scholarly journals Amyloid Oligomer Structures and Toxicity

2009 ◽  
Vol 2 (1) ◽  
pp. 222-227
Author(s):  
Charles G. Glabe
Keyword(s):  
Neurodegenerative Diseases ◽  
Broad Spectrum ◽  
Degenerative Diseases ◽  
Mechanisms Of Toxicity ◽  
Membrane Pores ◽  
Disease Mechanisms ◽  
Amyloid Accumulation ◽  
Amyloid Oligomers ◽  
Different Types ◽  
Amyloid Oligomer

Amyloid accumulation is commonly associated with a number of important human degenerative diseases and recent findings indicate that soluble amyloid oligomers may represent the primary pathological species in degenerative diseases. Amyloid oligomers are structurally and morphologically diverse, raising the question on whether this diversity is pathologically significant and whether different types of oligomers may have different toxic activities. Many of the amyloids associated with neurodegenerative diseases form three immunologically distinct types of oligomers. Fibrillar oligomers are structurally related to fibrils and may represent small pieces of fibrils or fibril protofilaments. Prefibrillar oligomers are kinetic intermediates in fibril formation and annular protofibrils that resemble membrane pores. These three classes of oligomers share common structures and toxic activities. Focus on these common mechanisms of toxicity provides a means of simplifying the list of primary disease mechanisms and opens the possibility of developing broad spectrum therapeutics that target several amyloid related degenerative diseases.

Abstract 260: Autophagy And Necrosis Underlie Polyglutamine Amyloid Oligomer Induced Heart Failure.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Scott Pattison ◽  
Atsushi Sanbe ◽  
Raisa Klevitsky ◽  
Hanna Osinska ◽  
Jeffrey Robbins
Keyword(s):  
Heart Failure ◽  
Neurodegenerative Diseases ◽  
Pathogenic Mechanism ◽  
Positive Staining ◽  
Neural Cells ◽  
Conformational Structure ◽  
Human Heart Failure ◽  
Specific Expression ◽  
Amyloid Oligomers ◽  
Amyloid Oligomer

Introduction: Amyloid oligomers, the entities believed to cause toxicity in many neurodegenerative diseases, have been observed in mouse and human heart failure samples. Amyloid oligomers are a diverse group of proteins that differ in sequence, but share a common conformational structure, and may impart a shared pathogenic mechanism. The purpose of this study was to test the hypothesis that expression and accumulation of amyloid oligomers are cytotoxic and sufficient to directly cause heart failure. Polyglutamine (PQ) repeats (>50) are known to form amyloid oligomers and induce toxicity in neural cells, causing Huntington′s and other neurodegenerative diseases, while shorter PQ peptides are benign. Hypothesis: Cardiomyocyte-autonomous expression of an exogenous PQ amyloid oligomer will be toxic to cardiomyocytes and result in heart failure. Methods: Transgenic mice were created with cardiomyocyte-specific expression of an amyloid oligomer forming peptide of 83 PQ repeats (PQ83) or a non-amyloid forming peptide of 19 PQ repeats (PQ19) as a non-pathological control. Both constructs were HA tagged. Results: A PQ83 line with relatively low levels of expression was generated, along with a PQ19 line that expressed at approximately 9-fold the levels observed in the PQ83 line. Hearts expressing PQ83 develop cardiac dysfunction and dilation by 5 months and exhibit 100% mortality by 8 months of age, whereas PQ19 mice have normal cardiac function, morphology and lifespan. PQ83 protein accumulates in cardiomyocytes as SDS-insoluble aggresomes with amyloid oligomer-positive staining. PQ83 hearts exhibited no signs of apoptosis. Ultrastructural analysis revealed that PQ83 hearts undergo autophagy, as evidenced by increased autophagosomal and lysosomal content. PQ83 hearts also show characteristics of necrotic death, including infiltration of inflammatory cells, cardiomyocyte vacuolization and increased staining for the membrane attack complex that causes sarcolemmal permeabilization. The data confirm the hypothesis that expression of an exogenous amyloid oligomer is toxic to cardiomyocytes and is sufficient to cause heart failure. The pathogenic mechanism appears to lead to cardiomyocyte death through autophagy and necrosis.

