Abnormal Mitochondrial Morphology in Sporadic Parkinson's and Alzheimer's Disease Cybrid Cell Lines

2000 ◽  
Vol 162 (1) ◽  
pp. 37-50 ◽  
Author(s):  
Patricia A. Trimmer ◽  
Russell H. Swerdlow ◽  
Janice K. Parks ◽  
Paula Keeney ◽  
James P. Bennett ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Lines ◽  
Mitochondrial Morphology ◽  
Cybrid Cell

scholarly journals OGA Inhibition Alters Energetics and Nutrient Sensing in Alzheimer’s Disease Cytoplasmic Hybrids

2020 ◽  
Vol 78 (4) ◽  
pp. 1743-1753
Author(s):  
Jarrod Flax ◽  
Heather M. Wilkins ◽  
Reegan Miller ◽  
Sarah Griffith ◽  
Gentry K. Cork ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Lines ◽  
Neuroblastoma Cells ◽  
Nutrient Sensing ◽  
Cytoplasmic Hybrids ◽  
And Control ◽  
The Impact ◽  
Cybrid Cell

Background: Alzheimer’s disease (AD) features reductions in key bioenergetic fluxes and perturbed mitochondrial function. Cytoplasmic hybrids (cybrids) generated through the transfer of AD subject mitochondria to mtDNA-depleted SH-SY5Y neuroblastoma cells recapitulate some of these features in an in vitro setting. Objective: For this study, we used the AD cybrid model to assess the impact of a nutrient-excess like-state via increasing O-GlcNAcylation on whole cell and mitochondrial homeostasis. Methods: We induced increased O-GlcNAc by treating AD and control cybrid cell lines with Thiamet G (TMG), an inhibitor of the O-GlcNAcase enzyme that mediates removal of the nutrient-dependent O-GlcNAc modification. Results: Relative to control cybrid cell lines, AD cybrid lines showed a blunted response to TMG-induced O-GlcNAcylation. At baseline, AD cybrid cell line mitochondria showed partial activation of several proteins that help maintain bioenergetic homeostasis such as AMP-Regulated Kinase suggesting that AD mitochondria initiate a state of nutrient stress promoting energetic compensation; however, this compensation reduces the capacity of cells to respond to additional nutrient-related stresses such as TMG treatment. Also, TMG caused disruptions in acetylation and Sirtuin 3 expression, while lowing total energetic output of the cell. Conclusion: Together, these findings suggest that modulation of O-GlcNAc is essential for proper energetic function of the mitochondria, and AD mitochondrial capacity to handle nutrient-excess is limited.

scholarly journals Arrayed CRISPR reveals genetic regulators of tau aggregation, autophagy and mitochondria in Alzheimer’s disease model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lishu Duan ◽  
Mufeng Hu ◽  
Joseph A. Tamm ◽  
Yelena Y. Grinberg ◽  
Fang Shen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Discovery ◽  
Disease Model ◽  
Mitochondrial Morphology ◽  
Individual Gene ◽  
Human Genes ◽  
Future Drug ◽  
Tau Aggregation

AbstractAlzheimer’s disease (AD) is a common neurodegenerative disease with poor prognosis. New options for drug discovery targets are needed. We developed an imaging based arrayed CRISPR method to interrogate the human genome for modulation of in vitro correlates of AD features, and used this to assess 1525 human genes related to tau aggregation, autophagy and mitochondria. This work revealed (I) a network of tau aggregation modulators including the NF-κB pathway and inflammatory signaling, (II) a correlation between mitochondrial morphology, respiratory function and transcriptomics, (III) machine learning predicted novel roles of genes and pathways in autophagic processes and (IV) individual gene function inferences and interactions among biological processes via multi-feature clustering. These studies provide a platform to interrogate underexplored aspects of AD biology and offer several specific hypotheses for future drug discovery efforts.

296 PRODUCTION OF HEMIZYGOUS AND HOMOZYGOUS EMBRYONIC STEM CELL-DERIVED NEURAL PROGENITOR CELLS FROM THE TRANSGENIC ALZHEIMER GÖTTINGEN MINIPIG

2011 ◽  
Vol 23 (1) ◽  
pp. 245
Author(s):  
V. J. Hall ◽  
J. Jakobsen ◽  
A. Gunnarsson ◽  
M. Schmidt ◽  
A. Lund Jørgensen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Cell Lines ◽  
Real Time Pcr ◽  
Embryonic Stem ◽  
Neural Progenitor ◽  
Novel Drugs

