scholarly journals Therapeutic Potential of Multifunctional Tacrine Analogues

2019 ◽  
Vol 17 (5) ◽  
pp. 472-490 ◽  
Author(s):  
Maja Przybyłowska ◽  
Szymon Kowalski ◽  
Krystyna Dzierzbicka ◽  
Iwona Inkielewicz-Stepniak
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Liver Toxicity ◽  
Potent Inhibitor ◽  
Therapeutic Potential ◽  
Treatment Strategies ◽  
Biological Properties ◽  
New Paradigm ◽  
Experimental Systems

Tacrine is a potent inhibitor of cholinesterases (acetylcholinesterase and butyrylcholinesterase) that shows limiting clinical application by liver toxicity. In spite of this, analogues of tacrine are considered as a model inhibitor of cholinesterases in the therapy of Alzheimer’s disease. The interest in these compounds is mainly related to a high variety of their structure and biological properties. In the present review, we have described the role of cholinergic transmission and treatment strategies in Alzheimer’s disease as well as the synthesis and biological activity of several recently developed classes of multifunctional tacrine analogues and hybrids, which consist of a new paradigm to treat Alzheimer’s disease. We have also reported potential of these analogues in the treatment of Alzheimer’s diseases in various experimental systems.

scholarly journals Extracellular Vesicles: A Possible Link between HIV and Alzheimer’s Disease-Like Pathology in HIV Subjects?

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 968 ◽  
Author(s):  
Sunitha Kodidela ◽  
Kelli Gerth ◽  
Sanjana Haque ◽  
Yuqing Gong ◽  
Saifudeen Ismael ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Extracellular Vesicles ◽  
Treatment Strategies ◽  
Progressive Dementia ◽  
Hiv Patients ◽  
Age Related ◽  
Infected Cells ◽  
New Treatment

The longevity of people with HIV/AIDS has been prolonged with the use of antiretroviral therapy (ART). The age-related complications, especially cognitive deficits, rise as HIV patients live longer. Deposition of beta-amyloid (Aβ), a hallmark of Alzheimer’s disease (AD), has been observed in subjects with HIV-associated neurocognitive disorders (HAND). Various mechanisms such as neuroinflammation induced by HIV proteins (e.g., Tat, gp120, Nef), excitotoxicity, oxidative stress, and the use of ART contribute to the deposition of Aβ, leading to dementia. However, progressive dementia in older subjects with HIV might be due to HAND, AD, or both. Recently, extracellular vesicles (EVs)/exosomes, have gained recognition for their importance in understanding the pathology of both HAND and AD. EVs can serve as a possible link between HIV and AD, due to their ability to package and transport the toxic proteins implicated in both AD and HIV (Aβ/tau and gp120/tat, respectively). Given that Aß is also elevated in neuron-derived exosomes isolated from the plasma of HIV patients, it is reasonable to suggest that neuron-to-neuron exosomal transport of Aβ and tau also contributes to AD-like pathology in HIV-infected subjects. Therefore, exploring exosomal contents is likely to help distinguish HAND from AD. However, future prospective clinical studies need to be conducted to compare the exosomal contents in the plasma of HIV subjects with and without HAND as well as those with and without AD. This would help to find new markers and develop new treatment strategies to treat AD in HIV-positive subjects. This review presents comprehensive literatures on the mechanisms contributing to Aβ deposition in HIV-infected cells, the role of EVs in the propagation of Aβ in AD, the possible role of EVs in HIV-induced AD-like pathology, and finally, possible therapeutic targets or molecules to treat HIV subjects with AD.

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.

The Role of Cardiovascular Risk Factors in Alzheimer's Disease

CNS Spectrums ◽  
2003 ◽  
Vol 8 (11) ◽  
pp. 824-831 ◽  
Author(s):  
Ramit Ravona-Springer ◽  
Michael Davidson ◽  
Shlomo Noy
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cardiovascular Risk ◽  
Vascular Dementia ◽  
Cardiovascular Risk Factors ◽  
Treatment Strategies ◽  
Mechanisms Of Action ◽  
Clinical Imaging

ABSTRACTThe distinction between Alzheimer's disease and vascular dementia, the two most common types of dementia, has been undermined by recent advances in epidemiologic, clinical, imaging, and neuropathological studies. Cardiovascular risk factors, traditionally regarded as distinguishing criteria between the two entities, have been shown to be associated with both AD and vascular dementia. In this article, we propose mechanisms of action of cardiovascular risk factors in AD, suggest possible explanations for the overlap with vascular dementia and discuss the implications this might have on future differential diagnosis, research, and treatment strategies.

