scholarly journals Reducing voltage-dependent potassium channel Kv3.4 levels ameliorates synapse loss in a mouse model of Alzheimers disease

2021 ◽  
Author(s):  
Jie Yeap ◽  
Chaitra Sathyaprakash ◽  
Jamie Toombs ◽  
Jane Tulloch ◽  
Cristina Scutariu ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Cortical Neurons ◽  
Amyloid Plaques ◽  
Brain Homogenate ◽  
Alzheimers Disease ◽  
Synapse Loss ◽  
Voltage Dependent ◽  
Control Virus ◽  
And Control ◽  
Human Ipsc

Synapse loss is associated with cognitive decline in Alzheimers disease (AD) and owing to their plastic nature, synapses are an ideal target for therapeutic intervention. Oligomeric amyloid beta (Ab) around amyloid plaques is known to contribute to synapse loss in mouse models and is associated with synapse loss in human AD brain tissue, but the mechanisms leading from Ab; to synapse loss remain unclear. Recent data suggest that the fast-activating and -inactivating voltage-gated potassium channel subtype 3.4 (Kv3.4) may play a role in Ab-mediated neurotoxicity. Here, we tested whether this channel could also be involved in Ab synaptotoxicity. Using adeno-associated virus and CRISPR (clustered regularly interspaced short palindromic repeats) technology, we reduced Kv3.4 expression in neurons of the somatosensory cortex of APP/PS1 mice. These mice express human familial AD associated mutations in amyloid precursor protein and presenilin 1 and develop amyloid plaques and plaque-associated synapse loss similar to that observed in AD brain. We observe that reducing Kv3.4 levels ameliorates dendritic spine loss and changes spine morphology compared to control virus. In support of translational relevance, Kv3.4 protein was observed in human AD and control brain and is associated with synapses in human iPSC-derived cortical neurons. Interestingly, we observe a decrease in Kv3.4 expression in iPSC derived cortical neurons when they are challenged with human Alzheimers disease derived brain homogenate. These results suggest that approaches to reduce Kv3.4 expression and/or function could be protective against Ab-induced synaptic alterations.

scholarly journals Astrocyte- and neuron-derived extracellular vesicles from Alzheimer’s disease patients effect complement-mediated neurotoxicity

2020 ◽  
Author(s):  
Carlos J Nogueras-Ortiz ◽  
Vasiliki Mahairaki ◽  
Francheska Delgado-Peraza ◽  
Debamitra Das ◽  
Konstantinos Avgerinos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Extracellular Vesicles ◽  
Cortical Neurons ◽  
Membrane Attack Complex ◽  
Neurite Density ◽  
Complement Inhibitors ◽  
Rat Cortical Neurons ◽  
And Control ◽  
Human Ipsc

AbstractWe have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer’s disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurodegeneration, we assessed the neurotoxicity of immunocaptured AEVs (with anti-GLAST antibody), neuronal-origin NEVs (with anti-L1CAM antibody), and multicellular-origin (with anti-CD81 antibody) EVs from the plasma of AD, frontotemporal lobar degeneration (FTLD) and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons, membrane disruption, reduced neurite density, and decreased cell viability in rat cortical neurons and human IPSC-derived neurons. Neurodegenerative effects were not produced by multicellular-origin EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and suggest that neuronal MAC deposition is necessary for AEV/NEV-mediated neurodegeneration in AD.

scholarly journals Cooperative interactions among subunits of a voltage-dependent potassium channel. Evidence from expression of concatenated cDNAs.

1992 ◽  
Vol 267 (33) ◽  
pp. 23742-23745
Author(s):  
R.S. Hurst ◽  
M.P. Kavanaugh ◽  
J Yakel ◽  
J.P. Adelman ◽  
R.A. North
Keyword(s):  
Potassium Channel ◽  
Cooperative Interactions ◽  
Voltage Dependent

scholarly journals Activation-inactivation of potassium channels and development of the potassium-channel spike in internally perfused squid giant axons.