scholarly journals Differential diagnosis of Alzheimer’s disease using spectrochemical analysis of blood

2017 ◽  
Vol 114 (38) ◽  
pp. E7929-E7938 ◽  
Author(s):  
Maria Paraskevaidi ◽  
Camilo L. M. Morais ◽  
Kássio M. G. Lima ◽  
Julie S. Snowden ◽  
Jennifer A. Saxon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Sensitivity And Specificity ◽  
Lewy Bodies ◽  
Total Reflection ◽  
Attenuated Total Reflection ◽  
Repeated Measurements ◽  
Healthy Individuals ◽  
Different Types

The progressive aging of the world’s population makes a higher prevalence of neurodegenerative diseases inevitable. The necessity for an accurate, but at the same time, inexpensive and minimally invasive, diagnostic test is urgently required, not only to confirm the presence of the disease but also to discriminate between different types of dementia to provide the appropriate management and treatment. In this study, attenuated total reflection FTIR (ATR-FTIR) spectroscopy combined with chemometric techniques were used to analyze blood plasma samples from our cohort. Blood samples are easily collected by conventional venepuncture, permitting repeated measurements from the same individuals to monitor their progression throughout the years or evaluate any tested drugs. We included 549 individuals: 347 with various neurodegenerative diseases and 202 age-matched healthy individuals. Alzheimer’s disease (AD;n= 164) was identified with 70% sensitivity and specificity, which after the incorporation of apolipoprotein ε4 genotype (APOEε4) information, increased to 86% when individuals carried one or two alleles of ε4, and to 72% sensitivity and 77% specificity when individuals did not carry ε4 alleles. Early AD cases (n= 14) were identified with 80% sensitivity and 74% specificity. Segregation of AD from dementia with Lewy bodies (DLB;n= 34) was achieved with 90% sensitivity and specificity. Other neurodegenerative diseases, such as frontotemporal dementia (FTD;n= 30), Parkinson’s disease (PD;n= 32), and progressive supranuclear palsy (PSP;n= 31), were included in our cohort for diagnostic purposes. Our method allows for both rapid and robust diagnosis of neurodegeneration and segregation between different dementias.

scholarly journals Aerobic or strength training and flexibility activities and mild cognitive impairment: CETI cohort

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
C Dupré ◽  
B Bongue ◽  
L Fruteau de Laclos ◽  
J Blais ◽  
M-J Sirois
Keyword(s):  
Physical Activity ◽  
Cognitive Impairment ◽  
Neurodegenerative Diseases ◽  
Cognitive Impairments ◽  
Cognitive Status ◽  
Physical Activities ◽  
Community Dwelling ◽  
Different Types ◽  
Initiative Program ◽  
The Impact

Abstract Background Previous studies have been notably criticized for not studying the different types of physical activity. The objective of this work was to examine the association between types of physical activity and cognitive decline in older people. Methods This is a sub-group analysis from the CETI cohort, a multicenter prospective study conducted by the Canadian Emergency Team Initiative Program (CETIE), between 2011 and 2016. Participants were community-dwelling seniors aged ≥ 65 years, consult emergency services for minor injuries with follow-up at 3 and 6 months. Physical activity was assessed by the RAPA (Rapid assessment of Physical activity), which describes the level of aerobic activities and the overall level of muscle strength and flexibility activities. The cognitive status was assessed with the Montreal Cognitive Assessment (MoCA) and the Telephone Interview for Cognitive Status (TICS), using their current cut-offs (MoCA <26/30 and TICS < = 35/50) for mild cognitive impairments (MCI). Logistic regression, COX models and splines were used to examine the association between the type of physical activities and the onset of cognitive impairment. Results At inclusion, 281 individuals were free of MCI, or 43.8% of the total sample, with an average age of 73 years. During follow-ups, MCI appeared in 31.7% of participants initially free of it. The risk of MCI was lower with higher muscular strength & flexibility physical activities (HR = 0.84 [0.70-0.99]), while the relationship with aerobic physical activities was not significant. Conclusions These results showed a potential link between strength & flexibility activities and cognitive impairments, but not with aerobic physical activities. Further analyses are needed to examine whether these relationships persist as a function of the adjustment variables, or statistical methods. This study contributes to the debate on the evaluation of physical activity in the elderly, and its link with neurodegenerative diseases. Key messages This study analyzed the link between types of physical activity and mild cognitive disorders. The aim is to put in place preventive policies of aging, specially in neurodegenerative diseases. The work allowed us to see the effect of the different types of physical activity and the impact of the statistical method on the results.

scholarly journals Amyloidogenic Peptides in Human Neuro-Degenerative Diseases and in Microorganisms: A Sorrow Shared Is a Sorrow Halved?

