scholarly journals Nucleolar PARP-1 Expression Is Decreased in Alzheimer’s Disease: Consequences for Epigenetic Regulation of rDNA and Cognition

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Jianying Zeng ◽  
Jenny Libien ◽  
Fatima Shaik ◽  
Jason Wolk ◽  
A. Iván Hernández
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Hippocampal Pyramidal Neurons ◽  
Functional Changes ◽  
Epigenetic Regulator ◽  
Parp 1 ◽  
Sensitive Marker ◽  
Hippocampal Pyramidal Cells

Synaptic dysfunction is thought to play a major role in memory impairment in Alzheimer’s disease (AD). PARP-1 has been identified as an epigenetic regulator of plasticity and memory. Thus, we hypothesize that PARP-1 may be altered in postmortem hippocampus of individuals with AD compared to age-matched controls without neurologic disease. We found a reduced level of PARP-1 nucleolar immunohistochemical staining in hippocampal pyramidal cells in AD. Nucleolar PARP-1 staining ranged from dispersed and less intense to entirely absent in AD compared to the distinct nucleolar localization in hippocampal pyramidal neurons in controls. In cases of AD, the percentage of hippocampal pyramidal cells with nucleoli that were positive for both PARP-1 and the nucleolar marker fibrillarin was significantly lower than in controls. PARP-1 nucleolar expression emerges as a sensitive marker of functional changes in AD and suggests a novel role for PARP-1 dysregulation in AD pathology.

scholarly journals Alzheimer’s disease brain-derived tau-containing extracellular vesicles: Pathobiology and GABAergic neuronal transmission

2020 ◽  
Author(s):  
Zhi Ruan ◽  
Dhruba Pathak ◽  
Srinidhi Venkatesan Kalavai ◽  
Asuka Yoshii-Kitahara ◽  
Satoshi Muraoka ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Extracellular Vesicles ◽  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Molecular Layer ◽  
Pyramidal Cells ◽  
Gabaergic Neurons ◽  
Dot Blot ◽  
Patch Clamp Recording

AbstractExtracellular vesicles (EVs) propagate tau pathology for Alzheimer’s disease (AD). How EV transmission influences AD are, nonetheless, poorly understood. To these ends, the physicochemical and molecular structure-function relationships of human brain-derived EVs, from AD and prodromal AD (pAD), were compared to non-demented controls (CTRL). AD EVs were shown to be significantly enriched in epitope-specific tau oligomers versus pAD or CTRL EVs assayed by dot-blot and atomic force microscopy tests. AD EVs were efficiently internalized by murine cortical neurons and transferred tau with higher aggregation potency than pAD and CTRL EVs. Strikingly, inoculation of tau-containing AD EVs into the outer molecular layer of the dentate gyrus induced tau propagation throughout the hippocampus. This was seen in 22 months-old C57BL/6 mice at 4.5 months post-injection by semiquantitative brain-wide immunohistochemistry tests with multiple anti-phospho-tau (p-tau) antibodies. Inoculation of the equal amount of tau from CTRL EVs or as oligomer or fibril-enriched fraction from the same AD donor showed little propagation. AD EVs induced tau accumulation in the hippocampus as oligomers or sarkosyl-insoluble proteins. Unexpectedly, p-tau cells were mostly GAD67+ GABAergic neurons and to a lesser extent, GluR2/3+ excitatory mossy cells, showing preferential EV-mediated GABAergic neuronal tau propagation. Whole-cell patch clamp recording of Cornu Ammonis (CA1) pyramidal cells showed significant reduction in the amplitude of spontaneous inhibitory post-synaptic currents. This was accompanied by reductions in c-fos+ GAD67+GABAergic neurons and GAD67+ GABAergic neuronal puncta surrounding pyramidal neurons in the CA1 region confirming reduced interneuronal projections. Our study posits a novel tau-associated pathological mechanism for brain-derived EVs.

Specific Subtypes of GABAA Receptors Mediate Phasic and Tonic Forms of Inhibition in Hippocampal Pyramidal Neurons

2006 ◽  
Vol 96 (2) ◽  
pp. 846-857 ◽  
Author(s):  
George A. Prenosil ◽  
Edith M. Schneider Gasser ◽  
Uwe Rudolph ◽  
Ruth Keist ◽  
Jean-Marc Fritschy ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Tonic Inhibition ◽  
Mammalian Brain ◽  
Triple Mutant ◽  
Α Subunit ◽  
Hippocampal Pyramidal Neurons ◽  
Inhibitory Neurotransmitter ◽  
Ca1 Area ◽  
Hippocampal Pyramidal Cells

