Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer’s disease DOI Creative Commons
Abdallah M. Eteleeb, Brenna C. Novotny, Carolina Soriano‐Tárraga

et al.

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(4), P. e3002607 - e3002607

Published: April 30, 2024

Unbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal profiles, one them showing signs poor cognitive function, a faster pace disease progression, shorter survival disease, severe neurodegeneration astrogliosis, reduced levels metabolomic profiles. found this profile be present in affected cortical regions associated higher Braak tau scores significant dysregulation synapse-related genes, endocytosis, phagosome, mTOR signaling pathways altered early late stages. cross-omics integration transcriptomic an SNCA mouse model revealed overlapping signature. Furthermore, leveraged single-nuclei RNA-seq identify distinct cell-types that most likely mediate Lastly, identified clusters uncovered cerebrospinal fluid biomarkers poised monitor progression possibly cognition. Our analyses provide novel critical insights into AD.

Language: Английский

Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study DOI Creative Commons
Adrian L. Oblak, Peter Bor‐Chian Lin, Kevin P. Kotredes

et al.

Frontiers in Aging Neuroscience, Journal Year: 2021, Volume and Issue: 13

Published: July 23, 2021

The ability to investigate therapeutic interventions in animal models of neurodegenerative diseases depends on extensive characterization the model(s) being used. There are numerous that have been generated study Alzheimer's disease (AD) and underlying pathogenesis disease. While transgenic instrumental understanding AD mechanisms risk factors, they limited degree characteristics displayed comparison with humans, full spectrum effects has yet be recapitulated a single mouse model. Model Organism Development Evaluation for Late-Onset Disease (MODEL-AD) consortium was assembled by National Institute Aging (NIA) develop more robust increased relevance human disease, standardize models, improve preclinical testing animals, establish clinically relevant biomarkers, among other aims toward enhancing translational value clinical drug design treatment development. Here we conducted detailed 5XFAD mouse, including transcriptomics, electroencephalogram, vivo imaging, biochemical characterization, behavioral assessments. data from this is publicly available through Knowledge Portal.

Language: Английский

Citations

227
Alzheimer’s pathogenic mechanisms and underlying sex difference DOI
Donghui Zhu, Axel Montagne, Zhen Zhao

et al.

Cellular and Molecular Life Sciences, Journal Year: 2021, Volume and Issue: 78(11), P. 4907 - 4920

Published: April 12, 2021

Language: Английский

Citations

162
The foundations and development of lipidomics DOI Creative Commons
Xianlin Han, Richard W. Gross

Journal of Lipid Research, Journal Year: 2021, Volume and Issue: 63(2), P. 100164 - 100164

Published: Dec. 22, 2021

For over a century, the importance of lipid metabolism in biology was recognized but difficult to mechanistically understand due lack sensitive and robust technologies for identification quantification molecular species. The enabling technological breakthroughs emerged 1980s with development soft ionization methods (Electrospray Ionization Matrix Assisted Laser Desorption/Ionization) that could identify quantify intact individual These laid foundations what be later named field lipidomics. Further innovative advances multistage fragmentation, dramatic improvements resolution mass accuracy, multiplexed sample analysis fueled early growth lipidomics through 1990s. exponentially grew use variety strategic approaches, which included direct infusion, chromatographic separation, charge-switch derivatization, facilitated access low abundance species lipidome. In this Thematic Review, we provide broad perspective foundations, advances, predicted future directions field.

Language: Английский

Citations

150
Crocetin promotes clearance of amyloid-β by inducing autophagy via the STK11/LKB1-mediated AMPK pathway DOI Open Access
Abubakar Wani, Sweilem B. Al Rihani, Ankita Sharma

et al.

