scholarly journals Therapeutic Potential Of Multifunctional Derivatives Of Cholinesterase Inhibitors

2020 ◽  
Vol 19 ◽  
Author(s):  
Maja Przybyłowska ◽  
Krystyna Dzierzbicka ◽  
Szymon Kowalski ◽  
Klaudia Chmielewska ◽  
Iwona Inkielewicz-Stepniak
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Amyloid Plaque ◽  
Β Amyloid ◽  
Derivatives Of ◽  
And Oxidative Stress ◽  
Pro Inflammatory Cytokines

: The aim of this work is review of tacrine analogues from the last three years, which were not included in the latest review work, donepezil and galantamine hybrids from 2015 and rivastigmine derivatives from 2014. In this account we summarize the efforts toward the development and characterization of non-toxic inhibitors of cholinesterases based on mentioned drugs with various interesting additional properties such as antioxidant, decreasing β-amyloid plaque aggregation, nitric oxide production, pro-inflammatory cytokines release, monoamine oxidase-B activity, cytotoxicity and oxidative stress in vitro and in animal model that classify these hybrids as potential multifunctional therapeutic agents for Alzheimer’s disease. Moreover, herein, we have described the cholinergic hypothesis, mechanisms of neurodegeneration and current pharmacotherapy of Alzheimer’s disease which is based on the restoration of cholinergic function through blocking enzymes that break down acetylcholine.

RANDOMIZED, PLACEBO CONTROLLED TRIAL OF NPT088, A PHAGE-DERIVED, AMYLOID-TARGETED TREATMENT FOR ALZHEIMER’S DISEASE

2019 ◽  
pp. 1-4
Author(s):  
D. Michelson ◽  
M. Grundman ◽  
K. Magnuson ◽  
R. Fisher ◽  
J.M. Levenson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Controlled Trial ◽  
Positron Emission Tomography Imaging ◽  
Amyloid Plaque ◽  
Disease Symptoms ◽  
Positron Emission ◽  
Infusion Reactions ◽  
Β Amyloid

The engineered fusion protein NPT088 targets amyloid in vitro and in animal models of Alzheimer’s disease. Previous studies showed that NPT088 treatment reduced β-amyloid plaque and tau aggregate loads in mouse disease models. Here, we present the results from an initial clinical study of NPT088 in patients with mild to moderate Alzheimer’s disease. Patients were treated with 4 dose levels of NPT088 for 6 months to evaluate its safety and tolerability. Exploratory measurements included measurement of change in β-amyloid plaque and tau burden utilizing Positron Emission Tomography imaging as well as measures of Alzheimer’s disease symptoms. At endpoint NPT088 was generally safe and well-tolerated with the most prominent finding being infusion reactions in a minority of patients. No effect of NPT088 on brain plaques, tau aggregates or Alzheimer’s disease symptoms was observed.

The Therapeutic Potential of Purinergic Receptors in Alzheimer’s Disease and Promising Therapeutic Modulators

2020 ◽  
Vol 20 ◽  
Author(s):  
Lili Pan ◽  
Yu Ma ◽  
Yunchun Li ◽  
Haoxing Wu ◽  
Rui Huang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Purinergic Receptors ◽  
Therapeutic Potential ◽  
Purinergic Signaling ◽  
Memory Loss ◽  
Related Research ◽  
Central Nervous System Disorders ◽  
G Protein Coupled

Abstract:: Recent studies have proven that the purinergic signaling pathway plays a key role in neurotransmission and neuromodulation, and is involved in various neurodegenerative diseases and psychiatric disorders. With the characterization of the subtypes of receptors in purinergic signaling, i.e. the P1 (adenosine), P2X (ion channel) and P2Y (G protein-coupled), more attentions were paid to the pathophysiology and therapeutic potential of purinergic signaling in central nervous system disorders. Alzheimer’s disease (AD) is a progressive and deadly neurodegenerative disease that is characterized by memory loss, cognitive impairment and dementia. However, as drug development aimed to prevent or control AD follows a series of failures in recent years, more researchers focused on the neuroprotection-related mechanisms such as purinergic signaling in AD patients to find a potential cure. This article reviews the recent discoveries of purinergic signaling in AD, summaries the potential agents as modulators for the receptors of purinergic signaling in AD related research and treatments. Thus, our paper provided an insight for purinergic signaling in the development of anti-AD therapies.