The main inhibitory neurotransmitter in the mammalian brain, GABA, mediates multiple forms of inhibitory signals, such as fast and slow inhibitory postsynaptic currents and tonic inhibition, by activating a diverse family of ionotropic GABAA receptors (GABAARs). Here, we studied whether distinct GABAAR subtypes mediate these various forms of inhibition using as approach mice carrying a point mutation in the α-subunit rendering individual GABAAR subtypes insensitive to diazepam without altering their GABA sensitivity and expression of receptors. Whole cell patch-clamp recordings were performed in hippocampal pyramidal cells from single, double, and triple mutant mice. Comparing diazepam effects in knock-in and wild-type mice allowed determining the contribution of α1, α2, α3, and α5 subunits containing GABAARs to phasic and tonic forms of inhibition. Fast phasic currents were mediated by synaptic α2-GABAARs on the soma and by synaptic α1-GABAARs on the dendrites. No contribution of α3- or α5-GABAARs was detectable. Slow phasic currents were produced by both synaptic and perisynaptic GABAARs, judged by their strong sensitivity to blockade of GABA reuptake. In the CA1 area, but not in the subiculum, perisynaptic α5-GABAARs contributed to slow phasic currents. In the CA1 area, the diazepam-sensitive component of tonic inhibition also involved activation of α5-GABAARs and slow phasic and tonic signals shared overlapping pools of receptors. These results show that the major forms of inhibitory neurotransmission in hippocampal pyramidal cells are mediated by distinct GABAARs subtypes.

scholarly journals Reduction of Dendritic Inhibition in CA1 Pyramidal Neurons in Amyloidosis Models of Early Alzheimer’s Disease

2020 ◽  
Vol 78 (3) ◽  
pp. 951-964
Author(s):  
Marvin Ruiter ◽  
Lotte J. Herstel ◽  
Corette J. Wierenga
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Early Stage ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Excitatory Input ◽  
Aβ Oligomers ◽  
Ca1 Pyramidal Neurons

Background: In an early stage of Alzheimer’s disease (AD), before the formation of amyloid plaques, neuronal network hyperactivity has been reported in both patients and animal models. This suggests an underlying disturbance of the balance between excitation and inhibition. Several studies have highlighted the role of somatic inhibition in early AD, while less is known about dendritic inhibition. Objective: In this study we investigated how inhibitory synaptic currents are affected by elevated Aβ levels. Methods: We performed whole-cell patch clamp recordings of CA1 pyramidal neurons in organotypic hippocampal slice cultures after treatment with Aβ-oligomers and in hippocampal brain slices from AppNL-F-G mice (APP-KI). Results: We found a reduction of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons in organotypic slices after 24 h Aβ treatment. sIPSCs with slow rise times were reduced, suggesting a specific loss of dendritic inhibitory inputs. As miniature IPSCs and synaptic density were unaffected, these results suggest a decrease in activity-dependent transmission after Aβ treatment. We observed a similar, although weaker, reduction in sIPSCs in CA1 pyramidal neurons from APP-KI mice compared to control. When separated by sex, the strongest reduction in sIPSC frequency was found in slices from male APP-KI mice. Consistent with hyperexcitability in pyramidal cells, dendritically targeting interneurons received slightly more excitatory input. GABAergic action potentials had faster kinetics in APP-KI slices. Conclusion: Our results show that Aβ affects dendritic inhibition via impaired action potential driven release, possibly due to altered kinetics of GABAergic action potentials. Reduced dendritic inhibition may contribute to neuronal hyperactivity in early AD.

scholarly journals The Molecular Basis for the Calcium-Dependent Slow Afterhyperpolarization in CA1 Hippocampal Pyramidal Neurons

2021 ◽  
Vol 12 ◽  
Author(s):  
Giriraj Sahu ◽  
Ray W. Turner
Keyword(s):  
Potassium Channels ◽  
Pyramidal Neurons ◽  
Signal Transmission ◽  
Ryanodine Receptors ◽  
Pyramidal Cells ◽  
Frequency Pattern ◽  
Hippocampal Pyramidal Neurons ◽  
Calcium Dependent ◽  
Ionic Basis ◽  
Hippocampal Pyramidal Cells

Neuronal signal transmission depends on the frequency, pattern, and timing of spike output, each of which are shaped by spike afterhyperpolarizations (AHPs). There are classically three post-spike AHPs of increasing duration categorized as fast, medium and slow AHPs that hyperpolarize a cell over a range of 10 ms to 30 s. Intensive early work on CA1 hippocampal pyramidal cells revealed that all three AHPs incorporate activation of calcium-gated potassium channels. The ionic basis for a fAHP was rapidly attributed to the actions of big conductance (BK) and the mAHP to small conductance (SK) or Kv7 potassium channels. In stark contrast, the ionic basis for a prominent slow AHP of up to 30 s duration remained an enigma for over 30 years. Recent advances in pharmacological, molecular, and imaging tools have uncovered the expression of a calcium-gated intermediate conductance potassium channel (IK, KCa3.1) in central neurons that proves to contribute to the slow AHP in CA1 hippocampal pyramidal cells. Together the data show that the sAHP arises in part from a core tripartite complex between Cav1.3 (L-type) calcium channels, ryanodine receptors, and IK channels at endoplasmic reticulum-plasma membrane junctions. Work on the sAHP in CA1 pyramidal neurons has again quickened pace, with identified contributions by both IK channels and the Na-K pump providing answers to several mysteries in the pharmacological properties of the sAHP.