Autophagy, Journal Year: 2021, Volume and Issue: 17(11), P. 3813 - 3832

Published: Jan. 6, 2021

Alzheimer disease (AD) is usually accompanied by two prominent pathological features, cerebral accumulation of amyloid-β (Aβ) plaques and presence MAPT/tau neurofibrillary tangles. Dysregulated clearance Aβ largely contributes to its plaque formation in the brain. Macroautophagy/autophagy a lysosomal degradative process, which plays an important role Aβ. Failure autophagic currently acknowledged as contributing factor increased AD brains. In this study, we have identified crocetin, pharmacologically active constituent from flower stigmas Crocus sativus, potential inducer autophagy AD. cellular model, crocetin induced N9 microglial primary neuron cells through STK11/LKB1 (serine/threonine kinase 11)-mediated AMP-activated protein (AMPK) pathway activation. Autophagy induction significantly cells. Moreover, crossed blood-brain barrier brains' hippocampi wild-type male C57BL/6 mice. Further studies transgenic 5XFAD mice, model AD, revealed that one-month treatment with reduced levels neuroinflammation mice brains improved memory function inducing was mediated AMPK Our findings support further development pharmacological prevent, slow down progression, and/or treat AD.Abbreviations: Aβ: amyloid-β; ABCB1/P-gp/P-glycoprotein: ATP-binding cassette, subfamily B (MDR/TAP), member 1; AD: disease; AMPK/PRKAA: kinase; APP: amyloid beta (A4) precursor protein; ATG: related; BBB: barrier; BECN1: beclin 1, CAMKK2/CaMKKβ: calcium/calmodulin-dependent 2, beta; CSE: sativus extract; CTSB: cathepsin B; EIF4EBP1: eukaryotic translation initiation 4E binding GFAP: glial fibrillary acidic GSK3B/GSK3β: glycogen synthase 3 Kp: brain partition coefficient; LRP1: low density lipoprotein receptor-related MAP1LC3B/LC3B: microtubule-associated 1 light chain MAP2: 2; MAPK/ERK: mitogen-activated MAPT/tau: tau; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTOR: mechanistic target rapamycin MWM: Morris water maze; NFKB/NF-κB: nuclear kappa polypeptide gene enhancer cells; NMDA: N-methyl-d-aspartic acid; RPTOR: regulatory associated MTOR; RPS6KB1/p70S6K: ribosomal S6 SQSTM1: sequestosome SRB: sulforhodamine STK11/LKB1: serine/threonine 11; TFEB: transcription EB; TSC2: TSC complex subunit ULK1: unc-51 like 1.

Language: Английский

Citations

118
Using the Alzheimer's Disease Neuroimaging Initiative to improve early detection, diagnosis, and treatment of Alzheimer's disease DOI
Dallas P. Veitch, Michael W. Weiner,

Paul Aisen

et al.

Alzheimer s & Dementia, Journal Year: 2021, Volume and Issue: 18(4), P. 824 - 857

Published: Sept. 28, 2021

The Alzheimer's Disease Neuroimaging Initiative (ADNI) has accumulated 15 years of clinical, neuroimaging, cognitive, biofluid biomarker and genetic data, samples available to researchers, resulting in more than 3500 publications. This review covers studies from 2018 2020.

Language: Английский

Citations

111
Integrative metabolomics‐genomics approach reveals key metabolic pathways and regulators of Alzheimer's disease DOI
Emrin Horgusluoglu, Ryan Neff, Won‐Min Song

et al.

Alzheimer s & Dementia, Journal Year: 2021, Volume and Issue: 18(6), P. 1260 - 1278

Published: Nov. 10, 2021

Metabolites, the biochemical products of cellular process, can be used to measure alterations in pathways related pathogenesis Alzheimer's disease (AD). However, relationships between systemic abnormalities metabolism and AD are poorly understood. In this study, we aim identify AD-specific metabolomic changes their potential upstream genetic transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, proteomic data AD. Metabolite co-expression network analysis blood Disease Neuroimaging Initiative (ADNI) shows short-chain acylcarnitines/amino acids medium/long-chain acylcarnitines most associated with clinical outcomes, including episodic memory scores severity. Integration gene expression both from ADNI brain Accelerating Medicines Partnership (AMP-AD) program reveals ABCA1 CPT1A involved regulation amino Gene AMP-AD RNA-seq suggests CPT1A- ABCA1-centered subnetworks neuronal system immune response, respectively. Increased adiponectin protein, a regulator ABCA1, correspond decreased amines ADNI. summary, our integrated large-scale multiomics systematically identifies novel metabolites findings pave way not only developing sensitive specific diagnostic biomarkers but also identifying molecular mechanisms pathogenesis.