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 925 ◽  
Author(s):  
Kristina Endres
Keyword(s):  
Neurodegenerative Diseases ◽  
Self Assembly ◽  
Amyloid Β ◽  
Degenerative Diseases ◽  
Human Beings ◽  
Precursor Proteins ◽  
Long Time ◽  
Health And Disease ◽  
Amyloidogenic Peptides ◽  
Toxic Peptides

The term “amyloid” refers to proteinaceous deposits of peptides that might be generated from larger precursor proteins e.g., by proteolysis. Common to these peptides is a stable cross-β dominated secondary structure which allows self-assembly, leading to insoluble oligomers and lastly to fibrils. These highly ordered protein aggregates have been, for a long time, mainly associated with human neurodegenerative diseases such as Alzheimer’s disease (Amyloid-β peptides). However, they also exert physiological functions such as in release of deposited hormones in human beings. In the light of the rediscovery of our microbial commensals as important companions in health and disease, the fact that microbes also possess amyloidogenic peptides is intriguing. Transmission of amyloids by iatrogenic means or by consumption of contaminated meat from diseased animals is a well-known fact. What if also our microbial commensals might drive human amyloidosis or suffer from our aggregated amyloids? Moreover, as the microbial amyloids are evolutionarily older, we might learn from these organisms how to cope with the sword of Damocles forged of endogenous, potentially toxic peptides. This review summarizes knowledge about the interplay between human amyloids involved in neurodegenerative diseases and microbial amyloids.

scholarly journals ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

2017 ◽  
Vol 4 (1) ◽  
Author(s):  
Felipe Cabral-Miranda ◽  
Claudio Hetz
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Major Element ◽  
Neuronal Loss ◽  
Therapeutic Interventions ◽  
Unfolded Protein ◽  
Disease Mechanisms ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe conception that protein aggregates composed by misfolded proteins underlies the occurrence of several neurodegenerative diseases suggests that this phenomenon may have a common origin, ultimately driven by disruption of proteostasis control. The unfolded protein response (UPR) embodies a major element of the proteostasis network, which is engaged by endoplasmic reticulum (ER) stress. Chronic ER stress may operate as a possible mechanism of neurodegeneration, contributing to synaptic alterations, neuroinflammation and neuronal loss. In this review we discuss most recent findings relating ER stress and the development of distinct neurodegenerative diseases, and the possible strategies for disease intervention.

scholarly journals From genetics to pathology: tau and a–synuclein assemblies in neurodegenerative diseases

2001 ◽  
Vol 356 (1406) ◽  
pp. 213-227 ◽  
Author(s):  
Michel Goedert ◽  
Maria Grazia Spillantini ◽  
Louise C. Serpell ◽  
John Berriman ◽  
Michael J. Smith ◽  
...  
Keyword(s):  
Human Brain ◽  
Neurodegenerative Diseases ◽  
Frontotemporal Dementia ◽  
Glial Cells ◽  
Tau Protein ◽  
Nerve Cells ◽  
Degenerative Diseases ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Filamentous Inclusions

The most common degenerative diseases of the human brain are characterized by the presence of abnormal filamentous inclusions in affected nerve cells and glial cells. These diseases can be grouped into two classes, based on the identity of the major proteinaceous components of the filamentous assemblies. The filaments are made of either the microtubule–associated protein tau or the protein α–synuclein. Importantly, the discovery of mutations in the tau gene in familial forms of frontotemporal dementia and of mutations in the α–synuclein gene in familial forms of Parkinson's disease has established that dysfunction of tau protein and α–synuclein can cause neurodegeneration.

