Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models

Cell Reports, Journal Year: 2020, Volume and Issue: 32(2), P. 107908 - 107908

Published: July 1, 2020

We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis differential gene expression 2,114 postmortem samples. discover 30 coexpression modules from seven regions as major source AD transcriptional perturbations. next examine overlap with 251 differentially expressed sets mouse models and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology reveal age- sex-dependent signatures for progression. Human enriched neuronal and/or microglial genes broadly AD, Huntington's disease, amyotrophic lateral sclerosis, aging. Other modules, including those implicated proteostasis, are not activated but rather following other, unexpected genetic manipulations. Our results comprise cross-species resource, highlighting networks altered by pathophysiology identifying correspondences preclinical studies.

Language: Английский

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Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer’s disease

Scientific Data, Journal Year: 2021, Volume and Issue: 8(1)

Published: Oct. 15, 2021

Abstract Mouse models of human diseases are invaluable tools for studying pathogenic mechanisms and testing interventions therapeutics. For disorders such as Alzheimer’s disease in which numerous being generated, a challenging first step is to identify the most appropriate model age effectively evaluate new therapeutic approaches. Here we conducted detailed phenotypic characterization 5xFAD on congenic C57BL/6 J strain background, across its lifespan – including seldomly analyzed 18-month old time point provide temporally correlated phenotyping this template LOAD they generated. This comprehensive analysis included quantification plaque burden, Aβ biochemical levels, neuropathology, neurophysiological measurements behavioral cognitive assessments, evaluation microglia, astrocytes, neurons. Analysis transcriptional changes was using bulk-tissue generated RNA-seq data from microdissected cortices hippocampi function aging, can be explored at MODEL-AD Explorer AD Knowledge Portal. deep-phenotyping pipeline identified novel aspects age-related pathology model.

Language: Английский

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What electrophysiology tells us about Alzheimer's disease: a window into the synchronization and connectivity of brain neurons

Neurobiology of Aging, Journal Year: 2019, Volume and Issue: 85, P. 58 - 73

Published: Sept. 19, 2019

Language: Английский

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Neuronal hyperexcitability in Alzheimer’s disease: what are the drivers behind this aberrant phenotype?

Translational Psychiatry, Journal Year: 2022, Volume and Issue: 12(1)

Published: June 22, 2022

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder leading to loss of cognitive abilities and ultimately, death. With no cure available, limited treatments mostly focus on symptom management. Identifying early changes in the course may provide new therapeutic targets halt or reverse progression. Clinical studies have shown that cortical hippocampal hyperactivity are feature shared by patients stages disease, progressing hypoactivity during later neurodegeneration. The exact mechanisms causing neuronal excitability not fully characterized; however, animal cell models provided insights into some factors involved this phenotype. In review, we summarize evidence for over AD onset progression molecular underpinning these differences. Specifically, discuss contributors aberrant excitability, including abnormal levels intracellular Ca 2+ glutamate, pathological amyloid β (Aβ) tau, genetic risk factors, APOE , impaired inhibitory interneuron glial function. light recent research indicating hyperexcitability could be predictive marker dysfunction, further argue phenotype leveraged improve diagnosis treatment AD, present potential future development.

Language: Английский

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Nrf2: a dark horse in Alzheimer's disease treatment

Ageing Research Reviews, Journal Year: 2020, Volume and Issue: 64, P. 101206 - 101206

Published: Nov. 2, 2020

Language: Английский

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Toxicology and pharmacology of synthetic organoselenium compounds: an update

Archives of Toxicology, Journal Year: 2021, Volume and Issue: 95(4), P. 1179 - 1226

Published: April 1, 2021

Language: Английский

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Alzheimer’s pathogenic mechanisms and underlying sex difference

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

Published: April 12, 2021

Language: Английский

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Organoid intelligence (OI): the new frontier in biocomputing and intelligence-in-a-dish