Language: Английский

Citations

111
APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge DOI Creative Commons
Sangderk Lee, Nicholas A. Devanney, Lesley R. Golden

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112196 - 112196

Published: March 1, 2023

The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response: two findings that may be intrinsically linked through the concept immunometabolism. Here, we combined bulk, single-cell, spatial transcriptomics cell-specific spatially resolved analyses in mice expressing human APOE to systematically address role across age, neuroinflammation, AD pathology. RNA sequencing (RNA-seq) highlighted immunometabolic changes APOE4 glial transcriptome, specifically subsets metabolically distinct microglia enriched brain during aging or following an inflammatory challenge. display increased Hif1α expression disrupted tricarboxylic acid (TCA) cycle are inherently pro-glycolytic, while mass spectrometry imaging highlight E4-specific response amyloid characterized by widespread alterations lipid metabolism. Taken together, our emphasize central for regulating microglial immunometabolism provide valuable, interactive resources discovery validation research.

Language: Английский

Citations

96
Apolipoprotein E in lipid metabolism and neurodegenerative disease DOI Creative Commons
Linda Yang, Zachary M. March, Roxan A. Stephenson

et al.

Trends in Endocrinology and Metabolism, Journal Year: 2023, Volume and Issue: 34(8), P. 430 - 445

Published: June 24, 2023

Dysregulation of lipid metabolism has emerged as a central component many neurodegenerative diseases. Variants the transport protein, apolipoprotein E (APOE), modulate risk and resilience in several diseases including late-onset Alzheimer's disease (LOAD). Allelic variants gene, APOE, alter cells tissues have been broadly associated with other cellular systemic phenotypes. Targeting APOE-associated metabolic pathways may offer opportunities to disease-related phenotypes consequently, attenuate impart multiple We review molecular, cellular, tissue-level alterations that arise from different APOE isoforms. These changes could help elucidate mechanisms tune resilience.

Language: Английский

Citations

81
Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease DOI Creative Commons
Yun Yang, Vı́ctor Tapias, Diana Acosta

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Jan. 10, 2022

Abstract Abnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques tangles are neuropathological hallmarks Alzheimer’s disease (AD), but their relationship to pathogenesis each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational modification (PTM), provides potential link between AD pathology. We quantified the lysine succinylomes proteomes from brains individuals with AD, healthy controls. In succinylation multiple mitochondrial proteins declined, small number cytosolic increased. The largest increases occurred at critical sites amyloid precursor (APP) microtubule-associated tau. vitro, APP disrupted its normal proteolytic processing thereby promoting Aβ plaque formation tau promoted aggregation impaired microtubule assembly. transgenic mouse models elevated associated soluble insoluble derivatives These findings indicate metabolism-linked PTM may be AD.

Language: Английский

Citations

73
Effects of a ketogenic and low‐fat diet on the human metabolome, microbiome, and foodome in adults at risk for Alzheimer's disease DOI Creative Commons
Amanda Hazel Dilmore, Cameron Martino, Bryan J. Neth

et al.

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 19(11), P. 4805 - 4816

Published: April 5, 2023

The ketogenic diet (KD) is an intriguing therapeutic candidate for Alzheimer's disease (AD) given its protective effects against metabolic dysregulation and seizures. Gut microbiota are essential KD-mediated neuroprotection seizures as well modulation of bile acids, which play a major role in cholesterol metabolism. These relationships motivated our analysis gut metabolites related to cognitive status following controlled KD intervention compared with low-fat-diet intervention.

Language: Английский

Citations

52