Recent Progress on the Drug Development for the Treatment of Alzheimer’s Disease Especially on Inhibition of Amyloid-Peptide Aggregation

: As the world's population is ageing, Alzheimer’s disease (AD) has become a big concern since patients suffering from AD have become younger and the population of AD patients is increasing worldwide. It has been revealed that the neuropathological hallmarks of AD are typically characterized by the presence of neurotoxic extracellular amyloid plaques in the brain, which are surrounded by tangles of neuronal neuronal fibers. However, the causes of AD have not been completely understood yet. Currently, there is no drug to effectively prevent AD or to completely reserve the symptoms in the patients. This article reviews the pathological features associated with AD, the recent research progress on the drug development to treat AD especially on discovery of natural product derivatives to inhibit Aβ peptide aggregation as well as design and synthesis of Aβ peptide aggregation inhibitors to treat AD.

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Anti-Aggregation Property of Allicin by In Vitro and Molecular Docking Studies

Journal of Experimental Neuroscience ◽

10.1177/1179069519866185 ◽

2019 ◽

Vol 13 ◽

pp. 117906951986618 ◽

Cited By ~ 2

Author(s):

Suresh Kumar ◽

Shivani Kumar ◽

Heera Ram

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Docking ◽

Molecular Interaction ◽

Fibril Formation ◽

Amyloid Peptide ◽

Peptide Aggregation ◽

Aβ Peptide ◽

In Silico Studies

Amyloidogenesis is the process in which amyloid beta (Aβ) peptide aggregation results in plaque formation in central nervous system (CNS) are associated with many neurological diseases such as Alzheimer’s disease. The peptide aggregation initiated from peptide monomers results in formation of dimers, tetramers, fibrils, and protofibrils. The ability of allicin, a lipid-soluble volatile organosulfur biological compound, present in freshly crushed garlic ( Allium sativum L.) to inhibit fibril formation by the Aβ peptide in vitro was investigated in the present study. Inhibition of fibrillogenesis was measured by a Thioflavin T (ThT) fluorescence assay and visualized by transmission electron microscopy (TEM). The molecular interaction between allicin and Aβ peptide was also demonstrated by in silico studies. The results show that allicin strongly inhibited Aβ fibrils by 97% at 300 µM, compared with control (Aβ only) ( P < .001). These results were further validated by visual of fibril formation by transmission microscopy and molecular interaction of amyloid peptide with allicin by molecular docking. Aβ forms favourable hydrophobic interaction with Ile32, Met35, Val36, and Val39, and oxygen of allicin forms hydrogen bond with the amino acid residue Lys28. Allicin anti-amyloidogenic property suggests that this naturally occurring compound may have potential to ameliorate and prevent Alzheimer’s disease.

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Multi-target-directed phenol–triazole ligands as therapeutic agents for Alzheimer's disease

Chemical Science ◽

10.1039/c7sc01269a ◽

2017 ◽

Vol 8 (8) ◽

pp. 5636-5643 ◽

Cited By ~ 51

Author(s):

Michael R. Jones ◽

Emilie Mathieu ◽

Christine Dyrager ◽

Simon Faissner ◽

Zavier Vaillancourt ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Agents ◽

Peptide Aggregation ◽

Primary Neurons ◽

Aβ Peptide

A series of multi-target-directed ligands are described that bind Cu, act as antioxidants, modulate Aβ peptide aggregation, and abolish Aβ toxicity in primary neurons.

