead Andrew A Sproul Pathology Cell Biology, Estela Area-Gomez Corresponding Author [email protected] orcid.org/0000-0002-0962-1570 Information Montesinos1,‡, Pera1,6,‡, Larrea1,‡, Guardia-Laguarta1, Agrawal2, Velasco1, Yun1, Stavrovskaya1, Xu3, Koo4, Snead4, Sproul4,5 *,1,2,4 1Department 2Institute 3Biomarkers 4Taub 5Department 6Present address: Basic Sciences Department, Faculty Medicine Health Sciences, Universitat Internacional de Catalunya, Barcelona, Spain ‡These authors contributed equally to work *Corresponding author. Tel: +1 212 305 1009; E-mail: EMBO Journal (2020)39:e103791https://doi.org/10.15252/embj.2019103791 PDFDownload PDF article text main figures. Peer ReviewDownload a summary editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract link between homeostasis cleavage amyloid precursor protein (APP), how relationship relates disease (AD) pathogenesis, is still unknown. Cellular levels are regulated through crosstalk plasma membrane (PM), where most resides, endoplasmic reticulum (ER), machinery that resides. intracellular transport from PM ER believed be activated lipid-sensing peptide(s) in can cluster PM-derived into transient detergent-resistant domains (DRMs) within ER, also called regulatory pool cholesterol. When formed, these cholesterol-rich maintain inducing esterification as mechanism detoxification while attenuating its novo synthesis. In manuscript, we propose 99-aa C-terminal (C99), when delivered γ-secretase, acts peptide forms DRMs mitochondria-associated membranes (MAM). Our data AD models indicates increased uncleaved an early phenotype disease, upregulates formation internalization extracellular ER. These results suggest novel role mediator disturbances AD, potentially explaining hallmarks disease. Synopsis increases APP-C99 induce sustained uptake resulting continuous activation lipid rafts Via affinity cholesterol, g-secretase, clusters forming detergent-resistan show MAM Higher MAM-C99 cell result inhibition synthesis Introduction composition undergoes modulation regulate processes such signal transduction transmembrane ion gradients (Lauwers et al, 2016). To support events, network enzymes interconnects metabolism all lipids promotes remodeling functional subregions (Lingwood Simons, 2010). Often, display characteristics rafts, or Lipid formed local free unesterified shielded aqueous phase interaction with sphingomyelin (SM) saturated phospholipids elevations create highly ordered microdomains passively segregate enrich lipid-binding proteins, facilitating protein–protein interaction(s) regulation specific signaling pathways Formation enabled "lipid-sensing" proteins capacity bind (Epand 2006). If were eliminated, would disperse, dissolving liquid-disordered state. critical event sphingomyelinases (SMases), which hydrolyze SM ceramide (Chang As opposed SM, creates electrostatically unfavorable environment (Yu 2005) makes accessible removal via, example, Hence, turnover raft their tightly linked homeostasis. Thus, alterations affect formation, vice versa. either synthesized (ER) taken up cholesteryl esters (CEs) lipoproteins sterol element binding isoform 2 (SREBP2, gene SREBF2) Golgi subsequent proteolytic (Brown Goldstein, 1999). processed form SREBP2 translocates nucleus induces transcription cholesterol-synthesizing genes well SREBF2 itself supply sufficient, retained form, preventing pathway lipoproteins, internalized CEs hydrolyzed endolysosomes transferred (PM) (Das 2014; Infante Radhakrishnan, 2017). Once concentration surpasses threshold, it transported enzyme, acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1; SOAT1), means detoxifying excess 2014). resultant stored droplets cytosol before being secreted preserve homeostasis, maintains PM, bulk cell's enzymatic activities reside (Litvinov 2018). This controlled as-yet-unknown sensor triggers communication ACAT1 located (Lange 1999; metabolism, particularly nervous system (Petrov It therefore not surprising dysregulation has been described multiple neurodegenerative diseases, (Di Paolo Kim, 2011). Specifically, abnormalities have widely reported 2011), but field currently lacks consensus cause(s). "amyloid cascade hypothesis" pathogenesis states β-amyloid (Aβ), derived processing, trigger neurodegeneration (Goedert Spillantini, addition higher Aβ, samples present endocytosed full-length β-secretase (BACE1) produce immediate domain (C99) due mutations PSEN1 [presenilin-1 (PS1)], PSEN2 [presenilin-2 (PS2)], familial (FAD), unknown causes sporadic cases (SAD) Further linking reciprocal distribution recently (DelBove 2019). Moreover, processing fragments (APP-CTFs) occurs (Cordy Notably, shown contribute pathology (Shen Kelleher, 2007), causing endosomal dysfunction (Jiang 2010) hippocampal degeneration (Lauritzen 2012; Pulina 