Addressing variability in iPSC-derived models of human disease: guidelines to promote reproducibility

Disease Models & Mechanisms, Journal Year: 2020, Volume and Issue: 13(1)

Published: Jan. 1, 2020

ABSTRACT Induced pluripotent stem cell (iPSC) technologies have provided in vitro models of inaccessible human types, yielding new insights into disease mechanisms especially for neurological disorders. However, without due consideration, the thousands iPSC lines generated past decade will inevitably affect reproducibility iPSC-based experiments. Differences between donor individuals, genetic stability and experimental variability contribute to model variation by impacting differentiation potency, cellular heterogeneity, morphology, transcript protein abundance. Such effects confound reproducible modelling absence appropriate strategies. In this Review, we explore causes propose approaches detect account studies, or even exploit it deeper biological insight.

Language: Английский

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Cadmium-Induced Oxidative Stress: Focus on the Central Nervous System

Antioxidants, Journal Year: 2020, Volume and Issue: 9(6), P. 492 - 492

Published: June 5, 2020

Cadmium (Cd), a category I human carcinogen, is well-known widespread environmental pollutant. Chronic Cd exposure affects different organs and tissues, such as the central nervous system (CNS), its deleterious effects can be linked to indirect reactive oxygen species (ROS) generation. Since predominantly present in +2 oxidation state, it interplay with plethora of channels transporters cell membrane surface order enter cells. Mitochondrial dysfunction, ROS production, glutathione depletion lipid peroxidation are reviewed better characterize Cd-elicited molecular pathways. Furthermore, on CNS types have been highlighted elucidate role neurodegenerative disorders. Indeed, increase blood-brain barrier (BBB) permeability promotes entry that, turn, stimulates pericytes maintaining BBB open. Once inside CNS, acts glial cells (astrocytes, microglia, oligodendrocytes) triggering pro-inflammatory cascade that accounts for neurons inducing destruction synaptic branches.

Language: Английский

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Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(21), P. 12841 - 12841

Published: Oct. 25, 2022

Alzheimer’s disease (AD) is the leading cause of dementia in elderly people. Amyloid beta (Aβ) deposits and neurofibrillary tangles are major pathological features an brain. These proteins highly expressed nerve cells found most tissues. Tau primarily provides stabilization to microtubules part axons dendrites. However, tau a state becomes hyperphosphorylated, causing dysfunction synaptic impairment degeneration neurons. This article presents summary role tau, phosphorylated (p-tau) AD, other tauopathies. Tauopathies, including Pick’s disease, frontotemporal dementia, corticobasal degeneration, argyrophilic grain progressive supranuclear palsy, Huntington’s result misprocessing accumulation within neuronal glial cells. also focuses on current research post-translational modifications genetics pathology, tauopathies development new drugs targeting p-tau, therapeutics for treating possibly preventing

Language: Английский

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The neuropathology of autism: A systematic review of post-mortem studies of autism and related disorders

Neuroscience & Biobehavioral Reviews, Journal Year: 2021, Volume and Issue: 129, P. 35 - 62

Published: July 14, 2021

Language: Английский

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Copper Induces Cognitive Impairment in Mice via Modulation of Cuproptosis and CREB Signaling

Nutrients, Journal Year: 2023, Volume and Issue: 15(4), P. 972 - 972

Published: Feb. 15, 2023

It has been reported that disordered Cu metabolism is associated with several neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's (PD). However, the underlying mechanism still unclear. In this study, 4-week-old male mice were exposed to by free-drinking water for three months. Then, effects of on cognitive functions in tested Morris maze tests, potential mechanisms investigated ELISA, immunochemistry, TUNEL, Western blot tests. was found exacerbates learning memory impairment, leads Cu-overload brain urine mice. The results showed induces neuronal degeneration oxidative damage, promotes expression apoptosis-related protein Bax, cuproptosis-related proteins FDX1 DLAT proteotoxic stress marker HSP70, decreases Fe-S cluster proteins. addition, affects pre-synaptic post-synaptic regulatory through inhibiting PSD-95 SYP. also suppresses phosphorylation levels CREB BDNF TrkB mouse hippocampus. conclusion, might mediate cuproptosis, damage synaptic plasticity inhibit CREB/BDNF pathway cause dysfunction

Language: Английский

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Fluid Biomarkers for Synaptic Dysfunction and Loss

Biomarker Insights, Journal Year: 2020, Volume and Issue: 15, P. 117727192095031 - 117727192095031

Published: Jan. 1, 2020

Synapses are the site for brain communication where information is transmitted between neurons and stored memory formation. Synaptic degeneration a global early pathogenic event in neurodegenerative disorders with reduced levels of pre- postsynaptic proteins being recognized as core feature Alzheimer’s disease (AD) pathophysiology. Together AD, other neurodevelopmental show altered synaptic homeostasis an important event, due to that, they commonly referred synaptopathies. The exact mechanisms synapse dysfunction different diseases not well understood their study would help understanding role degeneration, differences commonalities among them highlight candidate biomarkers specific disorders. assessment cerebrospinal fluid (CSF), which can reflect patients cognitive disorders, keen area interest. Substantial research efforts now directed toward investigation CSF pathology improve diagnosis at stage monitor clinical progression. In this review, we will first summarize pathological events that lead loss then discuss available data on established (eg, neurogranin, SNAP-25, synaptotagmin-1, GAP-43, α-syn) emerging vesicle glycoprotein 2A neuronal pentraxins) dysfunction, while highlighting possible utilities, specificity, technical challenges detection.

