Neuronal Dynamics and miRNA Signaling Differ between SH-SY5Y APPSwe and PSEN1 Mutant iPSC-Derived AD Models upon Modulation with miR-124 Mimic and Inhibitor

Neuronal miRNA dysregulation may have a role in the pathophysiology of Alzheimer’s disease (AD). miRNA(miR)-124 is largely abundant and a critical player in many neuronal functions. However, the lack of models reliably recapitulating AD pathophysiology hampers our understanding of miR-124’s role in the disease. Using the classical human SH-SY5Y-APP695 Swedish neuroblastoma cells (SH-SWE) and the PSEN1 mutant iPSC-derived neurons (iNEU-PSEN), we observed a sustained upregulation of miR-124/miR-125b/miR-21, but only miR-124 was consistently shuttled into their exosomes. The miR-124 mimic reduced APP gene expression in both AD models. While miR-124 mimic in SH-SWE neurons led to neurite outgrowth, mitochondria activation and small Aβ oligomer reduction, in iNEU-PSEN cells it diminished Tau phosphorylation, whereas miR-124 inhibitor decreased dendritic spine density. In exosomes, cellular transfection with the mimic predominantly downregulated miR-125b/miR-21/miR-146a/miR-155. The miR-124 inhibitor upregulated miR-146a in the two experimental cell models, while it led to distinct miRNA signatures in cells and exosomes. In sum, though miR-124 function may be dependent on the neuronal AD model, data indicate that keeping miR-124 level strictly controlled is crucial for proper neuronal function. Moreover, the iNEU-PSEN cellular model stands out as a useful tool for AD mechanistic studies and perhaps for the development of personalized therapeutic strategies.

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FMRP regulates the subcellular distribution of cortical dendritic spine density in a non-cell-autonomous manner

Neurobiology of Disease ◽

10.1016/j.nbd.2021.105253 ◽

2021 ◽

pp. 105253

Author(s):

Katherine M. Bland ◽

Adam Aharon ◽

Eden L. Widener ◽

M. Irene Song ◽

Zachary O. Casey ◽

...

Keyword(s):

Dendritic Spine ◽

Subcellular Distribution ◽

Spine Density ◽

Dendritic Spine Density

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FGF21 improves cognition by restored synaptic plasticity, dendritic spine density, brain mitochondrial function and cell apoptosis in obese-insulin resistant male rats

Hormones and Behavior ◽

10.1016/j.yhbeh.2016.08.006 ◽

2016 ◽

Vol 85 ◽

pp. 86-95 ◽

Cited By ~ 36

Author(s):

Piangkwan Sa-nguanmoo ◽

Pongpan Tanajak ◽

Sasiwan Kerdphoo ◽

Pattarapong Satjaritanun ◽

Xiaojie Wang ◽

...

Keyword(s):

Synaptic Plasticity ◽

Mitochondrial Function ◽

Dendritic Spine ◽

Cell Apoptosis ◽

Male Rats ◽

Spine Density ◽

Insulin Resistant ◽

Dendritic Spine Density ◽

Brain Mitochondrial Function

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Cardiac arrest with cardiopulmonary resuscitation reduces dendritic spine density in CA1 pyramidal cells and selectively alters acquisition of spatial memory

European Journal of Neuroscience ◽

10.1111/j.1460-9568.2004.03649.x ◽

2004 ◽

Vol 20 (7) ◽

pp. 1865-1872 ◽

Cited By ~ 36

Author(s):

Gretchen N. Neigh ◽

Erica R. Glasper ◽

Julia Kofler ◽

Richard J. Traystman ◽

Ronald F. Mervis ◽

...

Keyword(s):

Cardiac Arrest ◽

Cardiopulmonary Resuscitation ◽

Spatial Memory ◽

Dendritic Spine ◽

Pyramidal Cells ◽

Spine Density ◽

Ca1 Pyramidal Cells ◽

Dendritic Spine Density

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Post-Weaning Social Isolation Causes Sex-specific Alterations to Dendritic Spine Density in Subregions of the Prefrontal Cortex and Nucleus Accumbens of Adult Mice

Brain Research ◽

10.1016/j.brainres.2021.147755 ◽

2021 ◽

pp. 147755

Author(s):

Anna G. McGrath ◽

Lisa A. Briand

Keyword(s):

