Toward a More Nuanced Perception of Alzheimer’s Disease

2012 ◽  
Vol 27 (6) ◽  
pp. 388-396 ◽  
Author(s):  
Baldwin Van Gorp ◽  
Tom Vercruysse ◽  
Jan Van den Bulck
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Experimental Design ◽  
Fear Of Death ◽  
The Public ◽  
Starting Point

Starting point of this study was the assumption that Alzheimer’s disease is made worse for the person who has the disease by the negative regard in which the illness is held by society. The aim was to test by means of a campaign advertisement whether more nuanced counterframes could have an impact while remaining credible and comprehensible to the public. A sample of thousand people living in Belgium evaluated the campaign in an experimental design. This revealed that all the versions tested achieved a high average evaluation. The ad in which the heading referred to the fear of death and degeneration was judged to be most attention-grabbing, easier to understand, and more credible than the alternative heading with the idea that someone with Alzheimer’s could still enjoy playing cards. Together, these findings provided a basis for the use of counterframes to generating a more nuanced image of Alzheimer’s disease.

Consideration of a Pharmacological Combinatorial Approach to Inhibit Chronic Inflammation in Alzheimer’s Disease

2019 ◽  
Vol 16 (11) ◽  
pp. 1007-1017 ◽  
Author(s):  
James G. McLarnon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Chronic Inflammation ◽  
Preventive Strategy ◽  
Subsequent Work ◽  
Activated Microglia ◽  
Starting Point ◽  
Anti Inflammatory ◽  
Cocktail Approach

A combinatorial cocktail approach is suggested as a rationale intervention to attenuate chronic inflammation and confer neuroprotection in Alzheimer’s disease (AD). The requirement for an assemblage of pharmacological compounds follows from the host of pro-inflammatory pathways and mechanisms present in activated microglia in the disease process. This article suggests a starting point using four compounds which present some differential in anti-inflammatory targets and actions but a commonality in showing a finite permeability through Blood-brain Barrier (BBB). A basis for firstchoice compounds demonstrated neuroprotection in animal models (thalidomide and minocycline), clinical trial data showing some slowing in the progression of pathology in AD brain (ibuprofen) and indirect evidence for putative efficacy in blocking oxidative damage and chemotactic response mediated by activated microglia (dapsone). It is emphasized that a number of candidate compounds, other than ones suggested here, could be considered as components of the cocktail approach and would be expected to be examined in subsequent work. In this case, systematic testing in AD animal models is required to rigorously examine the efficacy of first-choice compounds and replace ones showing weaker effects. This protocol represents a practical approach to optimize the reduction of microglial-mediated chronic inflammation in AD pathology. Subsequent work would incorporate the anti-inflammatory cocktail delivery as an adjunctive treatment with ones independent of inflammation as an overall preventive strategy to slow the progression of AD.

scholarly journals Identification of Novel Cathepsin B Inhibitors with Implications in Alzheimer’s Disease: Computational Refining and Biochemical Evaluation

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1946
Author(s):  
Nitin Chitranshi ◽  
Ashutosh Kumar ◽  
Samran Sheriff ◽  
Veer Gupta ◽  
Angela Godinez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hydrogen Bond ◽  
Virtual Screening ◽  
Cathepsin B ◽  
Amyloid Β ◽  
Proteolytic Degradation ◽  
Hydrogen Bond Acceptor ◽  
Starting Point ◽  
The Brain

Amyloid precursor protein (APP), upon proteolytic degradation, forms aggregates of amyloid β (Aβ) and plaques in the brain, which are pathological hallmarks of Alzheimer’s disease (AD). Cathepsin B is a cysteine protease enzyme that catalyzes the proteolytic degradation of APP in the brain. Thus, cathepsin B inhibition is a crucial therapeutic aspect for the discovery of new anti-Alzheimer’s drugs. In this study, we have employed mixed-feature ligand-based virtual screening (LBVS) by integrating pharmacophore mapping, docking, and molecular dynamics to detect small, potent molecules that act as cathepsin B inhibitors. The LBVS model was generated by using hydrophobic (HY), hydrogen bond acceptor (HBA), and hydrogen bond donor (HBD) features, using a dataset of 24 known cathepsin B inhibitors of both natural and synthetic origins. A validated eight-feature pharmacophore hypothesis (Hypo III) was utilized to screen the Maybridge chemical database. The docking score, MM-PBSA, and MM-GBSA methodology was applied to prioritize the lead compounds as virtual screening hits. These compounds share a common amide scaffold, and showed important interactions with Gln23, Cys29, His110, His111, Glu122, His199, and Trp221. The identified inhibitors were further evaluated for cathepsin-B-inhibitory activity. Our study suggests that pyridine, acetamide, and benzohydrazide compounds could be used as a starting point for the development of novel therapeutics.

