Mechanism of neuron death in Alzheimer’s disease

2001 ◽  
pp. 201-207
Author(s):  
Akihiko Takashima ◽  
Ohoshi Murayama ◽  
Toshiyuki Honda ◽  
Xiaoyan Sun ◽  
Shinji Sato
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuron Death

scholarly journals Neuron loss associated with age but not Alzheimer's disease pathology in the chimpanzee brain

2020 ◽  
Vol 375 (1811) ◽  
pp. 20190619 ◽  
Author(s):  
Melissa K. Edler ◽  
Emily L. Munger ◽  
Richard S. Meindl ◽  
William D. Hopkins ◽  
John J. Ely ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangle ◽  
Cell Loss ◽  
Tau Proteins ◽  
Middle Temporal Gyrus ◽  
Neuron Death ◽  
Neuron Loss ◽  
Neuron Density ◽  
Age Related

In the absence of disease, ageing in the human brain is accompanied by mild cognitive dysfunction, gradual volumetric atrophy, a lack of significant cell loss, moderate neuroinflammation, and an increase in the amyloid beta (A β ) and tau proteins. Conversely, pathologic age-related conditions, particularly Alzheimer's disease (AD), result in extensive neocortical and hippocampal atrophy, neuron death, substantial A β plaque and tau-associated neurofibrillary tangle pathologies, glial activation and severe cognitive decline. Humans are considered uniquely susceptible to neurodegenerative disorders, although recent studies have revealed A β and tau pathology in non-human primate brains. Here, we investigate the effect of age and AD-like pathology on cell density in a large sample of postmortem chimpanzee brains ( n = 28, ages 12–62 years). Using a stereologic, unbiased design, we quantified neuron density, glia density and glia:neuron ratio in the dorsolateral prefrontal cortex, middle temporal gyrus, and CA1 and CA3 hippocampal subfields. Ageing was associated with decreased CA1 and CA3 neuron densities, while AD pathologies were not correlated with changes in neuron or glia densities. Differing from cerebral ageing and AD in humans, these data indicate that chimpanzees exhibit regional neuron loss with ageing but appear protected from the severe cell death found in AD. This article is part of the theme issue ‘Evolution of the primate ageing process’.

A network pharmacology approach to explore the mechanisms of action of Epimrdii Herba-Coicis Semen for treatment of Alzheimer's disease

2020 ◽  
Author(s):  
Yuxuan Zhou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Signaling Pathways ◽  
Mapk Signaling ◽  
Venn Diagram ◽  
Network Pharmacology ◽  
Pharmacokinetic Parameters ◽  
Neuron Death

Abstract Background: Traditional Chinese medicine (TCM) can treat diseases through its “multi-component, multi-target, multi-pathway” mechanisms. Especially have advantages in the treatment of diseases with complicated pathogenesis, such as Alzheimer’s disease (AD). Tonifying the kidney and strengthening the spleen is one of the common methods of Chinese Medicine to treat AD. The TCM combination of Epimrdii Herba and Coicis Semen can be used as the main drugs of a prescription for tonifying the kidney and strengthening the spleen. However, the mechanisms for Epimrdii Herba-Coicis Semen (EH-CS) to treat AD is vague. The purpose of this study was to explore the mechanisms of EH-CS on AD using a network pharmacological method.Methods: We retrieved the chemical compounds and targets of Epimrdii Herba-Coicis Semen from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). We screened the active ingredients based on the pharmacokinetic parameters (ADME). The Human Gene Database (GeenCards) was used to obtain disease targets of Alzheimer’s disease. Then we drew a venn diagram to obtain common targets of Chinese medicine and disease. Based on the topological properties, we screened the key targets. The protein-protein interaction (PPI) network was constructed using the STRING database, and the "Traditional Chinese Medicine-active ingredient-target" network was constructed using Cytoscape software. The key targets were respectively uploaded to the Metascape and DAVID database for GO and KEGG pathway analysis.Results: We obtained 31 active compounds for EH-CS. Flavonoids play important roles in the treatment of AD. A total of 29 key targets, including AKT1, MAPK1, and TP53, etc. The biological processes involve response to lipopolysaccharide, neuron death, neuroinflammatory response, etc. The main pathways include TNF signaling pathways, MAPK signaling pathways, PI3K-Akt signaling pathways and other signaling pathways.Conclusion: The network pharmacology method is an effective tool for exploring the mechanisms of TCM. Based on network pharmacology, this study systematically explained the potential mechanisms of EH-CS on AD. It provides a valuable reference for the development of AD drugs.

scholarly journals THE ALZHEIMER’S DISEASE IMPACT ON ARTIFICIAL NEURAL NETWORKS

2021 ◽  
Vol 2 ◽  
pp. 205-209
Author(s):  
Maksims Zigunovs
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prediction Models ◽  
Initial Conditions ◽  
Model Neuron ◽  
Memory Loss ◽  
Electrical Signal ◽  
Neuron Network ◽  
Neuron Death ◽  
Loss Prediction