2020). Previously, others found C99, distributed homogeneously concentrated (MAMs) (Area-Gomez 2009; Newman Schreiner 2015; Del Prete 2017; DRM/lipid subdomain (Hayashi Fujimoto, 2010; 2012) involved (Vance, We showed animal increase at (Pera 2017) upregulation Hedskog 2013), SMases 2017), known MAM-localized enzyme 2009). Remarkably, production caused inactivation functions now report C99's (Barrett 2012), pathogenic accumulation above-normal Trafficking activation, domains, previously observed cells patients Altogether, our via activity, disrupt cause commonly during pathogenesis. Results Accumulation Recently, co-activation SMase(s) "detoxify" light data, hypothesized sphingolipid could elevated levels, activate pathway. test this, measured homogenates subcellular fractions mouse embryonic fibroblasts (MEFs) null both (PS-DKO) (Herreman 2000) [these high 2017)] (Fig 1A) EV1A) liquid chromatography–mass spectrometry (LC-MS) (Chan 2012). displayed compared controls. membrane-bound was significant total which, previous indicate buildup elimination esterification. able recapitulate MEFs paralog APLP2 knocked out (APP-DKO) (Zhang transiently transfected plasmid expressing 1B). Conversely, APP-DKO APP-C83 (produced α-secretase), AICD γ-secretase), incubated Aβ42 oligomers did elevations, suggesting affects other do Figure 1. A. Quantification lipidomics analysis (TH), isolated WT PS-DKO cells. units represented molar mass over moles analyzed (mol %). Graphs represent fold change Unpaired t-test (n = 6 TH, n 3 ER; *P < 0.05). B. C83, peptides, treated 5 μM 16 h. Cholesterol control. One-way ANOVA 4; C. HMGCR activity DAPT-treated 3; D. incubating cells, untreated BACE inhibitor IV (BI, 100 nM), 2.5 μCi/ml 3H-cholesterol indicated times. Graph represents radioactivity (TH). Two-way repeated measures (Time, Group) independent experiments; E, F. delivery (E) (F) after Control BI-treated times, fractionation (Western blot Fig EV1F). calculated quantification fractions. G. Measurement fluorescent analog [NBD-cholesterol (2 μM; upper panel, nuclei blue)]. Endogenous stained filipin (lower panel). right fluorescence intensity (using ImageJ) percentage punctae. Scale bar 20 μm. (30–50 cells/condition least 0.05, **P 0.01, ***P 0.001). available online figure. Data [embj2019103791-sup-0003-SDataFig1.pdf] Download figure PowerPoint Click here expand EV1. Increases ester (FAD) analysis. (mol%). controls (WT). vs. 4–8; 0.01). decreased rate FAD patients. One-sample 3–4; WB reductions mature/active reduction full-length/precursor mature Note mutant abrogated upon BACE1 (BI). Coomassie staining loading D, E. (D) neuroblastoma lines (Neuro-2a) PS1, PS1 PS2, had silenced. Dashed line control levels. Western used 1E Erlin-2 ERp72 markers, respectively (TH: homogenate, CM: crude membrane). G, H. Ratio (CE):free lipidomic (G) (H) fibroblasts. I. efflux, 2, 4, h, h pulse-chase assayed DAPT (BI), respectively. DMSO vehicle. J. detected age-matched K. Representative confocal images co-staining (blue) markers (labeled red) endosomes (Rab7), (Sec61β), lysosomes (LAMP1), (GM130). Zoom 5×. upregulated synthesis, uptake, removal. determine whether occurred pathway, quantified 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), rate-limiting γ-secretase-deficient reduced significantly MEFs, γ-secretase inhibitors (DAPT) 1C), EV1B), agreement observations (Pierrot 2013). Consistent DAPT, EV1C). Ruling internalization. enhanced 1D), EV1D) neuronal silenced alone + PS2 EV1E). Interestingly, mentioned before, ACAT1. confirm trafficked models, tracked and/or that, incorporation 1E) 1F) inhibition, confirming influx mobilization toward C99. reflected ratio esters:free (CE:FC) (Slotte Bierman, 1988; EV1G) EV1H). assess dynamics, radiolabeled post-incubation times EV1I). efflux correlates rather than removal, phenotypes internalization, esterification, cell, triggered Supporting result, fluorescently labeled 1G, panel) artifact exposure exogenous indeed machinery, filipin, dye specifically binds controls, markedly different lower panel), EV1J), showing degree puncta cytosol. filipin-positive bodies co-localized late (Rab7) EV1K). extend cultured cortical neurons knock-in model carrying mutation (PS1M146V-KI mice) (Guo PS1M146V-KI mice EV2A B) Aβ42:Aβ40 ratios EV2C), EV2D). Similar radio-labeled EV2E F), number LipidTox cytoplasm EV2E, middle panels), level EV2G). Confirming reversed EV2E). EV2. Neurons PS1KI APP, C83 explanted PS1KIM146V mice. Upper panel shows shorter reveal unsaturated APP. Tubulin-β B, each (B) Aβ40 6; P 0.08) (C) neurons. measurement phospholipid transfer mitochondria (Montesinos 3H-serine phosphatidylserine (PS), conversion phosphatidylethanolamine (PE) phosphatidylcholine (PC) PS1-KI BI, indicated. incubation NBD-cholesterol (upper bl

