scholarly journals Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy

2019 ◽  
Author(s):  
Annie Lee ◽  
Chandana Kondapalli ◽  
Daniel M. Virga ◽  
Tommy L. Lewis ◽  
So Yeon Koo ◽  
...  
Keyword(s):  
Genome Engineering ◽  
Pyramidal Neurons ◽  
Es Cells ◽  
Mitochondrial Fission ◽  
Significant Loss ◽  
Synaptic Loss ◽  
Structural Remodeling ◽  
Swedish Mutation ◽  
Human Neurons

AbstractDuring the early stages of Alzheimer’s disease (AD) in both mouse models and human patients, soluble forms of Amyloid-β1-42 oligomers (Aβ42o) trigger loss of excitatory synapses (synaptotoxicity) in cortical and hippocampal pyramidal neurons (PNs) prior to the formation of insoluble Aβ plaques. We observed a spatially restricted structural remodeling of mitochondria in the apical tufts of CA1 PNs dendrites in the hAPPSWE,IND transgenic AD mouse model (J20), corresponding to the dendritic domain receiving presynaptic inputs from the entorhinal cortex and where the earliest synaptic loss is detected in vivo. We also observed significant loss of mitochondrial biomass in human neurons derived from a new model of human ES cells where CRISPR-Cas9-mediated genome engineering was used to introduce the ‘Swedish’ mutation bi-allelically (APPSWE/SWE). Recent work uncovered that Aβ42o mediates synaptic loss by over-activating the CAMKK2-AMPK kinase dyad, and that AMPK is a central regulator of mitochondria homeostasis in non-neuronal cells. Here, we demonstrate that Aβ42o-dependent over-activation of CAMKK2-AMPK mediates synaptic loss through coordinated MFF-dependent mitochondrial fission and ULK2-dependent mitophagy in dendrites of PNs. We also found that the ability of Aβ42o-dependent mitochondrial remodeling to trigger synaptic loss requires the ability of AMPK to phosphorylate Tau on Serine 262. Our results uncover a unifying stress-response pathway triggered by Aβo and causally linking structural remodeling of dendritic mitochondria to synaptic loss.

scholarly journals Synaptic loss and retention of different classic cadherins with LTP-associated synaptic structural remodeling in vivo

Hippocampus ◽  
2010 ◽  
Vol 22 (1) ◽  
pp. 17-28 ◽  
Author(s):  
George W. Huntley ◽  
Alice M. Elste ◽  
Shekhar B. Patil ◽  
Ozlem Bozdagi ◽  
Deanna L. Benson ◽  
...  
Keyword(s):  
Synaptic Loss ◽  
Structural Remodeling

scholarly journals Nutrient signaling pathways regulate amyloid clearance and synaptic loss in Alzheimer’s disease

2020 ◽  
Author(s):  
Mrityunjoy Mondal ◽  
Jitin Bali ◽  
Makis Tzioras ◽  
Rosa C. Paolicelli ◽  
Ali Jawaid ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Pathological State ◽  
Amyloid Formation ◽  
Synaptic Loss ◽  
Synapse Loss ◽  
Human Neurons ◽  
Nutrient Signaling

SummaryExtra-cellular accumulation of Amyloid-β (Aβ) plaques is causatively associated with Alzheimer’s disease (AD). However, mechanisms that mediate the pre-pathological state of amyloid plaque formation remain elusive. Here, using paired RNAi and kinase inhibitor screens, we discovered that AKT-mediated insulin/nutrient signaling suppresses lysosomal clearance of Aβ and promotes amyloid formation. This mechanism is cell-autonomous and functions in multiple systems, including iPSC-derived human neurons and in vivo. Nutrient signaling regulates amyloid formation via distinct lysosomal functional mechanisms, while enhanced amino acid signaling promotes amyloid formation by transcriptionally suppressing lysosome biogenesis, and high intracellular cholesterol levels suppress lysosomal clearance of amyloid by increasing the number of non-functional lysosomes. The nutrient signaling pathway, present in both neurons and microglia, regulates lysosomal clearance of amyloid and microglia mediated synapse loss, both in vitro and in vivo. Clinically, older hyperlipidemic patients showed less synapse loss through microglia and performed better in cognitive tests. Thus, our results reveal a bi-partite cellular quality control system regulated by the insulinnutrient signaling that in neurons regulates Aβ peptide clearance and in microglia regulates synaptic loss, both processes causally associated with AD. Our results also caution against reducing amyloid through such processes as this might also result in synapse loss.

scholarly journals Species-specific maturation profiles of human, chimpanzee and bonobo neural cells