Synthesis of a Novel Curcumin Derivative as a Potential Imaging Probe in Alzheimer’s Disease Imaging

2019 ◽  
Vol 16 (8) ◽  
pp. 723-731 ◽  
Author(s):  
Alexander Sturzu ◽  
Sumbla Sheikh ◽  
Hubert Kalbacher ◽  
Thomas Nägele ◽  
Christopher Weidenmaier ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Flow Cytometry ◽  
Transgenic Mice ◽  
Ex Vivo ◽  
Amyloid Plaques ◽  
Laser Scanning Microscopy ◽  
Β Amyloid ◽  
Curcumin Derivative

Background: Curcumin has been of interest in the field of Alzheimer’s disease. Early studies on transgenic mice showed promising results in the reduction of amyloid plaques.However, curcumin is very poorly soluble in aqueous solutions and not easily accessible to coupling as it contains only phenolic groups as potential coupling sites. For these reasons only few imaging studies using curcumin bound as an ester were performed and curcumin is mainly used as nutritional supplement. Methods: In the present study we produced an aminoethyl ether derivative of curcumin using a nucleophilic substitution reaction. This is a small modification and should not impact the properties of curcumin while introducing an easily accessible reactive amino group. This novel compound could be used to couple curcumin to other molecules using the standard methods of peptide synthesis. We studied the aminoethyl-curcumin compound and a tripeptide carrying this aminoethyl-curcumin and the fluorescent dye fluorescein (FITC-curcumin) in vitro on cell culture using confocal laser scanning microscopy and flow cytometry. Then these two substances were tested ex vivo on brain sections prepared from transgenic mice depicting Alzheimer-like β-amyloid plaques. Results: In the in vitro CLSM microscopy and flow cytometry experiments we found dot-like unspecific uptake and only slight cytotoxicity correlating with this uptake. As these measurements were optimized for the use of fluorescein as dye we found that the curcumin at 488nm fluorescence excitation was not strong enough to use it as a fluorescence marker in these applications. In the ex vivo sections CLSM experiments both the aminoethyl-curcumin and the FITC-curcumin peptide bound specifically to β- amyloid plaques. Conclusion: In conclusion we successfully produced a novel curcumin derivative which could easily be coupled to other imaging or therapeutic molecules as a sensor for amyloid plaques.

Dehydroepiandrosterone (DHEA) and its Sulphate (DHEAS) in Alzheimer’s Disease

2020 ◽  
Vol 17 (2) ◽  
pp. 141-157 ◽  
Author(s):  
Dubravka S. Strac ◽  
Marcela Konjevod ◽  
Matea N. Perkovic ◽  
Lucija Tudor ◽  
Gordana N. Erjavec ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Therapeutic Potential ◽  
Relevant Literature ◽  
Comprehensive Overview ◽  
Brain Functions ◽  
Specific Effects ◽  
And Behavior

Background: Neurosteroids Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulphate (DHEAS) are involved in many important brain functions, including neuronal plasticity and survival, cognition and behavior, demonstrating preventive and therapeutic potential in different neuropsychiatric and neurodegenerative disorders, including Alzheimer’s disease. Objective: The aim of the article was to provide a comprehensive overview of the literature on the involvement of DHEA and DHEAS in Alzheimer’s disease. Method: PubMed and MEDLINE databases were searched for relevant literature. The articles were selected considering their titles and abstracts. In the selected full texts, lists of references were searched manually for additional articles. Results: We performed a systematic review of the studies investigating the role of DHEA and DHEAS in various in vitro and animal models, as well as in patients with Alzheimer’s disease, and provided a comprehensive discussion on their potential preventive and therapeutic applications. Conclusion: Despite mixed results, the findings of various preclinical studies are generally supportive of the involvement of DHEA and DHEAS in the pathophysiology of Alzheimer’s disease, showing some promise for potential benefits of these neurosteroids in the prevention and treatment. However, so far small clinical trials brought little evidence to support their therapy in AD. Therefore, large-scale human studies are needed to elucidate the specific effects of DHEA and DHEAS and their mechanisms of action, prior to their applications in clinical practice.

Therapeutic Potential of Adipose-Derived Mesenchymal Stem Cells (Admscs) and/or Taurine in Aluminum Chloride-Induced Alzheimer's Disease Rat Model

2021 ◽  
Author(s):  
Mohamed Hosney ◽  
Alaa Sakraan ◽  
Aman Asaad ◽  
Mervat El-Deftar ◽  
Emad Elzayat
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Rat Model ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Brain Homogenate ◽  
Oxidative Stress Marker