scholarly journals Perphenazine-macrocycle conjugates divert Aβ42 towards non-toxic aggregates by monomer sequestration

2020 ◽  
Author(s):  
Sarah R Ball ◽  
Julius S P Adamson ◽  
Michael A Sullivan ◽  
Manuela R Zimmermann ◽  
Victor Lo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nmr Spectroscopy ◽  
Kinetic Analysis ◽  
Amyloid Β ◽  
Dimensional Structure ◽  
Amyloid Β Peptide ◽  
Monomeric Form ◽  
Starting Point ◽  
The Impact

AbstractThe amyloid-β peptide, the main protein component of amyloid plaques in Alzheimer’s disease, plays a key role in the neurotoxicity associated with the condition through the formation of small toxic oligomer species which mediate the disruption of calcium and glutamate homeostasis. The lack of therapeutic benefit associated with removal of mature amyloid-β fibrils has focused attention on the toxic oligomeric species formed during the process of fibril assembly. Here, we present the design and synthesis of a family of perphenazine-macrocyle conjugates. We find that two-armed perphenazine-cyclam conjugates divert the monomeric form of the amyloid-β peptide away from the amyloidogenic pathway into amorphous aggregates that are not toxic to differentiated SH-SY5Y cells in vitro. This strategy prevents the formation of damaging amyloid oligomers. Kinetic analysis of the effects of these compounds on the assembly pathway, together with NMR spectroscopy, identifies rapid monomer sequestration as the underlying neuroprotective mechanism. The ability to specifically target the monomeric form of amyloid-β allows for further understanding of the impact of the multiple species formed between peptide biogenesis and plaque deposition. The modular, three-dimensional structure of these compounds provides a starting point for the design of more potent modulators of this amyloid-forming peptide, and can be adapted to probe the protein self-assembly pathways associated with other proteinopathies.Significance statementThe aggregation pathway of the amyloid-β (Aβ) peptide in Alzheimer’s disease is complex and involves multiple different species. An inability to isolate and study the impact of distinct Aβ species has undermined efforts to develop effective therapies. To address this issue, we have developed a series of molecules that specifically sequester the monomeric form of the highly aggregation-prone Aβ42 peptide. Interaction with these molecules diverts Aβ42 from the amyloidogenic pathway and prevents formation of toxic oligomeric species. We use kinetic analysis and NMR spectroscopy to identify rapid monomer sequestration as the underlying neuroprotective mechanism. Future rational development of these molecules and characterisation of their interactions with Aβ will delineate the impact of different Aβ oligomers on neurobiology and pathology.

scholarly journals The Impact of Experience with a Family Member with Alzheimer’s Disease on Views about the Disease across Five Countries

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Robert J. Blendon ◽  
John M. Benson ◽  
Elizabeth M. Wikler ◽  
Kathleen J. Weldon ◽  
Jean Georges ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Family Member ◽  
Public Spending ◽  
The United States ◽  
Direct Experience ◽  
Fatal Disease ◽  
The Public ◽  
Educational Campaigns ◽  
The Impact

The objective of this paper is to understand how the public’s beliefs in five countries may change as more families have direct experience with Alzheimer’s disease. The data are derived from a questionnaire survey conducted by telephone (landline and cell) with 2678 randomly selected adults in France, Germany, Poland, Spain, and the United States. The paper analyzes the beliefs and anticipated behavior of those in each country who report having had a family member with Alzheimer’s disease versus those who do not. In one or more countries, differences were found between the two groups in their concern about getting Alzheimer’s disease, knowledge that the disease is fatal, awareness of certain symptoms, and support for increased public spending. The results suggest that as more people have experience with a family member who has Alzheimer’s disease, the public will generally become more concerned about Alzheimer’s disease and more likely to recognize that Alzheimer’s disease is a fatal disease. The findings suggest that other beliefs may only be affected if there are future major educational campaigns about the disease. The publics in individual countries, with differing cultures and health systems, are likely to respond in different ways as more families have experience with Alzheimer’s disease.

scholarly journals Alzheimer’s Disease and Specialized Pro-Resolving Lipid Mediators: Do MaR1, RvD1, and NPD1 Show Promise for Prevention and Treatment?