Frontiers in Science, Journal Year: 2023, Volume and Issue: 1

Published: Feb. 28, 2023

Recent advances in human stem cell-derived brain organoids promise to replicate critical molecular and cellular aspects of learning memory possibly cognition vitro . Coining the term “organoid intelligence” (OI) encompass these developments, we present a collaborative program implement vision multidisciplinary field OI. This aims establish OI as form genuine biological computing that harnesses using scientific bioengineering an ethically responsible manner. Standardized, 3D, myelinated can now be produced with high cell density enriched levels glial cells gene expression for learning. Integrated microfluidic perfusion systems support scalable durable culturing, spatiotemporal chemical signaling. Novel 3D microelectrode arrays permit high-resolution electrophysiological signaling recording explore capacity recapitulate mechanisms formation and, ultimately, their computational potential. Technologies could enable novel biocomputing models via stimulus-response training organoid-computer interfaces are development. We envisage complex, networked whereby connected real-world sensors output devices, ultimately each other sensory organ (e.g. retinal organoids), trained biofeedback, big-data warehousing, machine methods. In parallel, emphasize embedded ethics approach analyze ethical raised by research iterative, manner involving all relevant stakeholders. The many possible applications this urge strategic development discipline. anticipate OI-based allow faster decision-making, continuous during tasks, greater energy data efficiency. Furthermore, “intelligence-in-a-dish” help elucidate pathophysiology devastating developmental degenerative diseases (such dementia), potentially aiding identification therapeutic approaches address major global unmet needs.

Language: Английский

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Selective loss of cortical endothelial tight junction proteins during Alzheimer’s disease progression

Brain, Journal Year: 2019, Volume and Issue: 142(4), P. 1077 - 1092

Published: Jan. 23, 2019

While the accumulation and aggregation of amyloid-β tau are central events in pathogenesis Alzheimer's disease, there is increasing evidence that cerebrovascular pathology also abundant disease brains. In brain capillaries, endothelial cells connected closely with one another through transmembrane tight junction proteins forming blood-brain barrier. Because barrier tightly regulates exchange molecules between blood maintains homeostasis, its impairment increasingly recognized as a critical factor contributing to pathogenesis. However, pathological relationship properties progression human not fully understood. this study, we show loss cortical common event correlated synaptic degeneration. By quantifying amounts major proteins, claudin-5 occludin, 12 regions dissected from post-mortem brains normal ageing (n = 10), 14) patients 19), found they were selectively decreased areas disease. Cortical association Braak neurofibrillary tangle stage. There was negative correlation amount insoluble disease-related particular amyloid-β40, areas. addition, these positively those markers. Thus, associated amyloid-β40 Importantly, positive markers, synaptophysin, present independent amyloid-β42 values, suggesting degeneration present, at least part, proteins. Collectively, results indicate occurs predominantly neocortex during progression. Further, our findings provide neuropathological clue how may contribute both synergistic additive manners typical pathologies.

Language: Английский

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Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function

Acta Neuropathologica, Journal Year: 2021, Volume and Issue: 143(2), P. 179 - 224

Published: Dec. 1, 2021

Abstract In neurological diseases, the actions of microglia, resident myeloid cells CNS parenchyma, may diverge from, or intersect with, those recruited monocytes to drive immune-mediated pathology. However, defining precise roles each cell type has historically been impeded by lack discriminating markers and experimental systems capable accurately identifying them. Our ability distinguish microglia from in neuroinflammation advanced with single-cell technologies, new drugs that identify deplete them, respectively. Nevertheless, focus individual studies on particular types, diseases approaches limited our connect phenotype function more widely across diverse pathologies. Here, we critically review, tabulate integrate disease-specific functions immune profiles provide a comprehensive atlas responses viral encephalitis, demyelination, neurodegeneration ischemic injury. emphasizing differential severe neuroinflammatory disease inflammatory pathways common equally incapacitating less inflammation. We examine these findings context human highlight benefits inherent limitations animal models impede facilitate clinical translation. This enables us contrasting, non-redundant often opposing could be targeted therapeutically.

Language: Английский

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