Ca2+ Channels Involved in the Generation of the Slow Afterhyperpolarization in Cultured Rat Hippocampal Pyramidal Neurons

2000 ◽  
Vol 83 (5) ◽  
pp. 2554-2561 ◽  
Author(s):  
M. Shah ◽  
D. G. Haylett
Keyword(s):  
Calcium Channels ◽  
Action Potentials ◽  
Calcium Release ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Isolated Cells ◽  
Hippocampal Pyramidal Neurons ◽  
Calcium Induced Calcium Release ◽  
Ca2 Channels ◽  
Hippocampal Pyramidal Cells

The advantages of using isolated cells have led us to develop short-term cultures of hippocampal pyramidal cells, which retain many of the properties of cells in acute preparations and in particular the ability to generate afterhyperpolarizations after a train of action potentials. Using perforated-patch recordings, both medium and slow afterhyperpolarization currents (m I AHP and s I AHP, respectively) could be obtained from pyramidal cells that were cultured for 8–15 days. The s I AHP demonstrated the kinetics and pharmacologic characteristics reported for pyramidal cells in slices. In addition to confirming the insensitivity to 100 nM apamin and 1 mM TEA, we have shown that the s I AHP is also insensitive to 100 nM charybdotoxin but is inhibited by 100 μMd-tubocurarine. Concentrations of nifedipine (10 μM) and nimodipine (3 μM) that maximally inhibit L-type calcium channels reduced the s I AHP by 30 and 50%, respectively. However, higher concentrations of nimodipine (10 μM) abolished the s I AHP, which can be partially explained by an effect on action potentials. Both nifedipine and nimodipine at maximal concentrations were found to reduce the HVA calcium current in freshly dissociated neurons to the same extent. The N-type calcium channel inhibitor, ω-conotoxin GVIA (100 nM), irreversibly inhibited the s I AHP by 37%. Together, ω-conotoxin (100 nM) and nifedipine (10 μM) inhibited the s I AHP by 70%. 10 μM ryanodine also reduced the s I AHP by 30%, suggesting a role for calcium-induced calcium release. It is concluded that activation of the s I AHP in cultured hippocampal pyramidal cells is mediated by a rise in intracellular calcium involving multiple pathways and not just entry via L-type calcium channels.

scholarly journals Kaempferol promotes memory retention and density of hippocampal CA1 neurons in intra-cerebroventricular STZ-induced experimental AD model in Wistar rats

Biologija ◽  
2016 ◽  
Vol 62 (3) ◽  
Author(s):  
Niloufar Darbandi ◽  
Matin Ramezani ◽  
Fariba Khodagholi ◽  
Mitra Noori
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pyramidal Neurons ◽  
Neuronal Damage ◽  
Pyramidal Cells ◽  
Control Group ◽  
Memory Retention ◽  
Hippocampal Ca1 ◽  
Learning Test ◽  
Ca1 Area

Background. Alzheimer’s disease (AD) is a progressive degenerative disease which causes memory disorders, decreases cognitive functions and abilities, and results in behavioural changes. Some studies have indicated that the flavonoids are able to cross the blood–brain barrier and have a positive effect on the reduction of neuronal damage disorders in the brain such as Alzheimer’s disease. Materials and Methods. ICV administration of streptozotocin (3 mg/kg) was done on the first and the third day of the surgery and the animals’ memory was evaluated through passive avoidance tasks. Animals were divided into five groups: Salin-Salin, STZ-Salin, and STZ- different kaempferol doses (5, 7/5, 10 mg/kg). All animals received different doses of kaempferol or saline for 3 weeks starting one day before the surgery. Later, they were put into a learning test. After the memory test, the animals were killed and their brains were fixed with Paraformaldehyde 4%, and tissue processing was done. Finally, density of intact neurons in the CA1 area of the hippocampus in the brains of all groups was investigated. Results. The ICV injections of STZ significantly reduced memory retention and intact pyramidal cells compared to the control group. The kaempferol improved the effects of STZ. Conclusion. Our findings show that kaempferol can optimize cognitive deficits caused by injections of STZ and also has some useful impacts on hippocampal CA1 pyramidal neurons.

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