scholarly journals Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer’s disease mice

2022 ◽  
Vol 119 (3) ◽  
pp. e2115082119
Author(s):  
Min Hee Park ◽  
Kang Ho Park ◽  
Byung Jo Choi ◽  
Wan Hui Han ◽  
Hee Ji Yoon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Memory Function ◽  
Selective Inhibition ◽  
Acid Sphingomyelinase ◽  
Hippocampal Neurogenesis ◽  
Ghrelin Receptor ◽  
Dual Action

Alzheimer’s disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

Therapeutic Potential of Ferulic Acid in Alzheimer's Disease

2021 ◽  
Vol 19 ◽  
Author(s):  
Hasan Turkez ◽  
Mehmet Enes Arslan ◽  
Joice Nascimento Barboza ◽  
Cigdem Yuce Kahraman ◽  
Damiao Pergentino de Sousa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radical ◽  
Ferulic Acid ◽  
Therapeutic Potential ◽  
High Capacity ◽  
Biological Properties ◽  
Tau Proteins ◽  
Phosphorylated Tau ◽  
Anti Inflammatory

Abstract: Alzheimer's Disease (AD) is one of the most important neurodegenerative diseases and it covers 60% of whole dementia cases. AD is a constantly progressing neurodegenerative disease as a result of the production of β-amyloid (Aβ) protein and the accumulation of hyper-phosphorylated Tau protein; it causes breakages in the synaptic bonds and neuronal deaths to a large extent. Millions of people worldwide suffer from AD because there is no definitive drug for disease prevention, treatment or slowdown. Over the last decade, multiple target applications have been developed for AD treatments. These targets include Aβ accumulations, hyper-phosphorylated Tau proteins, mitochondrial dysfunction, and oxidative stress resulting in toxicity. Various natural or semisynthetic antioxidant formulations have been shown to protect brain cells from Aβ induced toxicity and provide promising potentials for AD treatment. Ferulic acid (FA), a high-capacity antioxidant molecule, is naturally synthesized from certain plants. FA has been shown to have different substantial biological properties, such as anticancer, antidiabetic, antimicrobial, anti-inflammatory, hepatoprotective, and cardioprotective actions, etc. Furthermore, FA exerted neuroprotection via preventing Aβ-fibril formation, acting as an anti-inflammatory agent, and inhibiting free radical generation and acetylcholinesterase (AChE) enzyme activity. In this review, we present key biological roles of FA and several FA derivatives in Aβ-induced neurotoxicity, protection against free radical attacks, and enzyme inhibitions and describe them as possible therapeutic agents for the treatment of AD.

scholarly journals Autophagy in Alzheimer’s disease pathogenesis: therapeutic potential and future perspectives

2020 ◽  
Author(s):  
Zhigang Zhang ◽  
You-Qiang Song ◽  
Jie Tu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
The Elderly ◽  
Future Perspectives ◽  
Aβ Peptides ◽  
Evolutionarily Conserved ◽  
Amyloid Aβ ◽  
Folded Proteins

Alzheimer’s disease (AD) is a complex neurodegenerative disease in the elderly. It is the most common cause of dementia in human. AD is characterized by accumulation of abnormal protein aggregates including amyloid plaques (composed of beta-amyloid (Aβ) peptides) and neurofibrillary tangles (formed by hyper-phosphorylated tau protein). Besides, synaptic plasticity, neuroinflammation, calcium signaling etc. are found to be dysfunctional as well in AD patients. Autophagy is an evolutionarily conserved lysosome-dependent cellular event in eukaryotes. It is closely linked to the modulation of protein metabolism, through which damaged organelles and mis-folded proteins are degraded and then recycled to maintain protein homeostasis. Accumulating evidence has showed that impaired autophagy contributes to AD pathogenesis. In the present review, we highlight the role of autophagy, including bulk and selective autophagy, in regulating metabolic circuits in AD pathogenesis. We also discuss the potential and future perspectives of autophagy-inducing strategy in AD therapeutics.

scholarly journals Clemastine Ameliorates Myelin Deficits via Preventing Senescence of Oligodendrocytes Precursor Cells in Alzheimer’s Disease Model Mouse

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuan-Yuan Xie ◽  
Ting-Ting Pan ◽  
De-en Xu ◽  
Xin Huang ◽  
Yong Tang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Short Term Memory ◽  
Therapeutic Potential ◽  
Disease Model ◽  
Model Mouse ◽  
Oligodendrocyte Precursor ◽  
Myelin Deficits ◽  
M1 Muscarinic