1981 ◽  
Vol 78 (1) ◽  
pp. 43-61 ◽  
Author(s):  
I Inoue
Keyword(s):  
Potassium Channels ◽  
Potassium Channel ◽  
Voltage Clamp ◽  
Time Constant ◽  
Equilibrium Potential ◽  
Giant Axons ◽  
Dependent Inactivation ◽  
Voltage Dependent ◽  
Time Courses ◽  
Calcium Permeability

A spike that is the result of calcium permeability through potassium channels was separated from the action potential is squid giant axons internally perfused with a 30 mM NaF solution and bathed in a 100 mM CaCl2 solution by blocking sodium channels with tetrodotoxin. Currents through potassium channels were studied under voltage clamp. The records showed a clear voltage-dependent inactivation of the currents. The inactivation was composed of at least two components; one relatively fast, having a time constant of 20--30 ms, and the other very slow, having a time constant of 5--10 s. Voltage clamp was carried out with a variety of salt compositions in both the internal and external solutions. A similar voltage-dependent inactivation, also composed of the two components, was recognized in all the current through potassium channels. Although the direction and intensity of current strongly depended on the salt composition of the solutions, the time-courses of these currents at corresponding voltages were very similar. These results strongly suggest that the inactivation of the currents in attributable to an essential, dynamic property of potassium channels themselves. Thus, the generation of a potassium-channel spike can be understood as an event that occurs when the equilibrium potential across the potassium channel becomes positive.

scholarly journals The incretin hormone glucagon‐like peptide 1 increases mitral cell excitability by decreasing conductance of a voltage‐dependent potassium channel

2016 ◽  
Vol 594 (10) ◽  
pp. 2607-2628 ◽  
Author(s):  
Nicolas Thiebaud ◽  
Ida J. Llewellyn‐Smith ◽  
Fiona Gribble ◽  
Frank Reimann ◽  
Stefan Trapp ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Mitral Cell ◽  
Incretin Hormone ◽  
Cell Excitability ◽  
Voltage Dependent ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Downregulation of CD40L–CD40 attenuates seizure susceptibility and severity of seizures

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Esther Pototskiy ◽  
Katherine Vinokuroff ◽  
Andrew Ojeda ◽  
C. Kendall Major ◽  
Deepak Sharma ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Molecular Techniques ◽  
Seizure Susceptibility ◽  
Wild Type ◽  
Upward Trend ◽  
Seizure Severity ◽  
Cd40 Expression ◽  
Neuro Inflammation ◽  
And Control ◽  
Deficient Mice

AbstractUnregulated neuro-inflammation mediates seizures in temporal lobe epilepsy (TLE). Our aim was to determine the effect of CD40–CD40L activation in experimental seizures. CD40 deficient mice (CD40KO) and control mice (wild type, WT) received pentenyltetrazole (PTZ) or pilocarpine to evaluate seizures and status epilepticus (SE) respectively. In mice, anti-CD40L antibody was administered intranasally before PTZ. Brain samples from human TLE and post-seizure mice were processed to determine CD40–CD40L expression using histological and molecular techniques. CD40 expression was higher in hippocampus from human TLE and in cortical neurons and hippocampal neural terminals after experimental seizures. CD40–CD40L levels increased after seizures in the hippocampus and in the cortex. After SE, CD40L/CD40 levels increased in cortex and showed an upward trend in the hippocampus. CD40KO mice demonstrated reduction in seizure severity and in latency compared to WT mice. Anti-CD40L antibody limited seizure susceptibility and seizure severity. CD40L–CD40 interaction can serve as a target for an immuno-therapy for TLE.

scholarly journals Action Potentials in Rhodnius Oocytes: Repolarization is Sensitive to Potassium Channel Blockers

1986 ◽  
Vol 126 (1) ◽  
pp. 119-132
Author(s):  
M. J. O'DONNELL
Keyword(s):  
Potassium Channel ◽  
Action Potentials ◽  
Potassium Conductance ◽  
Channel Blockers ◽  
Calcium Dependent ◽  
Outward Rectification ◽  
Current Voltage ◽  
Potassium Channel Blockers ◽  
Potassium Conductances ◽  
Voltage Dependent

Depolarization of Rhodnius oocytes evokes action potentials (APs) whose rising phase is calcium-dependent. The ionic basis for the repolarizing (i.e. falling) phase of the AP was examined. Addition of potassium channel blockers (tetraethylammonium, tetrabutylammonium, 4-aminopyridine, atropine) to the bathing saline increased the duration and overshoot of APs. Intracellular injection of tetraethyl ammonium had similar effects. These results suggest that a voltage-dependent potassium conductance normally contributes to repolarization. Repolarization does not require a chloride influx, because substitution of impermeant anions for chloride did not increase AP duration. AP duration and overshoot actually decreased progressively when chloride levels were reduced. Current/voltage curves show inward and outward rectification, properties often associated with potassium conductances. Outward rectification was largely blocked by external tetraethylammonium. Possible functions of the rectifying properties of the oocyte membrane are discussed.

Sign in / Sign up

Export Citation Format

Share Document