O4-02-02 Common structure and mechanism of soluble amyloid oligomer pathogenesis in degenerative diseases

2004 ◽  
Vol 25 ◽  
pp. S75-S76 ◽  
Author(s):  
Charles Glabe ◽  
Rakez Kayed ◽  
Yuri Sokolov ◽  
James Hall
Keyword(s):  
Degenerative Diseases ◽  
Common Structure ◽  
Amyloid Oligomer

scholarly journals Mitochondrial dysfunctions and neurodegenerative diseases: a mini-review

2021 ◽  
Vol 10 (4) ◽  
pp. 147-149
Author(s):  
Ratan Kumari ◽  
Nikhila Shekhar ◽  
Sakshi Tyagi ◽  
Ajit Kumar Thakur
Keyword(s):  
Reactive Oxygen Species ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorders ◽  
Oxygen Species ◽  
Primary Reason ◽  
Mitochondrial Dysfunctions ◽  
Detailed Understanding ◽  
Age Related ◽  
Different Types

Mitochondrial dysfunction is estimated to be the primary reason involved in different types of neurodegenerative disorders as mitochondria is suggested to be important in the production of reactive oxygen species. Recently, several evidences have emerged out for impaired mitochondrial structures and functions viz. shape, size, fission-fusion, distribution, movement etc. in neurodegenerative diseases especially with Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Therefore, apart from looking neurodegenerative diseases on the whole, a detailed understanding of the functioning of mitochondria and their role in degeneration would pave new options for the therapy of age-related neurodegenerative diseases.

scholarly journals Summarizing internal dynamics boosts differential analysis and functional interpretation of super enhancers

2021 ◽  
Author(s):  
Xiang Liu ◽  
Bo Zhao ◽  
Timothy Shaw ◽  
Brooke Fridley ◽  
Derek Duckett ◽  
...  
Keyword(s):  
Computational Method ◽  
Differential Analysis ◽  
Internal Dynamics ◽  
Functional Interpretation ◽  
Disease Mechanisms ◽  
Structural Differences ◽  
Different Types ◽  
Public Datasets ◽  
Regulatory Properties ◽  
State Of Art

Super enhancers (SEs) are broad enhancer domains usually containing multiple constitute enhancers with significantly elevated activities. The constitute enhancers work together through chromatin looping to build up distinct regulatory properties of SEs. Aberrant SE activities, which are critical to understand disease mechanisms, could be raised by the alterations of one or more of their constitute enhancers. However, the state-of-art binary strategy in calling differential SEs only relies on overall activity changes, neglecting the local differences of constitute enhancers within SEs. We propose a computational method to identify differential SEs by accounting for the combinatorial effects of constitute enhancers weighted with their activities and locations (internal dynamics). In addition to overall changes, our method finds four novel types of differential SEs pointing to the structural differences within SEs. When applied to public datasets for six cancer cells, we demonstrate that different types of differential SEs complement each other with distinct sets of gene targets and varied degrees of regulatory impacts. More importantly, we found that some cell-specific genes are linked to SE structural differences specifically, suggesting improved sensitivity by our methods in identifying and interpreting differential SEs. Such improvements further lead to increased discernment of cell identifies.

scholarly journals Broad-spectrum survey of medicinal plants as a potential source of anticancer agents

2022 ◽  
Vol 21 (1) ◽  
pp. 1-40
Author(s):  
K Saranya ◽  
◽  
V Manivasagan ◽  
K Gopi ◽  
K Karthik ◽  
...  
Keyword(s):  
Cell Division ◽  
Side Effects ◽  
Medicinal Plants ◽  
Broad Spectrum ◽  
Anticancer Agents ◽  
Cancer Treatments ◽  
Potential Source ◽  
African Populations ◽  
Different Types ◽  
Different Parts

Cancer is an abnormal and uncontrolled growth of cells that spreads through cell division. There are different types of medicines available to treat cancers, but no drug is found to be fully effective and safe for humans. The major problem involved in the cancer treatments is the toxicity of the established drug and their side effects. Medicinal plants are used as folk medicines in Asian and African populations for thousands of years. 60% of the drugs for treating cancer are derived from plants. More than 3000 plants have anticancer activity. The present review aims at the study of a broad spectrum survey of plants having anticancer components for different type of cancers. This article consists of 364 medicinal plants and their different parts as potential Source of Anticancer Agents.

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