Prefrontal Cortex ◽

Nucleus Accumbens ◽

Social Isolation ◽

Dendritic Spine ◽

Spine Density ◽

Adult Mice ◽

Dendritic Spine Density

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BDNF over-expression increases olfactory bulb granule cell dendritic spine density in vivo

Neuroscience ◽

10.1016/j.neuroscience.2015.07.056 ◽

2015 ◽

Vol 304 ◽

pp. 146-160 ◽

Cited By ~ 10

Author(s):

B. McDole ◽

C. Isgor ◽

C. Pare ◽

K. Guthrie

Keyword(s):

Olfactory Bulb ◽

Granule Cell ◽

Dendritic Spine ◽

Spine Density ◽

Over Expression ◽

Dendritic Spine Density

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BDNF-TrkB controls cocaine-induced dendritic spines in rodent nucleus accumbens dissociated from increases in addictive behaviors

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1702441114 ◽

2017 ◽

Vol 114 (35) ◽

pp. 9469-9474 ◽

Cited By ~ 12

Author(s):

Ethan M. Anderson ◽

Anne Marie Wissman ◽

Joyce Chemplanikal ◽

Nicole Buzin ◽

Daniel Guzman ◽

...

Keyword(s):

Nucleus Accumbens ◽

Dendritic Spine ◽

Morphological Changes ◽

Dominant Negative ◽

Addictive Behaviors ◽

Spine Density ◽

Nucleus Accumbens Shell ◽

Self Administration ◽

Dendritic Spine Density ◽

Chronic Cocaine

Chronic cocaine use is associated with prominent morphological changes in nucleus accumbens shell (NACsh) neurons, including increases in dendritic spine density along with enhanced motivation for cocaine, but a functional relationship between these morphological and behavioral phenomena has not been shown. Here we show that brain-derived neurotrophic factor (BDNF) signaling through tyrosine kinase B (TrkB) receptors in NACsh neurons is necessary for cocaine-induced dendritic spine formation by using either localized TrkB knockout or viral-mediated expression of a dominant negative, kinase-dead TrkB mutant. Interestingly, augmenting wild-type TrkB expression after chronic cocaine self-administration reverses the sustained increase in dendritic spine density, an effect mediated by TrkB signaling pathways that converge on extracellular regulated kinase. Loss of TrkB function after cocaine self-administration, however, leaves spine density intact but markedly enhances the motivation for cocaine, an effect mediated by specific loss of TrkB signaling through phospholipase Cgamma1 (PLCγ1). Conversely, overexpression of PLCγ1 both reduces the motivation for cocaine and reverses dendritic spine density, suggesting a potential target for the treatment of addiction in chronic users. Together, these findings indicate that BDNF-TrkB signaling both mediates and reverses cocaine-induced increases in dendritic spine density in NACsh neurons, and these morphological changes are entirely dissociable from changes in addictive behavior.

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Modulation of calcium signaling depends on the oligosaccharide of GM1 in Neuro2a mouse neuroblastoma cells

Glycoconjugate Journal ◽

10.1007/s10719-020-09963-7 ◽

2020 ◽

Vol 37 (6) ◽

pp. 713-727

Author(s):

Giulia Lunghi ◽

Maria Fazzari ◽

Erika Di Biase ◽

Laura Mauri ◽

Sandro Sonnino ◽

...

Keyword(s):

Plasma Membrane ◽

Calcium Channels ◽

Calcium Signaling ◽

Intracellular Calcium ◽

Calcium Imaging ◽

Neuroblastoma Cells ◽

Ganglioside Gm1 ◽

Mouse Neuroblastoma ◽

Neuro2a Cells ◽

Neuronal Functions

AbstractRecently, we demonstrated that the oligosaccharide portion of ganglioside GM1 is responsible, via direct interaction and activation of the TrkA pathway, for the ability of GM1 to promote neuritogenesis and to confer neuroprotection in Neuro2a mouse neuroblastoma cells. Recalling the knowledge that ganglioside GM1 modulates calcium channels activity, thus regulating the cytosolic calcium concentration necessary for neuronal functions, we investigated if the GM1-oligosaccharide would be able to overlap the GM1 properties in the regulation of calcium signaling, excluding a specific role played by the ceramide moiety inserted into the external layer of plasma membrane. We observed, by calcium imaging, that GM1-oligosaccharide administration to undifferentiated Neuro2a cells resulted in an increased calcium influx, which turned out to be mediated by the activation of TrkA receptor. The biochemical analysis demonstrated that PLCγ and PKC activation follows the TrkA stimulation by GM1-oligosaccharide, leading to the opening of calcium channels both on the plasma membrane and on intracellular storages, as confirmed by calcium imaging experiments performed with IP3 receptor inhibitor. Subsequently, we found that neurite elongation in Neuro2a cells was blocked by subtoxic administration of extracellular and intracellular calcium chelators, suggesting that the increase of intracellular calcium is responsible of GM1-oligosaccharide mediated differentiation. These results suggest that GM1-oligosaccharide is responsible for the regulation of calcium signaling and homeostasis at the base of the neuronal functions mediated by plasma membrane GM1.