Abstract Alzheimer's disease (AD) is the most prevalent type of dementia characterized by its progression, neurobehavioral and neuro-pathological characteristics, leading to a diverse neuronal loss. Adipose-derived mesenchymal stem cells (ADMSCs) have previously proved potential role in preventing the pathogenesis of several neurodegenerative disorders, so regarded as a promising new approach for AD regenerative therapy. Taurine was found to enhance stem cell activation and propagation yielding a higher concentration of neural progenitors and stem cells, and aid to lessen the number of activated microglia leading to down-regulated inflammation in vitro. The present study aimed to investigate the possible therapeutic potential of ADMSCs and/or taurine in treating AD rat model. It was planned to include three successive phases; induction, withdrawal, and therapeutic phases. Fifty male Wistar rats were divided into 2 main groups: control (C) group and AD model group. Behavioral changes, as manifested by the T-Maze experiment, had been recorded. β-amyloid levels had been measured in brain homogenate and serum by ELISA. Oxidative stress marker (MDA), and anti-oxidant enzymes activity (SOD, GSH, and CAT) in brain, as well as serum acetylcholine esterase activity were spectrophotometrically determined. Pro-apoptotic (p53 and Bax) and anti-apoptotic (Bcl2) gene expression in brain were evaluated using RT-qPCR. The histopathological alterations in brain tissues were also observed. The present study proved the potential therapeutic ability of ADMSCs and/or taurine in alleviating the adverse pathological changes induced by AlCl3 in AD rat model at both physiological and molecular levels.

scholarly journals Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau

2021 ◽  
Author(s):  
Niklas Mattsson-Carlgren ◽  
Shorena Janelidze ◽  
Randall Bateman ◽  
Ruben Smith ◽  
Erik Stomrud ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medial Temporal Lobe ◽  
Amyloid Plaques ◽  
Amyloid Plaque ◽  
Amyloid Pet ◽  
Tau Pathology ◽  
Β Amyloid ◽  
Tau Pet ◽  
Disease Stages

Abstract Alzheimer’s disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N=88), both plaque and tangle density contributed independently to higher P-tau217. Several findings were replicated in a cohort with PET imaging (“BioFINDER-2”, N=426), where β-amyloid and tau PET were independently associated to P-tau217. P-tau217 correlated with β-amyloid PET (but not tau PET) in early disease stages, and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles.

scholarly journals The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

2020 ◽  
Vol 2020 ◽  
pp. 1-18 ◽  
Author(s):  
Brhane Teklebrhan Assefa ◽  
Gebrehiwot Gebremedhin Tafere ◽  
Dawit Zewdu Wondafrash ◽  
Meles Tekie Gidey
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Plaque ◽  
Current Evidence ◽  
Negative Effects ◽  
Disease Modifying Therapy ◽  
Tau Aggregation ◽  
And Oxidative Stress ◽  
Remarkable Progress

Alzheimer’s disease is a multifactorial neurodegenerative disease characterized by progressive cognitive dysfunction. It is the most common form of dementia. The pathologic hallmarks of the disease include extracellular amyloid plaque, intracellular neurofibrillary tangles, and oxidative stress, to mention some of them. Despite remarkable progress in the understanding of the pathogenesis of the disease, drugs for cure or disease-modifying therapy remain somewhere in the distance. From recent time, the signaling molecule AMPK is gaining enormous attention in the AD drug research. AMPK is a master regulator of cellular energy metabolism, and recent pieces of evidence show that perturbation of its function is highly ascribed in the pathology of AD. Several drugs are known to activate AMPK, but their effect in AD remains to be controversial. In this review, the current shreds of evidence on the effect of AMPK activators in Aβ accumulation, tau aggregation, and oxidative stress are addressed. Positive and negative effects are reported with regard to Aβ and tauopathy but only positive in oxidative stress. We also tried to dissect the molecular interplays where the bewildering effects arise from.

scholarly journals The Therapeutic Potential of Berberis darwinii Stem-Bark: Quantification of Berberine and In Vitro Evidence for Alzheimer's Disease Therapy

2011 ◽  
Vol 6 (8) ◽  
pp. 1934578X1100600 ◽  
Author(s):  
Solomon Habtemariam
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Charles Darwin ◽  
Potent Inhibitor ◽  
Methanolic Extract ◽  
Therapeutic Potential ◽  
Stem Bark ◽  
Acetylcholinesterase Inhibition ◽  
Disease Therapy

Berberis darwinii is native to South America but has been widely distributed in Europe and other continents following its discovery by Charles Darwin. Herewith, the therapeutic potential of stem-bark of the plant for treating Alzheimer's disease was studied using an in vitro acetylcholinesterase inhibition assay. It was found that the methanolic extract of the stem-bark was a potent inhibitor of the enzyme with an IC50 value of 1.23 ± 0.05 μg/mL. An HPLC-based berberine quantification study revealed an astonishing 38% yield of the dried methanolic extract.

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