Alzheimer’s disease is the most prevalent cause of dementia and afflicts ∼26 million people worldwide. There are currently no cures for this disease. Production of in vitro models of the disease would be extremely useful for studying disease mechanisms and for potential screening of novel drugs. In this study we produced 2 hemizygote and 2 homozygote embryonic stem cell-derived neural progenitor cell lines from Day 8 transgenic blastocysts carrying a human gene linked to early-onset Alzheimer’s disease [Swedish mutation of the amyloid precursor protein (hAPPsw)]. Following onset of spontaneous oestrus, a mating of hAPPsw± × hAPPsw± Göttingen transgenic progeny was performed. Eight days after the first of 2 matings, embryos were flushed from the tip of both cornuas of the gilt under surgical anaesthesia. A total of 6 blastocysts were obtained and 7 corpora lutei recorded. Blastocysts were transported for 4 h in porcine zygote medium 3 (PZM-3) in hypoxic, humidified conditions at 39°C to the cell laboratory. Compact epiblasts were mechanically isolated from the embryo using insulin needles and cultured on inactivated mouse embryonic fibroblasts in embryonic stem cell medium, supplemented with 20 ng mL–1 human recombinant basic fibroblast growth factor (Prospec) and 20 ng mL–1 human recombinant Activin A (Prospec), for a period of 5 days in hypoxic conditions at 39°C. Five of the 6 epiblasts expanded to form embryonic stem-cell-like outgrowth colonies. These were cut into small colonies and plated on MS5 murine stromal cells to induce spontaneous neural differentiation in DMEM medium containing 15% knockout serum replacement. Neuronal rosette-like structures were identified from Day 10 of differentiation onward. Six rosette structures were mechanically isolated from 4 outgrowths and plated in serum-free conditions on Matrigel-coated dishes. Two of the 6 lines failed to proliferate beyond passage 2. The 4 remaining cell lines have currently been cultured to passage 7. These lines were analysed at passage 5 by comparative real-time PCR and found to be positive for the neural progenitor markers VIMENTIN, SOX2, NESTIN PAX6, MUSASHI; other neural markers BETAIIITUBULIN and NCAM; and the astrocyte marker, GFAP. These lines were also subjected to analysis by immunocytochemistry and found to express SOX2, VIMENTIN, and NESTIN. Further genotyping by comparative real-time PCR using primers designed to target the hAPPsw gene revealed that 2 lines carried a single copy of hAPPsw and 2 lines carried 2 copies of hAPPsw. The expression levels of the hAPPsw transgene in these cell lines were determined using quantitative PCR. These cell lines are currently being investigated for their ability to differentiate into cholinergic neurons and for their expression of hyperphosphorylated TAU and β-Amyloid secretion. These cell lines will be potentially relevant for the in vitro study of amyloid precursor protein accumulation in neural cells and its role in cell death, as well as for potential screening of novel drugs for Alzheimer’s disease.

scholarly journals Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines

2013 ◽  
Vol 22 (19) ◽  
pp. 3931-3946 ◽  
Author(s):  
D. F. Silva ◽  
J. E. Selfridge ◽  
J. Lu ◽  
L. E ◽  
N. Roy ◽  
...  
Keyword(s):  
Cell Lines ◽  
Mitochondrial Morphology ◽  
Mitochondrial Mass ◽  
Cybrid Cell

scholarly journals Mitochondrial Deficits With Neural and Social Damage in Early-Stage Alzheimer’s Disease Model Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Afzal Misrani ◽  
Sidra Tabassum ◽  
Qingwei Huo ◽  
Sumaiya Tabassum ◽  
Jinxiang Jiang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Morphology ◽  
Therapeutic Interventions ◽  
Early Event ◽  
Mitochondrial Morphology

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Mitochondrial dysfunction is thought to be an early event in the onset and progression of AD; however, the precise underlying mechanisms remain unclear. In this study, we investigated mitochondrial proteins involved in organelle dynamics, morphology and energy production in the medial prefrontal cortex (mPFC) and hippocampus (HIPP) of young (1∼2 months), adult (4∼5 months) and aged (9∼10, 12∼18 months) APP/PS1 mice. We observed increased levels of mitochondrial fission protein, Drp1, and decreased levels of ATP synthase subunit, ATP5A, leading to abnormal mitochondrial morphology, increased oxidative stress, glial activation, apoptosis, and altered neuronal morphology as early as 4∼5 months of age in APP/PS1 mice. Electrophysiological recordings revealed abnormal miniature excitatory postsynaptic current in the mPFC together with a minor connectivity change between the mPFC and HIPP, correlating with social deficits. These results suggest that abnormal mitochondrial dynamics, which worsen with disease progression, could be a biomarker of early-stage AD. Therapeutic interventions that improve mitochondrial function thus represent a promising approach for slowing the progression or delaying the onset of AD.

scholarly journals Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Afzal Misrani ◽  
Sidra Tabassum ◽  
Li Yang
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Morphology ◽  
Therapeutic Approaches ◽  
The Impact ◽  
And Oxidative Stress

Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly in response to external insults and changes in metabolic status via fission and fusion processes (so-called mitochondrial dynamics) that maintain mitochondrial quality and homeostasis. Damaged mitochondria are removed by a process known as mitophagy, which involves their degradation by a specific autophagosomal pathway. Over the last few years, remarkable efforts have been made to investigate the impact on the pathogenesis of Alzheimer’s disease (AD) of various forms of mitochondrial dysfunction, such as excessive reactive oxygen species (ROS) production, mitochondrial Ca2+ dyshomeostasis, loss of ATP, and defects in mitochondrial dynamics and transport, and mitophagy. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD. In this review, we focus on recent progress that highlights the crucial role of alterations in mitochondrial function and oxidative stress in the pathogenesis of AD, emphasizing a framework of existing and potential therapeutic approaches.

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