Applications of iPSC-derived beta cells from patients with diabetes DOI Creative Commons
Kristina G. Maxwell, Jeffrey R. Millman

Cell Reports Medicine, Journal Year: 2021, Volume and Issue: 2(4), P. 100238 - 100238

Published: April 1, 2021

Improved stem cell-derived pancreatic islet (SC-islet) differentiation protocols robustly generate insulin-secreting β cells from patient induced pluripotent (iPSCs). These advances are enabling in vitro disease modeling studies and the development of an autologous diabetes cell replacement therapy. SC-islet technology elucidates key features human pancreas progression through generation progenitors, endocrine derived diabetic nondiabetic iPSCs. Combining with gene editing next-generation sequencing reveals impact diabetes-causing mutations phenotypes on multiple types. In addition, supply SC-islets, containing other types, is unlimited, presenting opportunity for personalized medicine overcoming several disadvantages posed by donor islets. This review highlights relevant involving iPSC-β encompassing new conclusions patients therapeutic potential cells.

Language: Английский

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease DOI Creative Commons
Junling Yang, Leslie Wise,

Ken‐ichiro Fukuchi

et al.

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: April 23, 2020

Amyloid plaques, mainly composed of abnormally aggregated amyloid β-protein (Aβ) in the brain parenchyma, and neurofibrillary tangles (NFTs), abnormal aggregates hyperphosphorylated tau protein neurons, are two pathological hallmarks Alzheimer’s disease (AD). Fibrillar Aβ deposits accompanied with neuroinflammation synapse loss, characterized by activated microglia dystrophic neurites. Genome-wide association studies on patients late-onset AD have identified a dozen genetic risk variants that involved innate immune responses, highlighting importance cells pathogenesis AD. Additional lines evidence support notion microglia, central nervous system (CNS), play pivotal, dual roles progression: either clearing phagocytosis promoting neuron survival plasticity or releasing cytotoxic chemicals, inflammatory cytokines, exacerbating load synaptotoxicity. Aggregated binds to toll-like receptor 4 (TLR4) activates resulting increased cytokine production. Complement components associated plaques NFTs. can activate complement, leading pruning loss microglial phagocytosis. Systemic inflammation TLR4, NLRP3 inflammasome, complement brain, neuroinflammation, accumulation, neurodegeneration. The host response has been shown function through complex crosstalk between TLR, inflammasome signaling pathways. Accordingly, targeting molecular mechanisms underlying TLR-complement-NLRP3 pathways be preventive therapeutic approach for

Language: Английский

Citations

276
The landscape of aging DOI Open Access
Yusheng Cai, Wei Song, Jiaming Li

et al.

Science China Life Sciences, Journal Year: 2022, Volume and Issue: 65(12), P. 2354 - 2454

Published: Sept. 2, 2022

Language: Английский

Citations

243
The complexity of Alzheimer’s disease: an evolving puzzle DOI
Camilla Ferrari, Sandro Sorbi

Physiological Reviews, Journal Year: 2021, Volume and Issue: 101(3), P. 1047 - 1081

Published: Jan. 21, 2021

The history of Alzheimer's disease (AD) started in 1907, but we needed to wait until the end century identify components pathological hallmarks and genetic subtypes formulate first pathogenic hypothesis. Thanks biomarkers new technologies, concept AD then rapidly changed from a static view an amnestic dementia presenium biological entity that could be clinically manifested as normal cognition or different types. What is clearly emerging studies heterogeneous each aspect, such amyloid composition, tau distribution, relation between tau, clinical symptoms, background, thus it probably impossible explain with single process. scientific approach suffers chronological mismatches clinical, pathological, technological data, causing difficulty conceiving diagnostic gold standards creating models for drug discovery screening. A recent mathematical computer-based offers opportunity study real life provide point final missing pieces puzzle.

Language: Английский

Citations

208
Mitophagy pathways in health and disease DOI Creative Commons
Samuel A. Killackey, Dana J. Philpott, Stephen E. Girardin

et al.

The Journal of Cell Biology, Journal Year: 2020, Volume and Issue: 219(11)

Published: Aug. 14, 2020

Mitophagy is an evolutionarily conserved process involving the autophagic targeting and clearance of mitochondria destined for removal. Recent insights into complex nature overlapping pathways regulating mitophagy illustrate mitophagy's essential role in maintaining health mitochondrial network. In this review, we highlight recent studies that have changed way understood, from initiation through lysosomal degradation. We outline numerous mitophagic receptors triggers, with a focus on basal physiologically relevant cues, offering insight why they lead to also explore how maintains homeostasis at organ system levels loss may play diverse group diseases, including cardiovascular, metabolic, neurodegenerative diseases. With disrupted affecting such wide array physiological processes, deeper understanding modulate could provide avenues therapies.

