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 Hippocampal hyperactivity in a rat model of Alzheimer’s disease

2020 ◽  
Author(s):  
Liudmila Sosulina ◽  
Manuel Mittag ◽  
Hans-Rüdiger Geis ◽  
Kerstin Hoffmann ◽  
Igor Klyubin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rat Model ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Disease Stage ◽  
Intrinsic Excitability ◽  
Ca1 Neurons ◽  
Ca1 Pyramidal Neurons ◽  
Model Of Alzheimer’S Disease

AbstractNeuronal network dysfunction is a hallmark of Alzheimer’s disease (AD). However, the underlying pathomechanisms remain unknown. We analyzed the hippocampal micronetwork in a rat model of AD at an early disease stage at the beginning of extracellular amyloid beta (Aβ) deposition. We established two-photon Ca2+-imaging in vivo in the hippocampus of rats and found hyperactivity of CA1 neurons. Patch-clamp recordings in brain slices in vitro revealed changes in the passive properties and intrinsic excitability of CA1 pyramidal neurons. Furthermore, we observed increased neuronal input resistance and prolonged action potential width in CA1 pyramidal neurons. Surprisingly, all parameters measured to quantify synaptic inhibition and excitation onto CA1 pyramidal neurons were intact suggesting a cell immanent deficit. Our data support the view that altered intrinsic excitability of CA1 neurons may precede inhibitory dysfunction at an early stage of disease progression.

scholarly journals Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

2020 ◽  
Vol 21 (16) ◽  
pp. 5858 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Md. Sohanur Rahman ◽  
Tapan Behl ◽  
Philippe Jeandet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Aggregation ◽  
Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

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.

scholarly journals Effects of Memantine on the Spontaneous Firing Frequency of CA1 Pyramidal Neurons in Intact and Alzheimer's Rats Model: An Electrophysiological Study

2021 ◽  
Author(s):  
Nastaran Zamani ◽  
◽  
Ahmad Ali Moazedi ◽  
Mohamad Reza Afarinesh ◽  
Mehdi Pourmehdi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pyramidal Neurons ◽  
Saline Group ◽  
Firing Frequency ◽  
Male Rats ◽  
Spontaneous Firing ◽  
Ca1 Pyramidal Neurons ◽  
Model Of Alzheimer’S Disease ◽  
The Mean

Introduction: Memantine (MEM) is a noncompetitive NMDAR antagonist clinically used for the treatment Alzheimer’s disease (AD) in mild to severe conditions. The present study was conducted to investigate the effects of Memantine on the spontaneous firing frequency of CA1 pyramidal neurons in rats with electrical lesion of nucleus basalis magnocellularis (NBM) as an animal model of Alzheimer's disease compared with intact adult males. Methods: In this study, adult male rats were divided into two groups. Group I (Lesion NBM, n=53) includes the following subgroups: Lesion+Saline; Sham+Saline; Lesion+MEM5mg/kg; Lesion+MEM10mg/kg; Lesion+MEM20mg/kg. And Group II (Intact, n=48) include the following subgroups: Intact+Saline; Intact+MEM3mg/kg; Intact+MEM5mg/kg; Intact+MEM10mg/kg. Extracellular single unit recording (15 min baseline+105 min after MEM or saline) was performed under urethane-anesthetized rats. Results: The results showed that the mean frequency of CA1 pyramidal neurons after saline in the Lesion+Saline (P<0.001) group significantly decreases compared with the Intact+Saline and Sham+Saline groups. In addition, after saline and memantine, the mean frequency of CA1 pyramidal neurons in the Lesion+MEM10mg/kg (P<0.01) and Lesion+MEM20mg/kg (P<0.001) groups significantly increases compared with the Lesion+Saline group. In addition the mean frequencies of CA1 pyramidal neurons in the Intact+MEM10mg/kg (P<0.001) group significantly decreases compared with the intact+saline group. Conclusion: Results showed that memantine increases the electrical activity of CA1 pyramidal neurons in rats model of Alzheimer's disease. Furthermore, in intact adult male rats, it was shown that low-dose memantine contrary to its high dose not decrease the electrical activity of CA1 pyramidal neurons.

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 Accumulation of saposin in dystrophic neurites is linked to impaired lysosomal functions in Alzheimer’s disease brains

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Md Golam Sharoar ◽  
Sarah Palko ◽  
Yingying Ge ◽  
Takaomi C. Saido ◽  
Riqiang Yan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Amyloid Plaques ◽  
Dystrophic Neurites ◽  
Neuritic Plaques ◽  
Lysosomal Hydrolases ◽  
Aβ Oligomers ◽  
Plaque Growth ◽  
Lysosomal Proteins

AbstractNeuritic plaques in Alzheimer’s disease (AD) brains refer to β-amyloid (Aβ) plaques surrounded by dystrophic neurites (DNs), activated microglia and reactive astrocytes. Most recently, we showed that DNs form sequentially in three layers during plaque growth. Although lysosomal proteins such as LAMP1 are found in DNs, it is not clear how many and how early lysosomal proteins are involved in forming neuritic plaques. To answer this unmet question, we examined APP knock-in (APPNL-G-F), 5xFAD and APP/PS1ΔE9 mouse brains and found that the lysosomal activator proteins saposins (SAPs) and LAMP1 were accumulated to surround Aβ plaques at the earliest stage, namely the 1st layer of DNs. Noticeably, lysosomal hydrolases were not detectable in these early DNs, suggesting that DNs at this early stage likely enrich dysfunctional lysosomes. In old AD mouse brains and in the later stage of human AD brains, SAP-C+-DNs and LAMP1+-DNs were gradually reduced in concomitant with the growth of amyloid plaques. Remarkably, the observed LAMP1 immunoreactivity near plaques in aged AD mouse and human brains were actually associated with disease-associated microglia rather than neuronal sources, likely reflecting more severely impaired lysosomal functions in neurons. Western blot analyses showed increased levels of SAP-C in AD mouse brains, and Aβ oligomers induced elevated levels of SAP-C in cellular assays. The elevated protein levels of SAP-C in AD mouse brains during plaque growth potentially contributed lysosomal membrane leakage and loss of hydrolases. Together, our study indicates that lysosomal functions are impaired by being entrapped in DNs early during plaque growth, and this may viciously facilitate growth of amyloid plaques.

scholarly journals Evidence for Alzheimer’s disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons

2014 ◽  
Vol 220 (6) ◽  
pp. 3143-3165 ◽  
Author(s):  
Krystina M. Neuman ◽  
Elizabeth Molina-Campos ◽  
Timothy F. Musial ◽  
Andrea L. Price ◽  
Kwang-Jin Oh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pyramidal Neurons ◽  
Ca1 Pyramidal Neurons ◽  
Synapse Loss ◽  
Hippocampal Ca1
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