scholarly journals Identification of a Thyroid Hormone Derivative as a Pleiotropic Agent for the Treatment of Alzheimer’s Disease

2021 ◽  
Vol 14 (12) ◽  
pp. 1330
Author(s):  
Massimiliano Runfola ◽  
Michele Perni ◽  
Xiaoting Yang ◽  
Maria Marchese ◽  
Andrea Bacci ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Thyroid Hormone ◽  
Parent Compound ◽  
Metabolic Reprogramming ◽  
Pharmacological Intervention ◽  
Autophagic Flux ◽  
Learning Abilities ◽  
Toxicological Studies ◽  
Starting Point

The identification of effective pharmacological tools for Alzheimer’s disease (AD) represents one of the main challenges for therapeutic discovery. Due to the variety of pathological processes associated with AD, a promising route for pharmacological intervention involves the development of new chemical entities that can restore cellular homeostasis. To investigate this strategy, we designed and synthetized SG2, a compound related to the thyroid hormone thyroxine, that shares a pleiotropic activity with its endogenous parent compound, including autophagic flux promotion, neuroprotection, and metabolic reprogramming. We demonstrate herein that SG2 acts in a pleiotropic manner to induce recovery in a C. elegans model of AD based on the overexpression of Aβ42 and improves learning abilities in the 5XFAD mouse model of AD. Further, in vitro ADME-Tox profiling and toxicological studies in zebrafish confirmed the low toxicity of this compound, which represents a chemical starting point for AD drug development.

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.

Lighting and Alzheimer’s disease and related dementias: Spotlight on sleep and depression

2021 ◽  
Vol 53 (5) ◽  
pp. 405-422
Author(s):  
MG Figueiro ◽  
HC Kales
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disease ◽  
Sleep Disturbances ◽  
Well Being ◽  
Pharmacological Intervention ◽  
Negative Effects ◽  
Health And Well Being ◽  
Positive Results

Alzheimer’s disease and related dementias is the collective term for a progressive neurodegenerative disease for which there is presently no cure. This paper focuses on two symptoms of the disease, sleep disturbances and depression, and discusses how light can be used as a non-pharmacological intervention to mitigate their negative effects. Bright days and dark nights are needed for health and well-being, but the present components of the built environment, especially those places where older adults spend most of their days, are too dimly illuminated during the day and too bright at night. To be effective light needs to be correctly specified, implemented and measured. Yet, without the appropriate specification and measurement of the stimulus, researchers will not be able to successfully demonstrate positive results in the field, nor will lighting designers and specifiers have the confidence to implement lighting solutions for promoting better sleep and mood in this population.

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 PET imaging of 18F-florbetapir in cognitively impaired individuals: Lack of activity within the cerebellar cortex

2018 ◽  
Vol 10 (3) ◽  
Author(s):  
Michael A. Meyer ◽  
Allison Caccia ◽  
Danielle Martinez ◽  
Mark A. Mingos
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Cerebellar Cortex ◽  
Pet Imaging ◽  
Parent Compound ◽  
Hepatic Metabolism ◽  
Subcortical White Matter ◽  
Clinical Value ◽  
Type Pattern

Ten individuals suspected of having possible Alzheimer disease underwent PET imaging using 18F-Flubetapir. Only one of ten individuals had a pattern typical for normal elderly control subjects with 9 of the 10 showing a Alzheimer type pattern for the cerebral cortex yet all 10 subjects had uniformly low to absent tracer localization to the cerebellar cortex; significantly high tracer activity was noted within the subcortical white matter of the cerebellum in a symmetric manner in all cases. In consideration of studies that have shown amyloid deposits within the cerebellar cortex in 90% of pathologically proven cases of Alzheimer’s disease, these findings raise questions about the actual clinical value of florbetapir PET imaging in evaluating cerebellar involvement and raises questions whether PET imaging of this tracer accurately portrays patterns of amyloid deposition, as there is rapid hepatic metabolism of the parent compound after intravenous injection. Possible links to Alzheimer’s disease related alterations in blood-brain barrier permeability to the parent compound and subsequent radiolabelled metabolites are discussed as potential mechanisms that could explain the associated localization of the tracer to the brainstem and subcortical white matter within the cerebrum and cerebellum of Alzheimer’s disease patients.

scholarly journals Conversational System as Assistant Tool in Reminiscence Therapy for People with Early-Stage of Alzheimer’s

Healthcare ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1036
Author(s):  
Victor Morales-de-Jesús ◽  
Helena Gómez-Adorno ◽  
María Somodevilla-García ◽  
Darnes Vilariño
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Life History ◽  
Patient Information ◽  
Early Stage ◽  
Care Center ◽  
Pharmacological Intervention ◽  
Emotional States ◽  
Reminiscence Therapy ◽  
Past Experiences

Reminiscence therapy is a non-pharmacological intervention that helps mitigate unstable psychological and emotional states in patients with Alzheimer’s disease, where past experiences are evoked through conversations between the patients and their caregivers, stimulating autobiographical episodic memory. It is highly recommended that people with Alzheimer regularly receive this type of therapy. In this paper, we describe the development of a conversational system that can be used as a tool to provide reminiscence therapy to people with Alzheimer’s disease. The system has the ability to personalize the therapy according to the patients information related to their preferences, life history and lifestyle. An evaluation conducted with eleven people related to patient care (caregiver = 9, geriatric doctor = 1, care center assistant = 1) shows that the system is capable of carrying out a reminiscence therapy according to the patient information in a successful manner.

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.

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.

Fiat Lux: The Light Became Therapy. An Overview on the Bright Light Therapy in Alzheimer’s Disease Sleep Disorders

2020 ◽  
Vol 77 (1) ◽  
pp. 113-125 ◽  
Author(s):  
Ilaria Roccaro ◽  
Daniela Smirni
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sleep Disorders ◽  
Visual Information ◽  
Bright Light ◽  
Light Therapy ◽  
Pharmacological Intervention ◽  
Biological Clocks ◽  
Bright Light Therapy ◽  
Effective Response

Background: A system of photosensitive retinal ganglion cells provides ‘non-visual’ information on the circadian sequences of light to the suprachiasmatic nucleus (SCN), which, as the ‘master clock’, synchronizes the chronobiological mechanisms of all the biological clocks. Damage to SCN structure alters circadian behavioral and hormonal rhythms and interferes with a regular sleep-wake pattern. Several studies have shown that, in aging and in Alzheimer’s disease (AD), circadian rhythms change their synchronization with the environment and behavior loses sync with light. Objective: The current overview aims to examine research studies showing the effect of bright light therapy (BLT) on sleep disorders and sleep-wake patterns in AD. Methods: A literature search was conducted, taking into consideration the relevant studies over the last 20 years. Fifteen studies have been thorough: seven followed an environmental-architectural approach and eight followed a treatment devices approach. Results: Studies agree in considering BLT as a promising non-pharmacological intervention to compensate for circadian rhythm alterations and they support the need for standardized protocols that allow a comparison between multicenter studies. Conclusion: Interestingly, in an attempt to contain the spread of the COVID-19 pandemic, health authorities have forced the population to stay home. Therefore, AD people are not currently able to enjoy exposure to sunlight. It is predictable that they may experience an exacerbation of circadian disturbances and that the BLT can be an effective response to prevent such exacerbation.

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