Language: Английский

Citations

191
Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls DOI Creative Commons
Swagata Ghatak,

Nima Dolatabadi,

Dorit Trudler

et al.

eLife, Journal Year: 2019, Volume and Issue: 8

Published: Nov. 29, 2019

Human Alzheimer’s disease (AD) brains and transgenic AD mouse models manifest hyperexcitability. This aberrant electrical activity is caused by synaptic dysfunction that represents the major pathophysiological correlate of cognitive decline. However, underlying mechanism for this excessive excitability remains incompletely understood. To investigate basis hyperactivity, we performed electrophysiological immunofluorescence studies on hiPSC-derived cerebrocortical neuronal cultures cerebral organoids bearing AD-related mutations in presenilin-1 or amyloid precursor protein vs. isogenic gene corrected controls. In neurons/organoids, found increased excitatory bursting activity, which could be explained part a decrease neurite length. neurons also displayed sodium current density decreased inhibitory activity. Our findings establish as relevant model early pathophysiology provide mechanistic insight into observed

Language: Английский

Citations

187
Proteomic landscape of Alzheimer’s Disease: novel insights into pathogenesis and biomarker discovery DOI Creative Commons
Bing Bai, David Vanderwall, Yuxin Li

et al.

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: Aug. 12, 2021

Mass spectrometry-based proteomics empowers deep profiling of proteome and protein posttranslational modifications (PTMs) in Alzheimer's disease (AD). Here we review the advances limitations historic recent AD proteomic research. Complementary to genetic mapping, studies not only validate canonical amyloid tau pathways, but also uncover novel components broad networks, such as RNA splicing, development, immunity, membrane transport, lipid metabolism, synaptic function, mitochondrial activity. Meta-analysis seven datasets reveals 2,698 differentially expressed (DE) proteins landscape brain (n = 12,017 proteins/genes), covering 35 reported genes risk loci. The DE contain cellular markers enriched neurons, microglia, astrocytes, oligodendrocytes, epithelial cells, supporting involvement diverse cell types pathology. We discuss hypothesized protective or detrimental roles selected proteins, emphasizing top "amyloidome" (all biomolecules plaques) progression. Comprehensive PTM analysis represents another layer molecular events AD. In particular, PTMs are correlated with stages indicate heterogeneity individual patients. Moreover, unprecedented coverage biofluids, cerebrospinal fluid serum, procures putative biomarkers through meta-analysis. Thus, proteomics-driven systems biology presents a new frontier link genotype, proteotype, phenotype, accelerating development improved models treatment strategies.

Language: Английский

Citations

172
Cellular senescence at the crossroads of inflammation and Alzheimer's disease DOI
Ana Guerrero, Bart De Strooper, I. Lorena Arancibia-Cárcamo

et al.

Trends in Neurosciences, Journal Year: 2021, Volume and Issue: 44(9), P. 714 - 727

Published: Aug. 5, 2021

Language: Английский

Citations

170
Regenerative Stem Cell Therapy for Neurodegenerative Diseases: An Overview DOI Open Access
Farzane Sivandzade, Luca Cucullo

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(4), P. 2153 - 2153

Published: Feb. 22, 2021

Neurodegenerative diseases resulting from the progressive loss of structure and/or function neurons contribute to different paralysis degrees and cognition sensation. The lack successful curative therapies for neurodegenerative disorders leads a considerable burden on society high economic impact. Over past 20 years, regenerative cell therapy, also known as stem has provided an excellent opportunity investigate potentially powerful innovative strategies treating diseases. This is due cells’ capability repair injured neuronal tissue by replacing damaged or lost cells with differentiated cells, providing conducive environment that in favor regeneration, protecting existing healthy glial further damage. Thus, this review, various types current knowledge stem-cell-based diseases, recent advances field are summarized. Indeed, better understanding studies technologies cause progress into realistic efficacious treatments disorders.

Language: Английский

Citations

148
Interpretable learning based Dynamic Graph Convolutional Networks for Alzheimer’s Disease analysis DOI

Yonghua Zhu,

Junbo Ma, Changan Yuan

et al.

Information Fusion, Journal Year: 2021, Volume and Issue: 77, P. 53 - 61

Published: July 31, 2021

Language: Английский

Citations

138
Modeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure DOI Creative Commons
Xianwei Chen, Guoqiang Sun,

E Tian

et al.

Advanced Science, Journal Year: 2021, Volume and Issue: 8(18)

Published: Aug. 2, 2021

Alzheimer's disease (AD) is a progressive neurodegenerative with no cure. Huge efforts have been made to develop anti-AD drugs in the past decades. However, all drug development programs for disease-modifying therapies failed. Possible reasons high failure rate include incomplete understanding of complex pathophysiology AD, especially sporadic AD (sAD), and species difference between humans animal models used preclinical studies. In this study, sAD modeled using human induced pluripotent stem cell (hiPSC)-derived 3D brain organoids. Because blood-brain barrier (BBB) leakage well-known risk factor organoids are exposed serum mimic exposure consequence BBB breakdown patient brains. The serum-exposed able recapitulate AD-like pathologies, including increased amyloid beta (Aβ) aggregates phosphorylated microtubule-associated tau protein (p-Tau) level, synaptic loss, impaired neural network. Serum increases Aβ p-Tau levels through inducing beta-secretase 1 (BACE) glycogen synthase kinase-3 alpha / (GSK3α/β) levels, respectively. addition, single-cell transcriptomic analysis reveals that reduced function both neurons astrocytes immune response astrocytes. organoid-based model established study can provide powerful platform mechanistic therapeutic future.

Language: Английский

Citations

136