The Alzheimer’s Disease main impact on the brain is the memory loss effect. Therefore, in the “neuron world” this makes a disorder of signal impulses and disconnects neurons that causes the neuron death and memory loss. The research main aim is to determine the average loss of signal and develop memory loss prediction models for artificial neuron network. The Izhikevich neural networking model is often used for constructing neuron neural electrical signal modeling. The neuron model signal rhythm and spikes are used as model neuron characteristics for understanding if the system is stable at certain moment and in time. In addition, the electrical signal parameters are used in similar way as they are used in a biological brain. During the research the neural network initial conditions are assumed to be randomly selected in specified the working neuron average sigma I parameters range.

scholarly journals Intensive protein synthesis in neurons and phosphorylation of beta-amyloid precursor protein and tau-protein are triggering factors of neuronal amyloidosis and Alzheimer's disease

2013 ◽  
Vol 59 (2) ◽  
pp. 144-170 ◽  
Author(s):  
A.V. Maltsev ◽  
N.V. Dovidchenko ◽  
V.K. Uteshev ◽  
V.V. Sokolik ◽  
O.M. Shtang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Amyloid Precursor Protein ◽  
Tau Protein ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Tau Proteins ◽  
Neuron Death ◽  
Protective Mechanisms

Recently the studies of Alzheimer’s disease have become particularly actual and have attracted scientists from all over the world to this problem as a result of dissemination of this dangerous disorder. The reason for such pathogenesis is not known, but the final image, for the first time obtained on microscopic brain sections from patients with this disease more than a hundred years ago, is well known to clinicists. This is the deposition of Ab amyloid in the brain tissue of senile plaques and fibrils. Many authors suppose that the deposition of beta-amyloid provokes secondary neuronal changes which are the reason of neuron death. Other authors associate the death of neurons with hyperphosphorylation of tau-proteins which form neurofibrillar coils inside nerve cells and lead to their death. For creation of methods of preclinical diagnostics and effective treatment of Alzheimer’s disease novel knowledge is required on the nature of triggering factors of sporadic isoforms of Alzheimer’s disease, on cause-effect relationships of phosphorylation of amyloid precursor protein with formation of pathogenic beta-amyloids, on the relationship with these factors of hyperphosphorylation of tau-protein and neuron death. In this review we analyze the papers describing the increasing of intensity of biosynthesis in neurons in normal conditions and under the stress, the possibility of development of energetic unbalanced neurons and activation of their protective systems. Phosphorylation and hyperphosphorylation of tau-proteins is also tightly connected with protective mechanisms of cells and with processes of evacuation of phosphates, adenosine mono-phosphates and pyrophosphates from the region of protein synthesis. Upon long and high intensity of protein synthesis the protective mechanisms are overloaded and the complementarity of metabolitic processes is disturbed. This results in dysfunction of neurons, transport collapse, and neuron death.

scholarly journals Alzheimer’s Disease—Rationales for Potential Treatment with the Thrombin Inhibitor Dabigatran

2021 ◽  
Vol 22 (9) ◽  
pp. 4805
Author(s):  
Klaus Grossmann
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vascular Dysfunction ◽  
Amyloid Β ◽  
Brain Parenchyma ◽  
Thrombin Inhibitor ◽  
Amyloid Angiopathy ◽  
Barrier Dysfunction ◽  
Neuron Death ◽  
The Brain

Alzheimer’s disease (AD) is caused by neurodegenerative, but also vascular and hemostatic changes in the brain. The oral thrombin inhibitor dabigatran, which has been used for over a decade in preventing thromboembolism and has a well-known pharmacokinetic, safety and antidote profile, can be an option to treat vascular dysfunction in early AD, a condition known as cerebral amyloid angiopathy (CAA). Recent results have revealed that amyloid-β proteins (Aβ), thrombin and fibrin play a crucial role in triggering vascular and parenchymal brain abnormalities in CAA. Dabigatran blocks soluble thrombin, thrombin-mediated formation of fibrin and Aβ-containing fibrin clots. These clots are deposited in brain parenchyma and blood vessels in areas of CAA. Fibrin-Aβ deposition causes microvascular constriction, occlusion and hemorrhage, leading to vascular and blood–brain barrier dysfunction. As a result, blood flow, perfusion and oxygen and nutrient supply are chronically reduced, mainly in hippocampal and neocortical brain areas. Dabigatran has the potential to preserve perfusion and oxygen delivery to the brain, and to prevent parenchymal Aβ-, thrombin- and fibrin-triggered inflammatory and neurodegenerative processes, leading to synapse and neuron death, and cognitive decline. Beneficial effects of dabigatran on CAA and AD have recently been shown in preclinical studies and in retrospective observer studies on patients. Therefore, clinical studies are warranted, in order to possibly expand dabigatran approval for repositioning for AD treatment.

