scholarly journals Alzheimer’s Disease as a Result of Stimulus Reduction in a GABA-A-Deficient Brain: A Neurocomputational Model

2020 ◽  
Vol 2020 ◽  
pp. 1-26
Author(s):  
Mariana Antonia Aguiar-Furucho ◽  
Francisco Javier Ropero Peláez
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Computational Model ◽  
Sensory Information ◽  
Continuous Learning ◽  
Sensory Stimuli ◽  
Gaba A ◽  
Neural Excitability ◽  
Sensory Cortices ◽  
Synaptic Pruning

Several research studies point to the fact that sensory and cognitive reductions like cataracts, deafness, macular degeneration, or even lack of activity after job retirement, precede the onset of Alzheimer’s disease. To simulate Alzheimer’s disease earlier stages, which manifest in sensory cortices, we used a computational model of the koniocortex that is the first cortical stage processing sensory information. The architecture and physiology of the modeled koniocortex resemble those of its cerebral counterpart being capable of continuous learning. This model allows one to analyze the initial phases of Alzheimer’s disease by “aging” the artificial koniocortex through synaptic pruning, by the modification of acetylcholine and GABA-A signaling, and by reducing sensory stimuli, among other processes. The computational model shows that during aging, a GABA-A deficit followed by a reduction in sensory stimuli leads to a dysregulation of neural excitability, which in the biological brain is associated with hypermetabolism, one of the earliest symptoms of Alzheimer’s disease.

scholarly journals Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xin Ding ◽  
Jin Wang ◽  
Miaoxin Huang ◽  
Zhangpeng Chen ◽  
Jing Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Knock Out ◽  
Classical Complement Pathway ◽  
Synaptic Remodeling ◽  
The Central Nervous System ◽  
System Activation ◽  
Knock Out Mice ◽  
Synaptic Pruning

AbstractMicroglia play a key role in regulating synaptic remodeling in the central nervous system. Activation of classical complement pathway promotes microglia-mediated synaptic pruning during development and disease. CD47 protects synapses from excessive pruning during development, implicating microglial SIRPα, a CD47 receptor, in synaptic remodeling. However, the role of microglial SIRPα in synaptic pruning in disease remains unclear. Here, using conditional knock-out mice, we show that microglia-specific deletion of SIRPα results in decreased synaptic density. In human tissue, we observe that microglial SIRPα expression declines alongside the progression of Alzheimer’s disease. To investigate the role of SIRPα in neurodegeneration, we modulate the expression of microglial SIRPα in mouse models of Alzheimer’s disease. Loss of microglial SIRPα results in increased synaptic loss mediated by microglia engulfment and enhanced cognitive impairment. Together, these results suggest that microglial SIRPα regulates synaptic pruning in neurodegeneration.

scholarly journals Effects of optogenetic stimulation of basal forebrain parvalbumin neurons on Alzheimer’s disease pathology

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Caroline A. Wilson ◽  
Sarah Fouda ◽  
Shuzo Sakata
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Basal Forebrain ◽  
Gamma Oscillations ◽  
Cortical Region ◽  
Sensory Stimuli ◽  
Beneficial Effects ◽  
Amyloid Load ◽  
5Xfad Mice ◽  
Frontal Cortical Region

Abstract Neuronal activity can modify Alzheimer’s disease pathology. Overexcitation of neurons can facilitate disease progression whereas the induction of cortical gamma oscillations can reduce amyloid load and improve cognitive functions in mouse models. Although previous studies have induced cortical gamma oscillations by either optogenetic activation of cortical parvalbumin-positive (PV+) neurons or sensory stimuli, it is still unclear whether other approaches to induce gamma oscillations can also be beneficial. Here we show that optogenetic activation of PV+ neurons in the basal forebrain (BF) increases amyloid burden, rather than reducing it. We applied 40 Hz optical stimulation in the BF by expressing channelrhodopsin-2 (ChR2) in PV+ neurons of 5xFAD mice. After 1-h induction of cortical gamma oscillations over three days, we observed the increase in the concentration of amyloid-β42 in the frontal cortical region, but not amyloid-β40. Amyloid plaques were accumulated more in the medial prefrontal cortex and the septal nuclei, both of which are targets of BF PV+ neurons. These results suggest that beneficial effects of cortical gamma oscillations on Alzheimer’s disease pathology can depend on the induction mechanisms of cortical gamma oscillations.

