CA1 and CA3 pyramidal cell morphologies under Alzheimer’s disease Amyloid beta interaction (original) (raw)
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Molecular Psychiatry
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Simulation of Ca2+ oscillations in astrocytes mediated by amyloid beta in Alzheimer’s disease
2020
Disruptions of astrocyte Ca2+ signaling is important in Alzheimer’s disease (AD) with the unclear mechanism of amyloid beta peptide (Aβ). We have modified our previous computational model of spontaneous Ca2+ oscillations in astrocytes to investigate the effects of Aβ on intracellular Ca2+ dynamics. The simulation results have shown consistence with the previous experiments. Aβ can increase the resting concentration of intracellular Ca2+ and change the regime of Ca2+ oscillations by activating L-type voltage-gated calcium channels and the metabolic glutamate receptors, or by increasing ryanodine receptors sensitivity and Ca2+ leakage, respectively. This work have provided a toolkit to study the influence of Aβ on intracellular Ca2+ dynamics in AD. It is helpful for understanding the toxic role of Aβ during the progression of AD.Statement of SignificanceAlzheimer’s disease (AD) is the most common neurodegenerative disease with the unclear mechanism of amyloid beta peptide (Aβ). This w...
Frontiers in Physiology, 2021
The accumulation of amyloid β peptide (Aβ) in the brain is hypothesized to be the major factor driving Alzheimer’s disease (AD) pathogenesis. Mounting evidence suggests that astrocytes are the primary target of Aβ neurotoxicity. Aβ is known to interfere with multiple calcium fluxes, thus disrupting the calcium homeostasis regulation of astrocytes, which are likely to produce calcium oscillations. Ca2+ dyshomeostasis has been observed to precede the appearance of clinical symptoms of AD; however, it is experimentally very difficult to investigate the interactions of many mechanisms. Given that Ca2+ disruption is ubiquitously involved in AD progression, it is likely that focusing on Ca2+ dysregulation may serve as a potential therapeutic approach to preventing or treating AD, while current hypotheses concerning AD have so far failed to yield curable therapies. For this purpose, we derive and investigate a concise mathematical model for Aβ-mediated multi-pathway astrocytic intracellula...
Brain, 2021
Alzheimer’s disease is the most common form of dementia, characterized by a persistent and progressive impairment of cognitive functions. Alzheimer’s disease is typically associated with extracellular deposits of amyloid-β peptide and accumulation of abnormally phosphorylated tau protein inside neurons (amyloid-β and neurofibrillary pathologies). It has been proposed that these pathologies cause neuronal degeneration and synaptic alterations, which are thought to constitute the major neurobiological basis of cognitive dysfunction in Alzheimer’s disease. The hippocampal formation is especially vulnerable in the early stages of Alzheimer’s disease. However, the vast majority of electron microscopy studies have been performed in animal models. In the present study, we performed an extensive 3D study of the neuropil to investigate the synaptic organization in the stratum pyramidale and radiatum in the CA1 field of Alzheimer’s disease cases with different stages of the disease, using foc...
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Cells, 2022
Alzheimer’s disease is characterized by a marked dysregulation of intracellular Ca2+ homeostasis. In particular, toxic β-amyloids (Aβ) perturb the activities of numerous Ca2+ transporters or channels. Because of the tight coupling between Ca2+ dynamics and the membrane electrical activity, such perturbations are also expected to affect neuronal excitability. We used mathematical modeling to systematically investigate the effects of changing the activities of the various targets of Aβ peptides reported in the literature on calcium dynamics and neuronal excitability. We found that the evolution of Ca2+ concentration just below the plasma membrane is regulated by the exchanges with the extracellular medium, and is practically independent from the Ca2+ exchanges with the endoplasmic reticulum. Thus, disruptions of Ca2+ homeostasis interfering with signaling do not affect the electrical properties of the neurons at the single cell level. In contrast, the model predicts that by affecting ...
Analyzing and Modeling the Dysfunction of Inhibitory Neurons in Alzheimer's Disease
PloS one, 2016
Alzheimer's disease (AD) is characterized by the abnormal proteolytic processing of amyloid precursor protein, resulting in increased production of a self-aggregating form of beta amyloid (Aβ). Several lines of work on AD patients and transgenic mice with high Aβ levels exhibit altered rhythmicity, aberrant neuronal network activity and hyperexcitability reflected in clusters of hyperactive neurons, and spontaneous epileptic activity. Recent studies highlight that abnormal accumulation of Aβ changes intrinsic properties of inhibitory neurons, which is one of the main reasons underlying the impaired network activity. However, specific cellular mechanisms leading to interneuronal dysfunction are not completely understood. Using extended Hodgkin-Huxley (HH) formalism in conjunction with patch-clamp experiments, we investigate the mechanisms leading to the impaired activity of interneurons. Our detailed analysis indicates that increased Na+ leak explains several observations in inhi...