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Dendritic Spine Density of Pyramidal Neurons in Field CA1 of the Hippocampus Decreases due to Chronic Tryptophan Restriction

Nutritional Neuroscience ◽

10.1080/1028415x.1998.11747233 ◽

1998 ◽

Vol 1 (3) ◽

pp. 237-242 ◽

Cited By ~ 6

Author(s):

M.I. Pérez-Vega ◽

G. Barajas-López ◽

A.R. del Angel-Meza ◽

I. González-Burgos ◽

A. Feria-Velasco

Keyword(s):

Dendritic Spine ◽

Pyramidal Neurons ◽

Spine Density ◽

Dendritic Spine Density ◽

Field Ca1

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Exosomal miR-132-3p from Mesenchymal Stromal Cells Improve Synaptic Dysfunction and Cognitive Decline in Vascular Dementia

10.21203/rs.3.rs-1048848/v1 ◽

2021 ◽

Author(s):

Xiaotang Ma ◽

Yan Wang ◽

Yumeng Shi ◽

Suqing Li ◽

Jinhua Liu ◽

...

Keyword(s):

Synaptic Plasticity ◽

Cognitive Function ◽

Stromal Cells ◽

Memory Deficit ◽

Synaptic Dysfunction ◽

Spine Density ◽

Neuron Number ◽

Neurite Elongation ◽

Dendritic Spine Density ◽

Gsk 3Β

Abstract Background/Aims: Vascular dementia (VD) results in cognition and memory deficit. Exosomes and their carried microRNAs (miRs) contribute to the neuroprotective effects of mesenchymal stromal cells, and miR-132-3p plays a key role in neuron plasticity. Here we investigated the role and underlying mechanism of MSC EX and their miR-132-3p cargo in rescuing cognition and memory deficit in VD mice. Methods: Bilateral carotid artery occlusion was used to generate a VD mouse model. MiR-132-3p and MSC EX levels in the hippocampus and cortex were measured. At 24 h post-VD induction, mice were administered with MSC EX infected with control lentivirus (EXCon), pre-miR-132-3p-expressing lentivirus (EXmiR−132−3p), or miR-132-3p antago lentivirus (EXantagomiR−132−3p) intravenously. Behavioral and cognitive tests were performed and the mice were sacrificed in 21 days after VD. The effects of MSC EX on neuron number, synaptic plasticity, dendritic spine density, and Aβ and p-Tau levels in the hippocampus and cortex were determined. The effects of MSC EX on oxygen-glucose deprivation (OGD)-injured neurons with respect to apoptosis, and neurite elongation and branching were determined. Finally, the expression levels of Ras, phosphorylation of Akt, GSK-3β, and Tau were also measured. Results: Compared with normal mice, VD mice exhibited significantly decreased miR-132-3p and MSC EX levels in the cortex and hippocampus. Compared with EXCon treatment, the infusion of EXmiR−132−3p was more effective at improving cognitive function and increasing miR-132-3p level, neuron number, synaptic plasticity, and dendritic spine density, while decreasing Aβ and p-Tau levels in the cortex and hippocampus of VD mice. Conversely, EXantagomiR−132−3p treatment significantly decreased miR-132-3p expression in cortex and hippocampus, as well as attenuated EXmiR−132−3p treatment-induced functional improvement. In vitro, EXmiR−132−3p treatment inhibited RASA1 protein expression, but increased Ras and the phosphorylation of Akt and GSK-3β, and decreased p-Tau levels in primary neurons by delivering miR-132-3p, which resulted in reduced apoptosis, and increased neurite elongation and branching in OGD-injured neurons. Conclusions: Our studies suggest that miR-132-3p cluster-enriched MSC EX promotes the recovery of cognitive function by improving neuronal and synaptic dysfunction through activation of the Ras/Akt/GSK-3β pathway induced by downregulation of RASA1.

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