scholarly journals Therapeutic Mechanism and Key Alkaloids of Uncaria rhynchophylla in Alzheimer’s Disease From the Perspective of Pathophysiological Processes

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Zeng ◽  
Hong-Fei Su ◽  
Chao-Yuan Ye ◽  
Shuo-Wen Qiu ◽  
Qing Tian
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Performance ◽  
Amyloid Β ◽  
Pathological Process ◽  
Network Pharmacology ◽  
Disease Modifying Drugs ◽  
Uncaria Rhynchophylla ◽  
Therapeutic Mechanism ◽  
Aβ Production

Presently, there is a lack of effective disease-modifying drugs for the treatment of Alzheimer’s disease (AD). Uncaria rhynchophylla (UR) and its predominant active phytochemicals alkaloids have been studied to treat AD. This study used a novel network pharmacology strategy to identify UR alkaloids against AD from the perspective of AD pathophysiological processes and identified the key alkaloids for specific pathological process. The analysis identified 10 alkaloids from UR based on high-performance liquid chromatography (HPLC) that corresponded to 127 targets correlated with amyloid-β (Aβ) pathology, tau pathology and Alzheimer disease pathway. Based on the number of targets correlated with AD pathophysiological processes, angustoline, angustidine, corynoxine and isocorynoxeine are highly likely to become key phytochemicals in AD treatment. Among the 127 targets, JUN, STAT3, MAPK3, CCND1, MMP2, MAPK8, GSK3B, JAK3, LCK, CCR5, CDK5 and GRIN2B were identified as core targets. Based on the pathological process of AD, angustoline, angustidine and isocorynoxeine were identified as the key UR alkaloids regulating Aβ production and corynoxine, isocorynoxeine, dihydrocorynatheine, isorhynchophylline and hirsutine were identified as key alkaloids that regulate tau phosphorylation. The findings of this study contribute to a more comprehensive understanding of the key alkaloids and mechanisms of UR in the treatment of AD, as well as provide candidate compounds for drug research and development for specific AD pathological processes.

Is it All Said for NSAIDs in Alzheimer’s Disease? Role of Mitochondrial Calcium Uptake

2018 ◽  
Vol 15 (6) ◽  
pp. 504-510 ◽  
Author(s):  
Sara Sanz-Blasco ◽  
Maria Calvo-Rodríguez ◽  
Erica Caballero ◽  
Monica Garcia-Durillo ◽  
Lucia Nunez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Amyloid Β ◽  
Epidemiological Data ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Mitochondrial Potential ◽  
Disease Modifying Drugs ◽  
Definitive Evidence

Objectives: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ). Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death. Results: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.

Selective Secretase Targeting for Alzheimer’s Disease Therapy

2021 ◽  
pp. 1-17
Author(s):  
Alvaro Miranda ◽  
Enrique Montiel ◽  
Henning Ulrich ◽  
Cristian Paz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Neuroprotective Activity ◽  
Amyloid Β Protein ◽  
Secretase Activity ◽  
Membrane Bound ◽  
Aβ Production ◽  
Bace 1

Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

Cholesterol and Alzheimer's disease

2002 ◽  
Vol 30 (4) ◽  
pp. 525-529 ◽  
Author(s):  
B. Wolozin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Hmg Coa Reductase ◽  
Production Studies ◽  
Amino Acid Peptide ◽  
Reductase Inhibitors ◽  
Coa Reductase ◽  
Aβ Production

Accumulation of a 40–42-amino acid peptide, termed amyloid-β peptide (Aβ), is associated with Alzheimer's disease (AD), and identifying medicines that inhibit Aβ could help patients with AD. Recent evidence suggests that a class of medicines that lower cholesterol by blocking the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), termed statins, can inhibit Aβ production. Increasing evidence suggests that the enzymes that generate Aβ function best in a high-cholesterol environment, which might explain why reducing cholesterol would inhibit Aβ production. Studies using both neurons and peripheral cells show that reducing cellular cholesterol levels, by stripping off the cholesterol with methyl-β-cyclodextrin or by treating the cells with HMG-CoA reductase inhibitors, decreases Aβ production. Studies performed on animal models and on humans concur with these results. In humans, lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce Aβ levels in blood of patients by up to 40%. The putative role of Aβ in AD raises the possibility that treating patients with statins might lower Aβ, and thereby either delay the occurrence of AD or retard the progression of AD. Two large retrospective studies support this hypothesis. Both studies suggest that patients taking statins had an approx. 70% lower risk of developing AD. Since statins are widely used by doctors, their ability to reduce Aβ offers a putative therapeutic strategy for treating AD by using medicines that have already been proved safe to use in humans.

scholarly journals Implication of exosomes derived from cholesterol-accumulated astrocytes in Alzheimer's disease pathology