Язык: Английский

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ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer’s disease models

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Март 2, 2022

Predisposition to Alzheimer's disease (AD) may arise from lipid metabolism perturbation, however, the underlying mechanism remains elusive. Here, we identify ATPase family AAA-domain containing protein 3A (ATAD3A), a mitochondrial AAA-ATPase, as molecular switch that links cholesterol impairment AD phenotypes. In neuronal models of AD, 5XFAD mouse model and post-mortem brains, ATAD3A is oligomerized accumulated at mitochondria-associated ER membranes (MAMs), where it induces accumulation by inhibiting gene expression CYP46A1, an enzyme governing brain clearance. CYP46A1 cooperate promote APP processing synaptic loss. Suppressing oligomerization heterozygous knockout or pharmacological inhibition with DA1 restores levels, normalizes turnover MAM integrity, suppresses loss, consequently reduces neuropathology cognitive deficits in transgenic mice. These findings reveal role for pathogenesis suggest potential therapeutic target AD.

Язык: Английский

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Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease

Frontiers in Molecular Neuroscience, Год журнала: 2022, Номер 15

Опубликована: Авг. 25, 2022

Alzheimer’s disease (AD) is a neurodegenerative disorder that one of the most devastating and widespread diseases worldwide, mainly affecting aging population. One key factors contributing to AD-related neurotoxicity production aggregation amyloid β (Aβ). Many studies have shown ability Aβ bind cell membrane disrupt its structure, leading death. Because damage affects different parts brain differently, it seems likely not only but also nature interface with which interacts, helps determine final neurotoxic effect. cholesterol dominant component plasma membrane, plays an important role in Aβ-induced toxicity. Elevated levels their regulation by statins been be influencing progression neurodegeneration. However, data from many has both neuroprotective aggravating effects relation development AD. In this review, we attempt summarize recent findings on toxicity mediated binding pathogenesis AD consider broader context lipid composition membranes.

Язык: Английский

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TrkB transmembrane domain: bridging structural understanding with therapeutic strategy

Trends in Biochemical Sciences, Год журнала: 2024, Номер 49(5), С. 445 - 456

Опубликована: Март 2, 2024

TrkB (neuronal receptor tyrosine kinase-2, NTRK2) is the for brain-derived neurotrophic factor (BDNF) and a critical regulator of activity-dependent neuronal plasticity. The past few years have witnessed an increasing understanding structure function TrkB, including its transmembrane domain (TMD). interacts with membrane cholesterol, which bidirectionally regulates signaling. Additionally, has recently been recognized as binding target antidepressant drugs. A variety different antidepressants, typical rapid-acting well psychedelic compounds, act allosteric potentiators BDNF signaling through TrkB. This suggests that common compounds. Although more research needed, current knowledge promising further drug development.

Язык: Английский

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The multifaceted role of mitochondria in autism spectrum disorder

Molecular Psychiatry, Год журнала: 2024, Номер unknown

Опубликована: Сен. 2, 2024

Abstract Normal brain functioning relies on high aerobic energy production provided by mitochondria. Failure to supply a sufficient amount of energy, seen in different disorders, including autism spectrum disorder (ASD), may have significant negative impact development and support functions. Mitochondrial dysfunction, manifested the abnormal activities electron transport chain impaired metabolism, greatly contributes ASD. The aberrant this organelle is such importance that ASD has been proposed as mitochondrial disease. It should be noted not only function In particular, these organelles are involved regulation Ca 2+ homeostasis, mechanisms programmed cell death, autophagy, reactive oxygen nitrogen species (ROS RNS) production. Several syndromes originated from mitochondria-related mutations display phenotype. Abnormalities handling ATP mitochondria affect synaptic transmission, plasticity, development, contributing ROS regulate activity permeability transition pore (mPTP). prolonged opening affects redox state mitochondria, impairs oxidative phosphorylation, activates apoptosis, ultimately leading death. A dysregulation between enhanced processes apoptosis inhibited autophagy leads accumulation toxic products brains individuals with Although many still investigated, whether they cause or consequence unknown, accumulating data show breakdown any functions contribute review, we discuss multifaceted role various aspects neuroscience.

Язык: Английский

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A Crosstalk Between Brain Cholesterol Oxidation and Glucose Metabolism in Alzheimer’s Disease

Frontiers in Neuroscience, Год журнала: 2019, Номер 13

Опубликована: Май 31, 2019

In Alzheimer's disease (AD), both cholesterol and glucose dysmetabolism precede the onset of memory deficit contribute to progression. It is indeed now believed that oxidized in form oxysterols altered uptake are main triggers AD affecting production clearance Aβ, tau phosphorylation. However, only a few studies highlight relationship between them, suggesting importance further extensive on this topic. Recently, molecular link was demonstrated oxidative metabolism brain. particular, 27-hydroxycholesterol, key linker hypercholesterolemia increased risk, considered biomarker for reduced metabolism. fact, its excess increases activity renin-angiotensin system brain, thus reducing insulin-mediated uptake, which has major impact brain functioning. Despite important evidence regarding role oxysterol regulating by neurons, involvement other oxidation products have been clearly be players AD, cannot ruled out. This review highlights current understanding potential progression, bidirectional crosstalk these two phenomena.

Язык: Английский

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