Language: Английский

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From Neurodevelopmental to Neurodegenerative Disorders: The Vascular Continuum

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

Published: Oct. 20, 2021

Structural and functional integrity of the cerebral vasculature ensures proper brain development function, as well healthy aging. The inability to store energy makes it exceptionally dependent on an adequate supply oxygen nutrients from blood stream for matching colossal demands neural glial cells. Key vascular features including a dense vasculature, tightly controlled environment, regulation flow (CBF) all take part in health throughout life. As such, aging are both ensured by anatomical interaction between nervous systems that established during maintained lifespan. During critical periods development, networks remodel until they can actively respond increases activity through neurovascular coupling, which particularly vulnerable alterations. has been strongly associated with onset and/or progression conditions aging, more recently neurodevelopmental disorders. Our understanding cerebrovascular contributions neurological disorders is rapidly evolving, increasing evidence shows deficits angiogenesis, CBF blood-brain barrier (BBB) causally linked cognitive impairment. Moreover, utmost curiosity although neurodegenerative express different clinical at stages life, share similar abnormalities. In this review, we present overview dysfunctions (autism spectrum disorders, schizophrenia, Down Syndrome) (multiple sclerosis, Huntington’s, Parkinson’s, Alzheimer’s diseases) focus impairments BBB. Finally, discuss impact early expression diseases.

Language: Английский

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Imaging Synaptic Density: The Next Holy Grail of Neuroscience?

Frontiers in Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: March 25, 2022

The brain is the central and most complex organ in nervous system, comprising billions of neurons that constantly communicate through trillions connections called synapses. Despite being formed mainly during prenatal early postnatal development, synapses are continually refined eliminated throughout life via complicated hitherto incompletely understood mechanisms. Failure to correctly regulate numbers distribution has been associated with many neurological psychiatric disorders, including autism, epilepsy, Alzheimer’s disease, schizophrenia. Therefore, measurements synaptic density, as well detection dysfunction, essential for understanding normal abnormal development. To date, multiple density markers have proposed investigated experimental models disorders. majority gold standard methodologies (e.g., electron microscopy or immunohistochemistry) visualize measure changes pre- postsynaptic proteins ex vivo . However, invasive nature these classic precludes their use living organisms. recent development positron emission tomography (PET) tracers [such ( 18 F)UCB-H 11 C)UCB-J] bind a putative marker, vesicle 2A (SV2A) protein, heralding likely paradigm shift detecting alterations patients. limited specificity, novel, non-invasive magnetic resonance (MR)-based methods also show promise inferring information by linking glutamate neurotransmission. Although promising, all entail various advantages limitations must be addressed before becoming part routine clinical practice. In this review, we summarize discuss current quantifying an evaluation reliability utility. We conclude critical assessment challenges need overcome successfully employing biomarkers diagnostic and/or prognostic tools study neuropsychiatric

Language: Английский

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Role of Calcium Modulation in the Pathophysiology and Treatment of Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 9067 - 9067

Published: May 22, 2023

Alzheimer’s disease (AD) is a chronic neurodegenerative and the most frequent cause of progressive dementia in senior adults. It characterized by memory loss cognitive impairment secondary to cholinergic dysfunction N-methyl-D-aspartate (NMDA)-mediated neurotoxicity. Intracellular neurofibrillary tangles, extracellular plaques composed amyloid-β (Aβ), selective neurodegeneration are anatomopathological hallmarks this disease. The dysregulation calcium may be present all stages AD, it associated with other pathophysiological mechanisms, such as mitochondrial failure, oxidative stress, neuroinflammation. Although cytosolic alterations AD not completely elucidated, some calcium-permeable channels, transporters, pumps, receptors have been shown involved at neuronal glial levels. In particular, relationship between glutamatergic NMDA receptor (NMDAR) activity amyloidosis has widely documented. Other mechanisms dyshomeostasis include activation L-type voltage-dependent transient potential ryanodine receptors, among many others. This review aims update calcium-dysregulation discuss targets molecules therapeutic based on their modulation.

Language: Английский

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Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson’s disease

Journal of Neural Transmission, Journal Year: 2023, Volume and Issue: 130(5), P. 627 - 646

Published: April 16, 2023

Abstract Since the description of some peculiar symptoms by James Parkinson in 1817, attempts have been made to define its cause or at least enlighten pathology “Parkinson’s disease (PD).” The vast majority PD subtypes and most cases sporadic share Lewy bodies (LBs) as a characteristic pathological hallmark. However, processes underlying LBs generation causal triggers are still unknown. ɑ-Synuclein (ɑ-syn, encoded SNCA gene) is major component LBs, missense mutations duplications/triplications for rare hereditary forms PD. Thus, it imperative study ɑ-syn protein pathology, including oligomerization, fibril formation, aggregation, spreading mechanisms. Furthermore, there synergistic effects pathogenic mechanisms PD, multiple factors—contributing with different ratios—appear be progression factors. For example, oxidative stress, reduced antioxidative capacity, mitochondrial dysfunction, proteasomal disturbances each suggested formation aggregation contribute neuroinflammation neural cell death. Aging also risk factor Iron, well neuromelanin (NM), show age-dependent increases, iron significantly increased Parkinsonian substantia nigra (SN). Iron-induced include changes molecular structure ɑ-syn. more recent research demonstrates that (i) detected not only dopaminergic neurons glia but various neurotransmitter systems, (ii) sympathetic nerve fibres degenerate first, (iii) “brain-first” deficiency evident before induced NM. These findings support ɑ-syn/LBs iron- NM-induced important facts via their interaction potentiate process SN. As such, multifactorial toxic posted on personal genetic assumed neurodegenerative Differences ratios factors spatiotemporal development, fact common hard identify, imply existence several phenotypical subtypes, which supported arguments from both “bottom-up/dual-hit” models. Therapeutic strategies necessary avoid single initiation leading

Language: Английский

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