2021 ◽  
Author(s):  
Qi Wu ◽  
Leonardo Cortez ◽  
Razieh Kamali-Jamil ◽  
Valerie Sim ◽  
Holger Wille ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Influence Function ◽  
Critical Role ◽  
Amyloid Β ◽  
Cholesterol Accumulation ◽  
Aβ Peptides ◽  
Neuronal Viability ◽  
Cultured Astrocytes ◽  
Aβ Production

Amyloid β (Aβ) peptides generated from the amyloid precursor protein (APP) play a critical role in the development of Alzheimer's disease (AD) pathology. Aβ-containing neuronal exosomes, which represent a novel form of intercellular communication, have been shown to influence function/vulnerability of neurons in AD. Unlike neurons, the significance of exosomes derived from astrocytes remains unclear. In this study, we evaluated the significance of exosomes derived from U18666A-induced cholesterol-accumulated astrocytes in the development of AD pathology. Our results show that cholesterol accumulation decreases exosome secretion, whereas lowering cholesterol level increases exosome secretion from cultured astrocytes. Interestingly, exosomes secreted from U18666A-treated astrocytes contain higher levels of APP, APP-CTFs, soluble APP, APP secretases and Aβ1-40 than exosomes secreted from control astrocytes. Furthermore, we show that exosomes derived from U18666A-treated astrocytes can lead to neurodegeneration, which is attenuated by decreasing Aβ production or by neutralizing exosomal Aβ peptide with an Aβ antibody. These results, taken together, suggest that exosomes derived from cholesterol-accumulated astrocytes can play an important role in trafficking APP/Aβ peptides and influencing neuronal viability in the affected regions of the AD brain.

Alzheimer’s Disease and other Tauopathies: Exploring Efficacy of Medicinal Plant-Derived Compounds in Alleviating Tau-Mediated Neurodegeneration

2021 ◽  
Vol 14 ◽  
Author(s):  
Siva Sundara Kumar Durairajan ◽  
Karthikeyan Selvarasu ◽  
Minu Rani Bera ◽  
Kaushik Rajaram ◽  
Ashok Iyaswamy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medicinal Plant ◽  
Tau Protein ◽  
Amyloid Β ◽  
Corticobasal Degeneration ◽  
Phase Iii ◽  
Disease Modifying Drugs ◽  
Stabilizing Agents ◽  
Phase Iii Clinical Trials

: Alzheimer’s disease (AD), a major form of dementia, has been reported to affect more than 50 million people worldwide. It is characterized by the presence of amyloid-β (Aβ) plaques and hyperphosphorylated Tau-associated neurofibrillary tangles in the brain. Apart from AD, microtubule (MT)-associated protein Tau is also involved in other neurodegenerative diseases called tauopathies, including Pick’s disease, frontotemporal lobar degeneration, progressive supranuclear palsy, and corticobasal degeneration. The recently unsuccessful phase III clinical trials related to Aβ-targeted therapeutic drugs indicated that alternative targets, such as Tau, should be studied to discover more effective and safer drugs. Recent drug discovery approaches to reduce AD-related Tau pathologies are primarily based on blocking Tau aggregation, inhibiting Tau phosphorylation, compensating impaired Tau function with MT-stabilizing agents, and targeting the degradation pathways in neuronal cells to degrade Tau protein aggregates. Owing to several limitations of the currently-available Tau-directed drugs, further studies are required to generate further effective and safer Tau-based disease-modifying drugs. Here, we review the studies that focused on medicinal plant-derived compounds capable of modulating the Tau protein, which is significantly elevated and hyperphosphorylated in AD and other tauopathies. We mainly considered the studies that focused on Tau protein as a therapeutic target. We reviewed several pertinent papers retrieved from PubMed and ScienceDirect using relevant keywords, with a primary focus on the Tau-targeting compounds from medicinal plants. These compounds include indolines, phenolics, flavonoids, coumarins, alkaloids, and iridoids, which have been scientifically proven to be Tau-targeting candidates for the treatment of AD.

scholarly journals The Role of APP O-Glycosylation in Alzheimer’s Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1569
Author(s):  
Keiko Akasaka-Manya ◽  
Hiroshi Manya
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaque ◽  
Amyloid Β ◽  
Pathological Feature ◽  
People With Dementia ◽  
New Findings ◽  
Neurodegenerative Dementia ◽  
Aβ Production

The number of people with dementia is increasing rapidly due to the increase in the aging population. Alzheimer’s disease (AD) is a type of neurodegenerative dementia caused by the accumulation of abnormal proteins. Genetic mutations, smoking, and several other factors have been reported as causes of AD, but alterations in glycans have recently been demonstrated to play a role in AD. Amyloid-β (Aβ), a cleaved fragment of APP, is the source of senile plaque, a pathological feature of AD. APP has been reported to undergo N- and O-glycosylation, and several Polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts) have been shown to have catalytic activity for the transfer of GalNAc to APP. Since O-glycosylation in the proximity of a cleavage site in many proteins has been reported to be involved in protein processing, O-glycans may affect the cleavage of APP during the Aβ production process. In this report, we describe new findings on the O-glycosylation of APP and Aβ production.