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Bidirectional regulation of Aβ levels by Presenilin 1

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1705235114 ◽

2017 ◽

Vol 114 (27) ◽

pp. 7142-7147 ◽

Cited By ~ 28

Author(s):

Victor Bustos ◽

Maria V. Pulina ◽

Yildiz Kelahmetoglu ◽

Subhash C. Sinha ◽

Fred S. Gorelick ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cultured Cells ◽

Amyloid Peptide ◽

Presenilin 1 ◽

Aβ Peptide ◽

Bifunctional Mechanism ◽

Bidirectional Regulation ◽

Plaque Load

Alzheimer’s disease (AD) is characterized by accumulation of the β-amyloid peptide (Aβ), which is generated through sequential proteolysis of the amyloid precursor protein (APP), first by the action of β-secretase, generating the β-C-terminal fragment (βCTF), and then by the Presenilin 1 (PS1) enzyme in the γ-secretase complex, generating Aβ. γ-Secretase is an intramembranous protein complex composed of Aph1, Pen2, Nicastrin, and Presenilin 1. Although it has a central role in the pathogenesis of AD, knowledge of the mechanisms that regulate PS1 function is limited. Here, we show that phosphorylation of PS1 at Ser367 does not affect γ-secretase activity, but has a dramatic effect on Aβ levels in vivo. We identified CK1γ2 as the endogenous kinase responsible for the phosphorylation of PS1 at Ser367. Inhibition of CK1γ leads to a decrease in PS1 Ser367 phosphorylation and an increase in Aβ levels in cultured cells. Transgenic mice in which Ser367 of PS1 was mutated to Ala, show dramatic increases in Aβ peptide and in βCTF levels in vivo. Finally, we show that this mutation impairs the autophagic degradation of βCTF, resulting in its accumulation and increased levels of Aβ peptide and plaque load in the brain. Our results demonstrate that PS1 regulates Aβ levels by a unique bifunctional mechanism. In addition to its known role as the catalytic subunit of the γ-secretase complex, selective phosphorylation of PS1 on Ser367 also decreases Aβ levels by increasing βCTF degradation through autophagy. Elucidation of the mechanism by which PS1 regulates βCTF degradation may aid in the development of potential therapies for Alzheimer’s disease.

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Baicalein suppresses Tau fibrillization by sequestering oligomers

10.1101/704536 ◽

2019 ◽

Author(s):

Shweta Kishor Sonawane ◽

Abhishek Ankur Balmik ◽

Debjyoti Boral ◽

Sureshkumar Ramasamy ◽

Subashchandrabose Chinnathambi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Misfolding ◽

Natural Compound ◽

Neurodegenerative Disorder ◽

Chinese Herb ◽

Tau Oligomers ◽

Aggregation Inhibitors ◽

The Brain

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder caused by protein misfolding, aggregation and accumulation in the brain. A large number of molecules are being screened against these pathogenic proteins but the focus for therapeutics is shifting towards the natural compounds as aggregation inhibitors, mainly due to their minimum adverse effects. Baicalein is a natural compound belonging to the class of flavonoids isolated from the Chinese herb Scutellaria baicalensis. Here we applied fluorescence, absorbance, microscopy, MALDI-TOF spectrophotometry and other biochemical techniques to investigate the interaction between Tau and Baicalein in vitro. We found the aggregation inhibitory properties of Baicalein for the repeat Tau. Overall, the potential of Baicalein in dissolving the preformed Tau oligomers as well as mature fibrils can be of utmost importance in therapeutics for Alzheimer’s disease.

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Amyloid-Beta Peptide, Oxidative Stress and Inflammation in Alzheimer's Disease: Potential Neuroprotective Effects of Omega-3 Polyunsaturated Fatty Acids

International Journal of Alzheimer s Disease ◽

10.4061/2010/274128 ◽

2010 ◽

Vol 2010 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

S. C. Dyall

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

The Elderly ◽

Amyloid Peptide ◽

Omega 3 ◽

Neuroprotective Effects ◽

Beta Peptide ◽

The Brain

Alzheimer's disease is the most common form of dementia in the elderly and is a progressive neurodegenerative disorder characterised by a decline in cognitive function and also profound alterations in mood and behaviour. The pathology of the disease is characterised by the presence of extracellular amyloid peptide deposits and intracellular neurofibrillary tangles in the brain. Although many hypotheses have been put forward for the aetiology of the disease, increased inflammation and oxidative stress appear key to be features contributing to the pathology. The omega-3 polyunsaturated fats, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have well-characterised effects on inflammation and may have neuroprotective effects in a number of neurodegenerative conditions including Alzheimer's disease. The aims of this paper are to review the neuroprotective effects of EPA and DHA in Alzheimer's disease, with special emphasis on their role in modulating oxidative stress and inflammation and also examine their potential as therapeutic agents.