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Maria C Marchetto ◽  
Branka Hrvoj-Mihic ◽  
Bilal E Kerman ◽  
Diana X Yu ◽  
Krishna C Vadodaria ◽  
...  
Keyword(s):  
Neural Progenitor Cells ◽  
Pyramidal Neurons ◽  
Induced Pluripotent Stem Cell ◽  
Neural Cells ◽  
Important Species ◽  
Comparative Analyses ◽  
Human Neurons ◽  
Species Specific

Comparative analyses of neuronal phenotypes in closely related species can shed light on neuronal changes occurring during evolution. The study of post-mortem brains of nonhuman primates (NHPs) has been limited and often does not recapitulate important species-specific developmental hallmarks. We utilize induced pluripotent stem cell (iPSC) technology to investigate the development of cortical pyramidal neurons following migration and maturation of cells grafted in the developing mouse cortex. Our results show differential migration patterns in human neural progenitor cells compared to those of chimpanzees and bonobos both in vitro and in vivo, suggesting heterochronic changes in human neurons. The strategy proposed here lays the groundwork for further comparative analyses between humans and NHPs and opens new avenues for understanding the differences in the neural underpinnings of cognition and neurological disease susceptibility between species.

scholarly journals MFF-dependent mitochondrial fission regulates presynaptic release and axon branching by limiting axonal mitochondria size

2018 ◽  
Author(s):  
Tommy L. Lewis ◽  
Seok-Kyu Kwon ◽  
Annie Lee ◽  
Reuben Shaw ◽  
Franck Polleux
Keyword(s):  
Pyramidal Neurons ◽  
Mitochondrial Fission ◽  
Axon Branching ◽  
Atp Production ◽  
Terminal Axon ◽  
Cortical Pyramidal Neurons ◽  
Presynaptic Release ◽  
Organelle Morphology

ABSTRACTNeurons display extreme degrees of polarization, including compartment-specific organelle morphology. In cortical pyramidal neurons, dendritic mitochondria are long and tubular whereas axonal mitochondria display uniformly short length. Here, we explored the functional significance of maintaining small mitochondria for axonal development in vitro and in vivo. We report that the Drp1 ‘receptor’ Mitochondrial fission factor (MFF) is required for determining the size of mitochondria entering the axon and then for maintenance of their size along the distal portions of the axon without affecting their trafficking properties, presynaptic capture, membrane potential or capacity for ATP production. Strikingly, this increase in presynaptic mitochondrial size upon MFF downregulation augments their capacity for Ca2+ ([Ca2+]m) uptake during neurotransmission, leading to reduced presynaptic [Ca2+]c accumulation, decreased presynaptic release and terminal axon branching. Our results uncover a novel mechanism controlling neurotransmitter release and axon branching through fission-dependent regulation of presynaptic mitochondrial size.

scholarly journals All-Trans Retinoic Acid Increases DRP1 Levels and Promotes Mitochondrial Fission

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1202
Author(s):  
Bojjibabu Chidipi ◽  
Syed Islamuddin Shah ◽  
Michelle Reiser ◽  
Manasa Kanithi ◽  
Amanda Garces ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Mitochondrial Fission ◽  
Normal Function ◽  
Mitochondrial Network ◽  
Protein Levels ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Area And Perimeter

In the heart, mitochondrial homeostasis is critical for sustaining normal function and optimal responses to metabolic and environmental stressors. Mitochondrial fusion and fission are thought to be necessary for maintaining a robust population of mitochondria, and disruptions in mitochondrial fission and/or fusion can lead to cellular dysfunction. The dynamin-related protein (DRP1) is an important mediator of mitochondrial fission. In this study, we investigated the direct effects of the micronutrient retinoid all-trans retinoic acid (ATRA) on the mitochondrial structure in vivo and in vitro using Western blot, confocal, and transmission electron microscopy, as well as mitochondrial network quantification using stochastic modeling. Our results showed that ATRA increases DRP1 protein levels, increases the localization of DRP1 to mitochondria in isolated mitochondrial preparations. Our results also suggested that ATRA remodels the mitochondrial ultrastructure where the mitochondrial area and perimeter were decreased and the circularity was increased. Microscopically, mitochondrial network remodeling is driven by an increased rate of fission over fusion events in ATRA, as suggested by our numerical modeling. In conclusion, ATRA results in a pharmacologically mediated increase in the DRP1 protein. It also results in the modulation of cardiac mitochondria by promoting fission events, altering the mitochondrial network, and modifying the ultrastructure of mitochondria in the heart.

scholarly journals miR-379 deletion ameliorates features of diabetic kidney disease by enhancing adaptive mitophagy via FIS1

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Mitsuo Kato ◽  
Maryam Abdollahi ◽  
Ragadeepthi Tunduguru ◽  
Walter Tsark ◽  
Zhuo Chen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Mesangial Cells ◽  
Mitochondrial Fission ◽  
Major Complication ◽  
Body Weight Loss ◽  
Diabetic Kidney ◽  
Guide Rna ◽  
And Oxidative Stress