2020 ◽  
Vol 21 (16) ◽  
pp. 5783 ◽  
Author(s):  
Keishi Miyazawa ◽  
Hisanori Fukunaga ◽  
Yasuko Tatewaki ◽  
Yumi Takano ◽  
Shuzo Yamamoto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Mediators ◽  
Major Contributor ◽  
Resolvin D1 ◽  
The Public ◽  
Aging Society ◽  
Neuroprotectin D1 ◽  
Chronic Neuroinflammation ◽  
Progressive Cognitive Impairment

Alzheimer’s disease (AD) is a common neurodegenerative disease and a major contributor to progressive cognitive impairment in an aging society. As the pathophysiology of AD involves chronic neuroinflammation, the resolution of inflammation and the group of lipid mediators that actively regulate it—i.e., specialized pro-resolving lipid mediators (SPMs)—attracted attention in recent years as therapeutic targets. This review focuses on the following three specific SPMs and summarizes their relationships to AD, as they were shown to effectively address and reduce the risk of AD-related neuroinflammation: maresin 1 (MaR1), resolvin D1 (RvD1), and neuroprotectin D1 (NPD1). These three SPMs are metabolites of docosahexaenoic acid (DHA), which is contained in fish oils and is thus easily available to the public. They are expected to become incorporated into promising avenues for preventing and treating AD in the future.

Accessibility in public space as perceived by people with Alzheimer’s disease

Dementia ◽  
2011 ◽  
Vol 10 (4) ◽  
pp. 587-602 ◽  
Author(s):  
Anna Brorsson ◽  
Annika Öhman ◽  
Stefan Lundberg ◽  
Louise Nygård
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Public Space ◽  
Theory Approach ◽  
The Public ◽  
People With Dementia ◽  
Core Category ◽  
Problematic Situations ◽  
The Relationship ◽  
Grounded Theory Approach

Most people with dementia remain living at home as long as possible after being diagnosed, and hence their lives also include activities in the public space. The aim of this study was to illuminate experiences of accessibility in public space in people with Alzheimer’s disease. A qualitative grounded theory approach with repeated in-depth interviews was used. The core category, accessibility as a constantly changing experience, was characterized by changes in the relationship between informants and public space. Changes in the relationship took place in activities and use of place and related to familiarity and comfort, individual motives and interests, and planning and protecting. Other changes occurred in places and problematic situations related to everyday technologies, crowded places with high tempo and noise, and change of landmarks. These changes reduced feelings of accessibility and increased difficulties in carrying out activities in public space. These findings may be helpful when providing support, and supporting community living.

Toward Better Alzheimer’s Research Information Sources for the Public

2013 ◽  
Vol 28 (2) ◽  
pp. 108-110
Author(s):  
Perry W. Payne
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Information Sources ◽  
Information Source ◽  
Research Literature ◽  
National Plan ◽  
Research Information ◽  
The Public ◽  
User Friendly ◽  
Social Networking Tools

The National Plan to Address Alzheimer's Disease calls for a new relationship between researchers and members of the public. This relationship is one that provides research information to patients and allows patients to provide ideas to researchers. One way to describe it is a “bidirectional translational relationship.” Despite the numerous sources of online and offline information about Alzheimer's disease, there is no information source which currently provides this interaction. This article proposes the creation an Alzheimer's research information source dedicated to monitoring Alzheimer's research literature and providing user friendly, publicly accessible summaries of data written specifically for a lay audience. This information source should contain comprehensive, updated, user friendly, publicly available, reviews of Alzheimer's research and utilize existing online multimedia/social networking tools to provide information in useful formats that help patients, caregivers, and researchers learn rapidly from one another.

Identification of Human Acetylcholinesterase Inhibitors from the Constituents of EGb761 by Modeling Docking and Molecular Dynamics Simulations

2018 ◽  
Vol 21 (1) ◽  
pp. 41-49 ◽  
Author(s):  
Lihu Zhang ◽  
Dongdong Li ◽  
Fuliang Cao ◽  
Wei Xiao ◽  
Linguo Zhao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Serine Proteases ◽  
Colorimetric Method ◽  
Acetylcholinesterase Inhibitors ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Ache Inhibitors ◽  
Starting Point