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Study on Protection Against β-Amyloid Peptide Toxicity With Oral Administration of Medicinal Herbs

Journal of Evidence-Based Complementary & Alternative Medicine ◽

10.1177/2156587211429463 ◽

2011 ◽

Vol 17 (1) ◽

pp. 57-65 ◽

Cited By ~ 1

Author(s):

Songhee Jeon ◽

Jae-Hyun Kang ◽

Sok Cheon Pak ◽

Byung-Soo Koo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuroblastoma Cells ◽

Amyloid Β ◽

Complementary Therapy ◽

Amyloid Peptide ◽

Avoidance Task ◽

Cerebral Disease ◽

Impaired Performance ◽

The Brain

Seonghyangjeongkisan has been used as a therapeutic agent for cerebral disease in Korea, but its effectiveness in Alzheimer’s disease is not well known. In this study, we examined whether Seonghyangjeongkisan could protect against amyloid β–induced cytotoxicity in neuroblastoma cells and the brain. Seonghyangjeongkisan rescued amyloid β–induced cytotoxicity dose dependently and reduced amyloid β–induced apoptosis and reactive oxygen species. Injection of mice with amyloid β impaired performance on the passive avoidance task, but Seonghyangjeongkisan markedly improved memory impairment in mice, with it being more effective than tacrine treatment in mice. Moreover, the activation of stress-related kinases such as extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38 was suppressed, and the phosphorylation of τ protein, which is known as a marker of Alzheimer’s disease, was also suppressed by Seonghyangjeongkisan treatment in the hippocampus. These results demonstrate that Seonghyangjeongkisan reduces amyloid β-induced toxicity in the brain, suggesting that it may be a useful complementary therapy against Alzheimer’s disease.

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Hyperphosphorylated tau aggregation and cytotoxicity modulators screen identified prescription drugs linked to Alzheimer's disease and cognitive functions

Scientific Reports ◽

10.1038/s41598-020-73680-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Mengyu Liu ◽

Thomas Dexheimer ◽

Dexin Sui ◽

Stacy Hovde ◽

Xiexiong Deng ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Prescription Drugs ◽

Intracerebral Injection ◽

Hyperphosphorylated Tau ◽

Brain Correlates ◽

Aggregation Inhibitors ◽

Tau Aggregation ◽

The Brain

Abstract The neurodegenerative Alzheimer’s disease (AD) affects more than 30 million people worldwide. There is thus far no cure or prevention for AD. Aggregation of hyperphosphorylated tau in the brain correlates with the cognitive decline of patients of AD and other neurodegenerative tauopathies. Intracerebral injection of tau aggregates isolated from tauopathy brains causes similar pathology in the recipient mice, demonstrating the pathogenic role of abnormally phosphorylated tau. Compounds controlling the aggregation of hyperphosphorylated tau therefore are probable modulators for the disease. Here we report the use of recombinant hyperphosphorylated tau (p-tau) to identify potential tauopathy therapeutics and risk factors. Hyperphosphorylation renders tau prone to aggregate and to impair cell viability. Taking advantage of these two characters of p-tau, we performed a screen of a 1280-compound library, and tested a selective group of prescription drugs in p-tau aggregation and cytotoxicity assays. R-(−)-apomorphine and raloxifene were found to be p-tau aggregation inhibitors that protected p-tau-treated cells. In contrast, a subset of benzodiazepines exacerbated p-tau cytotoxicity apparently via enhancing p-tau aggregation. R-(−)apomorphine and raloxifene have been shown to improve cognition in animals or in humans, whereas benzodiazepines were linked to increased risks of dementia. Our results demonstrate the feasibility and potential of using hyperphosphorylated tau-based assays for AD drug discovery and risk factor identification.

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