AbstractDiabetic kidney disease (DKD) is a major complication of diabetes. Expression of members of the microRNA (miRNA) miR-379 cluster is increased in DKD. miR-379, the most upstream 5′-miRNA in the cluster, functions in endoplasmic reticulum (ER) stress by targeting EDEM3. However, the in vivo functions of miR-379 remain unclear. We created miR-379 knockout (KO) mice using CRISPR-Cas9 nickase and dual guide RNA technique and characterized their phenotype in diabetes. We screened for miR-379 targets in renal mesangial cells from WT vs. miR-379KO mice using AGO2-immunopreciptation and CLASH (cross-linking, ligation, sequencing hybrids) and identified the redox protein thioredoxin and mitochondrial fission-1 protein. miR-379KO mice were protected from features of DKD as well as body weight loss associated with mitochondrial dysfunction, ER- and oxidative stress. These results reveal a role for miR-379 in DKD and metabolic processes via reducing adaptive mitophagy. Strategies targeting miR-379 could offer therapeutic options for DKD.

scholarly journals Non-alcoholic fatty liver disease in mice with hepatocyte-specific deletion of mitochondrial fission factor

Diabetologia ◽  
2021 ◽  
Author(s):  
Yukina Takeichi ◽  
Takashi Miyazawa ◽  
Shohei Sakamoto ◽  
Yuki Hanada ◽  
Lixiang Wang ◽  
...  
Keyword(s):  
Er Stress ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Primary Hepatocytes ◽  
Alcoholic Fatty Liver ◽  
Expression Of Genes ◽  
Specific Deletion

Abstract Aims/hypothesis Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred to as mitochondrial dynamics, to adapt to nutritional demands. Evidence suggests that impaired mitochondrial dynamics leads to metabolic abnormalities such as non-alcoholic steatohepatitis (NASH) phenotypes. However, how mitochondrial dynamics are involved in the development of NASH is poorly understood. This study aimed to elucidate the role of mitochondrial fission factor (MFF) in the development of NASH. Methods We created mice with hepatocyte-specific deletion of MFF (MffLiKO). MffLiKO mice fed normal chow diet (NCD) or high-fat diet (HFD) were evaluated for metabolic variables and their livers were examined by histological analysis. To elucidate the mechanism of development of NASH, we examined the expression of genes related to endoplasmic reticulum (ER) stress and lipid metabolism, and the secretion of triacylglycerol (TG) using the liver and primary hepatocytes isolated from MffLiKO and control mice. Results MffLiKO mice showed aberrant mitochondrial morphologies with no obvious NASH phenotypes during NCD, while they developed full-blown NASH phenotypes in response to HFD. Expression of genes related to ER stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic TG secretion was downregulated, with reduced hepatic TG secretion in MffLiKO mice in vivo and in primary cultures of MFF-deficient hepatocytes in vitro. Furthermore, thapsigargin-induced ER stress suppressed TG secretion in primary hepatocytes isolated from control mice. Conclusions/interpretation We demonstrated that ablation of MFF in liver provoked ER stress and reduced hepatic TG secretion in vivo and in vitro. Moreover, MffLiKO mice were more susceptible to HFD-induced NASH phenotype than control mice, partly because of ER stress-induced apoptosis of hepatocytes and suppression of TG secretion from hepatocytes. This study provides evidence for the role of mitochondrial fission in the development of NASH. Graphical abstract

scholarly journals Neuronal pannexin-1 channels are not molecular routes of water influx during spreading depolarization-induced dendritic beading

2016 ◽  
Vol 37 (5) ◽  
pp. 1626-1633 ◽  
Author(s):  
Jeremy Sword ◽  
Deborah Croom ◽  
Phil L Wang ◽  
Roger J Thompson ◽  
Sergei A Kirov
Keyword(s):  
Pyramidal Neurons ◽  
Transport Mechanisms ◽  
Coupled Transport ◽  
Pannexin 1 ◽  
Two Photon ◽  
Spreading Depolarization ◽  
Water Influx ◽  
Membrane Bound ◽  
Genetic Deletion

Spreading depolarization-induced focal dendritic swelling (beading) is an early hallmark of neuronal cytotoxic edema. Pyramidal neurons lack membrane-bound aquaporins posing a question of how water enters neurons during spreading depolarization. Recently, we have identified chloride-coupled transport mechanisms that can, at least in part, participate in dendritic beading. Yet transporter-mediated ion and water fluxes could be paralleled by water entry through additional pathways such as large-pore pannexin-1 channels opened by spreading depolarization. Using real-time in vivo two-photon imaging in mice with pharmacological inhibition or conditional genetic deletion of pannexin-1, we showed that pannexin-1 channels are not required for spreading depolarization-induced focal dendritic swelling.

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