Sensory Stimuli Reminiscence for Patients with Alzheimer's Disease

1994 ◽  
Vol 14 (4) ◽  
pp. 29-46 ◽  
Author(s):  
Kevan H. Namazi ◽  
Sharon R. Haynes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sensory Stimuli

scholarly journals A TREM2-derived circRNA is upregulated in the entorhinal cortex of Alzheimer's disease patients

2021 ◽  
Author(s):  
Amaya Urdanoz-Casado ◽  
Javier Sanchez-Ruiz de Gordoa ◽  
Maitane Robles ◽  
Miren Roldan ◽  
Maria Victoria Zelaya ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Alternative Splicing ◽  
Entorhinal Cortex ◽  
Neurological Diseases ◽  
Circular Rnas ◽  
Rt Pcr ◽  
Neural Tissues ◽  
Primer Sets ◽  
Synaptic Pruning

Circular RNAs (circRNAs) are a novel class of noncoding RNAs characterized by a covalent and stable closed loop structure. circRNAs are enriched in neural tissues, particularly at synapses, where they are involved in synaptic plasticity. Alzheimer's disease (AD) is considered a synaptopathy since neurodegeneration causes loss or dysfunction of synapses. Microglia participate in synaptic pruning and also play a crucial role in developing AD. For instance, genetic variants in TREM2, a microglia-related gene, are risk factors for AD. Alterations in circRNAs expression have been described in different neurological diseases, including AD. However, no TREM2-derived circRNAs have been described so far. TREM2 has 3 linear RNA variants due to alternative splicing. We hypothesized that alternative splicing of exon 4 might be favoring circRNAs originating from TREM2 (circTREM2s), which in turn might be involved in AD pathogenesis. First, divergent primers (overlapping exons 3-4 and 4-5) were designed to amplify circRNAs by RT-PCR, which were confirmed by Sanger sequencing. Three candidate TREM2-derived circRNAs were identified on control human entorhinal samples. Then, additional primer sets were used to confirm back-splicing junctions. One of the circRNAs, circTREM2_1, was consistently amplified with all primer sets. In addition, circTREM2_1 was also present in AD entorhinal cortex samples and in HMC3 cells. We observed that circTREM2_1 is up-regulated in AD entorhinal cortex samples compared to controls, particularly at early stages of the disease, when we performed RT-qPCR. In conclusion, we have identified a novel circRNA derived from the TREM2 gene that could play a role in AD pathogenesis.

scholarly journals Simulation of Ca2+ oscillations in astrocytes mediated by amyloid beta in Alzheimer’s disease

2020 ◽  
Author(s):  
Huayi Gao ◽  
Langzhou Liu ◽  
Shangbin Chen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Computational Model ◽  
Glutamate Receptors ◽  
Amyloid Beta ◽  
Amyloid Beta Peptide ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Beta Peptide ◽  
Intracellular Ca

AbstractDisruptions 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 work have implemented a computational model to address the Ca2+ dynamics of astrocyte mediated by Aβ with the four different pathways: voltage-gated calcium channels, metabotropic glutamate receptors 5, ryanodine receptor channels and membrane leak. The Ca2+ oscillations and bifurcation diagram indicate that astrocytes exhibit ionic excitability mediated by Aβ and become the potential targets of Aβ neurotoxicity. We expect this shared computational model would advance the understanding of AD.

scholarly journals Putative Involvement of Endocrine Disruptors in the Alzheimer's disease Via the Insulin-Regulated Aminopeptidase / GLUT4 Pathway

2020 ◽  
Vol 18 ◽  
Author(s):  
María Jesús Ramírez-Expósito ◽  
Jose Manuel Martínez-Martos ◽  
Vanesa Cantón-Habas ◽  
María del Pilar Carrera González
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Surface ◽  
Glucose Transporter ◽  
Cell Function ◽  
Sensory Information ◽  
Inhibitory Effect ◽  
Pharmacological Intervention ◽  
Pancreatic Cell ◽  
The One

: It has been well established that there is a connection between type II diabetes (DMTII) and Alzheimer's disease (AD). In fact, the increase in AD incidence may be an emerging complication of DMTII. Both pathologies are related to estradiol (E2) exposure; on the one hand, estrogen receptors (ER) are emerging as important modulators of glucose homeostasis through ß-pancreatic cell function; on the other hand, brain bioenergetic and cognitive deficits have been related to the down regulation of brain ERs, contributing to women ageing and AD susceptibility, both related to the reduction in estradiol levels and the deficits in brain metabolism. Here we discuss that environmental contaminants with estrogenic capacity such as bisphenol A (BPA) could develop pharmacological effects similar to those of E2, which could affect ß-pancreatic cell function by increasing the biosynthesis of glucose-induced insulin after extranuclear ER binding. BPA-induced hyperinsulinemia would promote the translocation of glucose transporter 4 (GLUT4) which is located next to insulin-regulated aminopeptidase (IRAP) in intracellular vesicles. In insulin-responsive tissues, IRAP and GLUT 4 are routed together to the cell surface after insulin stimulation. IRAP is also the angiotensin IV (AngIV) receptor, and AngIV associates the brain reninangiotensin system (bRAS) with AD, since AngIV is related to learning, memory, emotional responses, and processing of sensory information not only through its inhibitory effect on IRAP but also through the stimulation of glucose uptake by increasing the presence of IRAP/GLUT4 at the cell surface. Thus, the IRAP/GLUT4 pathway is an emerging target for the pharmacological intervention against AD.

scholarly journals COMPASS: A computational model to predict changes in MMSE scores 24-months after initial assessment of Alzheimer’s disease

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Fan Zhu ◽  
Bharat Panwar ◽  
Hiroko H. Dodge ◽  
Hongdong Li ◽  
Benjamin M. Hampstead ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Computational Model ◽  
Initial Assessment
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