scholarly journals Microglia, TREM2, and Therapeutic Methods of Alzheimer’s Disease

2021 ◽  
Author(s):  
Siwei Xu ◽  
Yaya Ji ◽  
Tianle Sha ◽  
Haoming Li
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dynamic Change ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Pathological Process ◽  
Amyloid Β Protein ◽  
Transmembrane Glycoprotein ◽  
Β Protein ◽  
The Central Nervous System

Alzheimer’s disease (AD) is one of the most common causes of dementia all around the world. It is characterized by the deposition of amyloid-β protein (Aβ) and the formation of neurofibrillary tangles (NFTs), which contribute to neuronal loss and cognitive decline. Microglia, as innate immune cells in brain, plays dual roles in the pathological process of AD. Expression in different subtypes of microglia is diverse in AD genes. Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane glycoprotein mainly expressed on microglia in the central nervous system (CNS). Soluble TREM2 (sTREM2), a proteolytic product of TREM2, which is abundant in the cerebrospinal fluid, shows a dynamic change in different stages and ameliorates the pathological process of AD. The interplay between the different subtypes of apolipoprotein and TREM2 is closely related to the mechanism of AD and serves as important regulatory sites. Moreover, several therapeutic strategies targeting TREM2 have shown positive outcomes during clinical trials and some novel therapies at different points are in progress. In this review, we mainly talk about the interrelationships among microglia, TREM2, and AD, and hope to give an overview of the strategies of AD.

Amyloid toxicity in Alzheimer’s disease

2018 ◽  
Vol 29 (6) ◽  
pp. 613-627 ◽  
Author(s):  
Allison B. Reiss ◽  
Hirra A. Arain ◽  
Mark M. Stecker ◽  
Nicolle M. Siegart ◽  
Lora J. Kasselman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pore Formation ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Calcium Balance ◽  
Aβ Oligomers ◽  
Synaptic Loss ◽  
Amyloid Toxicity ◽  
Aβ Production

Abstract A major feature of Alzheimer’s disease (AD) pathology is the plaque composed of aggregated amyloid-β (Aβ) peptide. Although these plaques may have harmful properties, there is much evidence to implicate soluble oligomeric Aβ as the primary noxious form. Aβ oligomers can be generated both extracellularly and intracellularly. Aβ is toxic to neurons in a myriad of ways. It can cause pore formation resulting in the leakage of ions, disruption of cellular calcium balance, and loss of membrane potential. It can promote apoptosis, cause synaptic loss, and disrupt the cytoskeleton. Current treatments for AD are limited and palliative. Much research and effort is being devoted to reducing Aβ production as an approach to slowing or preventing the development of AD. Aβ formation results from the amyloidogenic cleavage of human amyloid precursor protein (APP). Reconfiguring this process to disfavor amyloid generation might be possible through the reduction of APP or inhibition of enzymes that convert the precursor protein to amyloid.

scholarly journals Structural Studies Providing Insights into Production and Conformational Behavior of Amyloid-β Peptide Associated with Alzheimer’s Disease Development

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2897
Author(s):  
Anatoly S. Urban ◽  
Konstantin V. Pavlov ◽  
Anna V. Kamynina ◽  
Ivan S. Okhrimenko ◽  
Alexander S. Arseniev ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Transmembrane Domain ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Conformational Behavior ◽  
Amyloid Β Peptide ◽  
Structural Studies ◽  
Aβ Production

Alzheimer’s disease is the most common type of neurodegenerative disease in the world. Genetic evidence strongly suggests that aberrant generation, aggregation, and/or clearance of neurotoxic amyloid-β peptides (Aβ) triggers the disease. Aβ accumulates at the points of contact of neurons in ordered cords and fibrils, forming the so-called senile plaques. Aβ isoforms of different lengths are found in healthy human brains regardless of age and appear to play a role in signaling pathways in the brain and to have neuroprotective properties at low concentrations. In recent years, different substances have been developed targeting Aβ production, aggregation, interaction with other molecules, and clearance, including peptide-based drugs. Aβ is a product of sequential cleavage of the membrane glycoprotein APP (amyloid precursor protein) by β- and γ-secretases. A number of familial mutations causing an early onset of the disease have been identified in the APP, especially in its transmembrane domain. The mutations are reported to influence the production, oligomerization, and conformational behavior of Aβ peptides. This review highlights the results of structural studies of the main proteins involved in Alzheimer’s disease pathogenesis and the molecular mechanisms by which perspective therapeutic substances can affect Aβ production and nucleation.

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