Disrupted myelin and impaired myelin repair have been observed in the brains of patients and various mouse models of Alzheimer’s disease (AD). Clemastine, an H1-antihistamine, shows the capability to induce oligodendrocyte precursor cell (OPC) differentiation and myelin formation under different neuropathological conditions featuring demyelination via the antagonism of M1 muscarinic receptor. In this study, we investigated if aged APPSwe/PS1dE9 mice, a model of AD, can benefit from chronic clemastine treatment. We found the treatment reduced brain amyloid-beta deposition and rescued the short-term memory deficit of the mice. The densities of OPCs, oligodendrocytes, and myelin were enhanced upon the treatment, whereas the levels of degraded MBP were reduced, a marker for degenerated myelin. In addition, we also suggest the role of clemastine in preventing OPCs from entering the state of cellular senescence, which was shown recently as an essential causal factor in AD pathogenesis. Thus, clemastine exhibits therapeutic potential in AD via preventing senescence of OPCs.

The Possible Role of Antioxidant Vitamin C in Alzheimer’s Disease Treatment and Prevention

2013 ◽  
Vol 28 (2) ◽  
pp. 120-125 ◽  
Author(s):  
Jae-Hyeok Heo ◽  
Hyon-Lee ◽  
Kyoung-Min Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vitamin C ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Acetylcholinesterase Activity ◽  
Antioxidant Vitamin ◽  
Treatment And Prevention ◽  
Current Article

Oxidative stress is suggested to play a major role in the pathogenesis of Alzheimer’s disease (AD). Among the antioxidants, vitamin C has been regarded as the most important one in neural tissue. It also decreases β-amyloid generation and acetylcholinesterase activity and prevents endothelial dysfunction by regulating nitric oxide, a newly discovered factor in the pathogenesis and progression of AD. However, clinical trials using antioxidants, including vitamin C, in patients with AD yielded equivocal results. The current article discusses the relevance of vitamin C in the cellular and molecular pathogenesis of AD and explores its therapeutic potential against this neurodegenerative disorder.

A bifunctional non-natural tetrapeptide modulates amyloid-beta peptide aggregation in the presence of Cu(ii)

Metallomics ◽  
2014 ◽  
Vol 6 (12) ◽  
pp. 2189-2192 ◽  
Author(s):  
Maripaz Márquez ◽  
Luis M. Blancas-Mejía ◽  
Adriana Campos ◽  
Luis Rojas ◽  
Gilberto Castañeda-Hernández ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Therapeutic Potential ◽  
Amyloid Beta Peptide ◽  
Peptide Aggregation ◽  
Beta Peptide ◽  
Aβ Aggregation

A novel bifunctional non-natural tetrapeptide, Met-Asp-d-Trp-Aib, is capable of binding copper, competing with amyloid-beta peptide (Aβ) for Cu(ii), and modulating Aβ aggregation. The study of this tetrapeptide provides further insights into the role of Cu(ii) in the Aβ aggregation pathway, and into the design of compounds with therapeutic potential for Alzheimer's disease.

scholarly journals Therapeutic Potential of Neu1 in Alzheimer’s Disease Via the Immune System

2021 ◽  
Vol 36 ◽  
pp. 153331752199614
Author(s):  
Aiza Khan ◽  
Sumit Das ◽  
Consolato Sergi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune System ◽  
Therapeutic Potential ◽  
Amyloid Plaques ◽  
Beta Amyloid ◽  
Underlying Mechanism ◽  
Amyloid Deposits ◽  
Potential Therapeutic Role

Alzheimer’s Disease (AD) is pathologically characterized by the accumulation of soluble oligomers causing extracellular beta-amyloid deposits in form of neuritic plaques and tau-containing intraneuronal neurofibrillary tangles in brain. One proposed mechanism explaining the formation of these proteins is impaired phagocytosis by microglia/macrophages resulting in defective clearance of soluble oligomers of beta-amyloid stimulating aggregation of amyloid plaques subsequently causing AD. However, research indicates that activating macrophages in M2 state may reduce toxic oligomers. NEU1 mutation is associated with a rare disease, sialidosis. NEU1 deficiency may also cause AD-like amyloidogenic process. Amyloid plaques have successfully been reduced using NEU1.Thus, NEU1 is suggested to have therapeutic potential for AD, with lysosomal exocytosis being suggested as underlying mechanism. Studies however demonstrate that NEU1 may activate macrophages in M2 state, which as noted earlier, is crucial to reducing toxic oligomers. In this review, authors discuss the potential therapeutic role of NEU1 in AD via immune system.

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