scholarly journals TrkA-mediated endocytosis of p75-CTF prevents cholinergic neuron death upon γ-secretase inhibition

2021 ◽  
Vol 4 (4) ◽  
pp. e202000844
Author(s):  
María Luisa Franco ◽  
Irmina García-Carpio ◽  
Raquel Comaposada-Baró ◽  
Juan J Escribano-Saiz ◽  
Lucía Chávez-Gutiérrez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Side Effects ◽  
Cholinergic Neurons ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Recognition Sequence ◽  
Neuron Death ◽  
Aged Patients

γ-secretase inhibitors (GSI) were developed to reduce the generation of Aβ peptide to find new Alzheimer’s disease treatments. Clinical trials on Alzheimer’s disease patients, however, showed several side effects that worsened the cognitive symptoms of the treated patients. The observed side effects were partially attributed to Notch signaling. However, the effect on other γ-secretase substrates, such as the p75 neurotrophin receptor (p75NTR) has not been studied in detail. p75NTR is highly expressed in the basal forebrain cholinergic neurons (BFCNs) during all life. Here, we show that GSI treatment induces the oligomerization of p75CTF leading to the cell death of BFCNs, and that this event is dependent on TrkA activity. The oligomerization of p75CTF requires an intact cholesterol recognition sequence (CRAC) and the constitutive binding of TRAF6, which activates the JNK and p38 pathways. Remarkably, TrkA rescues from cell death by a mechanism involving the endocytosis of p75CTF. These results suggest that the inhibition of γ-secretase activity in aged patients, where the expression of TrkA in the BFCNs is already reduced, could accelerate cholinergic dysfunction and promote neurodegeneration.

scholarly journals Single Point Mutation from E22-to-K in Aβ Initiates Early-Onset Alzheimer’s Disease by Binding with Catalase

2020 ◽  
Vol 2020 ◽  
pp. 1-21
Author(s):  
Wenjing Jiang ◽  
YanYu ◽  
Dandan Yao ◽  
Xuechao Fei ◽  
Li Ai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Point Mutation ◽  
Early Onset ◽  
Late Onset ◽  
Single Point ◽  
Single Point Mutation ◽  
Neuron Death ◽  
Mutation Site

Amyloid-beta (Aβ) is a critical etiological factor for late-onset familial Alzheimer’s disease (AD). However, an early-onset AD has been found to be related with an Aβ mutation in glutamic acid 22-to-lysine (Italian type E22K). Why only one single point mutation at E22 residue induces AD remains unclear. Here, we report that a Chinese familial AD pedigree with E22K mutation was associated with higher levels of serum hydrogen peroxide (H2O2) and lower activity of catalase (a H2O2 degrading enzyme) than controls. Further, we found that E22K binding with catalase caused more severe H2O2 accumulation in the brains of E22K-injected rats than Aβ-injected rats. Unexpectedly, H2O2 bound with the mutation site 22K residue of E22K and elicited more rapid aggregation of E22K than Aβ in vitro. Moreover, H2O2 acted with E22K synergistically to induce higher cellular toxicity than with Aβ. Notably, intrahippocampal infusion of E22K led to more severe plaque deposition, neuron death, and more rapid memory decline than Aβ-injected rats. However, L-cysteine, a H2O2 scavenger, not only prevented self-aggregation of E22K but also reduced H2O2-promoted E22K assembly in vitro; subsequently, it alleviated Alzheimer-related phenotypes. Hence, E22K binding with catalase promotes the early onset of familial AD, and L-cys may reverse this disease.

scholarly journals A Comparative Study of Five Mouse Models of Alzheimer's Disease: Cell Cycle Events Reveal New Insights into Neurons at Risk for Death

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Luming Li ◽  
Timmy Cheung ◽  
Jianmin Chen ◽  
Karl Herrup
Keyword(s):  
Alzheimer’S Disease ◽  
Cell Cycle ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Disease Model ◽  
Neuronal Loss ◽  
Cerebellar Nuclei ◽  
Neuron Death ◽  
Neurodegenerative Process ◽  
Preclinical Trials

Ectopic cell cycle events (CCEs) in postmitotic neurons link the neurodegenerative process in human Alzheimer's disease (AD) with the brain phenotype of transgenic mouse models with known familial AD genes. Most reports on the mouse models use the appearance of brain amyloid pathology as a key outcome measure. In the current paper, we focus on the induction of neurodegeneration using CCEs as markers for impending neuronal loss. We compare 5 mouse models of familial AD for the appearance of CCEs in subcortical regions—deep cerebellar nuclei, amygdala, locus coeruleus, hippocampus, and dorsal raphe. We find that the models differ in their CCE involvement as well as in the appearance of phosphorylated tau and amyloid deposition, suggesting that each model represents a different disease phenotype. Comparison with the pattern of neuron death in human AD suggests that each may represent a distinctly different disease model when used in preclinical trials.

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