Aim and Objective: EGb761, a standardized and well-defined product extract of Ginkgo biloba leaves, has beneficial role in the treatment of multiple diseases, particularly Alzheimer's disease (AD). Identification of natural acetylcholinesterase (AChE) inhibitors from EGb761 would provide a novel therapeutic approach against the Alzheimer's disease. Material and Method: A series of 21 kinds of promising EGb761 compounds were selected, and subsequently evaluated for their potential ability to bind AChE enzyme by molecular docking and a deep analysis of protein surface pocket features. Results: Docking results indicated that these compounds can bind tightly with the active site of human AChE, with favorable distinct interactions around several important residues Asp74, Leu289, Phe295, Ser293, Tyr341, Trp286 and Val294 in the active pocket. Most EGB761 compounds could form the hydrogen bond interactions with the negatively charged Asp74 and Phe295 residues. Among these compounds, diosmetin is the one with the best-predicted docking score while three key hydrogen bonds can be formed between small molecule and corresponding residues of the binding site. Besides, other three compounds luteolin, apigenin, and isorhamnetin have better predicted docking scores towards AChE than other serine proteases, i.e Elastase, Tryptase, Factor XA, exhibiting specificity for AChE inhibition. The RMSD and MM-GBSA results from molecular dymamic simulations indicated that the docking pose of diosmetin-AChE complex displayed highly stable, which can be used for validating the accuracy of molecular docking study. Subsequently, the AChE inhibitory activities of these compounds were evaluated by the Ellman's colorimetric method. Conclusion: The obtained results revealed that all the four compounds exhibited modest AChE inhibitory activity, among which Diosmetin manifested remarkable anti-AChE activity, comparable with the reference compound, Physostigmine. It can be deduced that these EGB761 compounds can be regarded as a promising starting point for developing AChE inhibitors against AD.

scholarly journals Alzheimer's disease alters astrocytic functions related to neuronal support and transcellular internalization of mitochondria

2021 ◽  
Author(s):  
Riikka Lampinen ◽  
Irina Belaya ◽  
Liudmila Saveleva ◽  
Jeffrey R Liddell ◽  
Dzhessi Rait ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Physiological Conditions ◽  
Human Neurons ◽  
Mitochondrial Transfer ◽  
Starting Point ◽  
First Time

Under physiological conditions in vivo astrocytes internalize and degrade neuronal mitochondria in a process called transmitophagy. Mitophagy is widely reported to be impaired in neurodegeneration but it is unknown whether and how transmitophagy is altered in Alzheimer's disease (AD). Here we report that the internalization and degradation of neuronal mitochondria are significantly increased in astrocytes isolated from aged AD mouse brains. We also demonstrate for the first time a similar phenomenon between human neurons and AD astrocytes, and in murine hippocampi in vivo. The results suggest the involvement of S100a4 in impaired mitochondrial transfer between neurons and aged AD astrocytes. Significant increases in the mitophagy regulator Ambra1 were observed in the aged AD astrocytes. These findings demonstrate altered neuron-supporting functions of aged AD astrocytes and provide a starting point for studying the molecular mechanisms of transmitophagy in AD.

scholarly journals Brain, immune system and selenium: a starting point for a new diagnostic marker for Alzheimer’s disease?

2018 ◽  
Vol 138 (4) ◽  
pp. 223-226 ◽  
Author(s):  
Cesare Achilli ◽  
Annarita Ciana ◽  
Giampaolo Minetti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune System ◽  
Blood Cells ◽  
Senile Dementia ◽  
Imaging Techniques ◽  
Normal Subjects ◽  
Methionine Sulfoxide Reductase ◽  
Neutrophil Granulocytes ◽  
Starting Point

The clinical diagnosis of Alzheimer’s disease (AD) is based primarily on neuropsychological tests, which assess the involutive damage, and imaging techniques that evaluate morphologic changes in the brain. Currently available diagnostic tests do not show complete specificity and do not permit accurate differentiation between AD and other forms of senile dementia. The correlation of these tests with laboratory investigations based on biochemical parameters could increase the certainty of diagnosis. In recent years, several biochemical markers for the diagnosis of AD have been proposed, but in most cases they show a limited specificity and their application is invasive, requiring, in general, sampling of cerebrospinal fluid. Thus, the use of a peripheral biochemical marker could represent a valuable complement for the diagnosis of this disease. Several studies have shown a relationship between neurodegenerative disorders typical of the ageing process, weakening of the immune system and alterations in the levels of selenium and of the antioxidant selenoenzymes in brain tissues and blood cells. Among blood cells, neutrophil granulocytes uniquely express the selenoenzyme methionine sulfoxide reductase B1 (MsrB1). In a preliminary analysis carried out on neutrophils from subjects affected by AD, we observed a significant decline in MsrB1 activity compared to normal subjects. Therefore, we deem it of particular interest to explore the potential use of MsrB1 as a selective peripheral marker for the diagnosis of AD.

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