Molecular mechanisms in Alzheimer's disease and related potential treatments such as structural target convergence of antibodies and simple organic molecules

Oumata, Nassima; Lu, Kui; Teng, Yuou; Cavé, Christian; Yu, Peng; Galons, Hervé; Roques, Bernárd P.

doi:10.1016/j.ejmech.2022.114578

Cited by 28 publications

(21 citation statements)

References 111 publications

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“…Hence, in spite of remarkable efforts to realize the etiology and pathophysiology of AD, until now, scientists have not developed and introduced medications that can permanently cease the progression of AD. However, there is evidence that the new monoclonal antibody, aducanumab, can prevent neurodegeneration and delay disease progression (Delrieu et al, 2022; Nascimento et al, 2022; Oumata et al, 2022). Nowadays, research on the role of natural products in the treatment and prevention of AD has attracted great attention (Deshpande et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Kaempferol as a potential neuroprotector in Alzheimer's disease

Nejabati

Roshangar

2022

Journal of Food Biochemistry

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Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, is largely associated with cognitive disability, amnesia, and abnormal behavior, which accounts for about two third of people with dementia worldwide. A growing body of research demonstrates that AD is connected to several factors, such as aberrant accumulation of amyloid‐beta (Aβ), increase in the hyperphosphorylation of Tau protein, and the formation of neurofibrillary tangles, mitochondrial dysfunction, and inordinate production of reactive oxygen species (ROS). Despite remarkable efforts to realize the etiology and pathophysiology of AD, until now, scientists have not developed and introduced medications that can permanently cease the progression of AD. Thus, nowadays, research on the role of natural products in the treatment and prevention of AD has attracted great attention. Kaempferol (KMP), one of the prominent members of flavonols, exerts its ameliorative actions via attenuating oxidative stress and inflammation, reducing Aβ‐induced neurotoxicity, and regulating the cholinergic system. Therefore, in this review article, we outlined the possible effects of KMP in the prevention and treatment of AD. Practical applications Kaempferol (KMP) exerts its ameliorative actions against AD via attenuating oxidative stress and inflammation, reducing Aβ‐induced neurotoxicity, and regulating the cholinergic system. The beneficial effects of KMP were addressed in both in vitro and in vivo studies; however, conducting further research can warrant its long‐term effects as a safe agent. Therefore, after confirming its favorable functions in the prevention and treatment of AD, it could be used as a safe and effective agent.

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Section: Introductionmentioning

confidence: 99%

Kaempferol as a potential neuroprotector in Alzheimer's disease

Nejabati

Roshangar

2022

Journal of Food Biochemistry

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“…Alzheimer's disease is a neurodegenerative disorder to memory loss and progresses to dementia and death (Oumata et al, 2022). A decrease in the concentration of acetylcholinesterase (AChE) and butyrylcholinesterase enzymes which act as essential neurotransmitters, neuronal damage, and the accumulation of beta‐amyloid plaques are the significant pathophysiological changes in Alzheimer's disease (Minati et al, 2009; Reisberg et al, 2003; Selkoe, 2001).…”

Section: Introductionmentioning

confidence: 99%

In vitro enzymatic evaluation of some pyrazolo[1,5‐a]pyrimidine derivatives: Design, synthesis, antioxidant, anti‐diabetic, anti‐Alzheimer, and anti‐arthritic activities with molecular modeling simulation

Hassan

Morsy

Aboulthana

2022

Drug Development Research

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The strategy of utilizing nitrogen compounds in various biological applications has recently emerged as a powerful approach to exploring novel classes of therapeutics to face the challenge of diseases. A series of pyrazolo[1,5‐a]pyrimidine‐based compounds 3a–l and 5a–f were prepared by the direct cyclo‐condensation reaction of 5‐amino‐1H‐pyrazoles 1a, b with 2‐(arylidene)malononitriles and 3‐(dimethylamino)‐1‐aryl‐prop‐2‐en‐1‐ones, respectively. The structures of the new pyrazolo[1,5‐a]pyrimidine compounds were confirmed via spectroscopic techniques. The in vitro biological activities of all pyrazolo[1,5‐a]pyrimidines 3a–l and 5a–f were evaluated by assaying total antioxidant capacity, iron‐reducing power, the scavenging activity against 1‐diphenyl‐2‐picryl‐hydrazyl (DPPH) and 2, 2'‐azinobis‐(3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS) radicals, anti‐diabetic, anti‐Alzheimer, and anti‐arthritic biological activities. All compounds displayed good to potent bioactivity, and three compounds 3g, 3h, and 3l displayed the most active derivatives. Among these derivatives, compound 3l exhibited the highest antioxidant (total antioxidant capacity [TAC] = 83.09 mg gallic acid/g; iron‐reducing power [IRP] = 47.93 µg/ml) and free radicals scavenging activities with (DPPH = 18.77 µg/ml; ABTS = 40.44%) compared with ascorbic acid (DPPH = 4.28 µg/ml; ABTS = 38.84%). Furthermore, compound 3l demonstrated the strongest inhibition of α‐amylase with a percent inhibition of 72.91 ± 0.14 compared to acarbose = 67.92 ± 0.09%. Similarly, it displayed acetylcholinesterase inhibition of 62.80 ± 0.06%. However, compound 3i showed a significantly higher inhibition percentage for protein denaturation and proteinase at 20.66 ± 0.00 and 26.42 ± 0.06%, respectively. Additionally, some in silico ADMET properties were predicted and studied. Finally, molecular docking simulation was performed inside the active site of α‐amylase and acetylcholinesterase to study their interactions.

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“…Several newer molecules that have been identified for AD in the last four decades act by preventing amyloid deposition in the brain and removing existing amyloid plaques along with other recognized mechanisms associated with the disease. 12 Although these compounds demonstrate promising data from preclinical AD models, the clinical failure rate in AD treatment is almost 100%. Several factors can be alleged for the failure, but the primary concern remains with the preclinical models used at the preliminary stages of drug development.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Models for Alzheimer’s Disease: Past, Present, and Future Approaches

et al. 2022

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A robust preclinical disease model is a primary requirement to understand the underlying mechanisms, signaling pathways, and drug screening for human diseases. Although various preclinical models are available for several diseases, clinical models for Alzheimer’s disease (AD) remain underdeveloped and inaccurate. The pathophysiology of AD mainly includes the presence of amyloid plaques and neurofibrillary tangles (NFT). Furthermore, neuroinflammation and free radical generation also contribute to AD. Currently, there is a wide gap in scientific approaches to preventing AD progression. Most of the available drugs are limited to symptomatic relief and improve deteriorating cognitive functions. To mimic the pathogenesis of human AD, animal models like 3XTg-AD and 5XFAD are the primarily used mice models in AD therapeutics. Animal models for AD include intracerebroventricular-streptozotocin (ICV-STZ), amyloid beta-induced, colchicine-induced, etc., focusing on parameters such as cognitive decline and dementia. Unfortunately, the translational rate of the potential drug candidates in clinical trials is poor due to limitations in imitating human AD pathology in animal models. Therefore, the available preclinical models possess a gap in AD modeling. This paper presents an outline that critically assesses the applicability and limitations of the current approaches in disease modeling for AD. Also, we attempted to provide key suggestions for the best-fit model to evaluate potential therapies, which might improve therapy translation from preclinical studies to patients with AD.

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Molecular mechanisms in Alzheimer's disease and related potential treatments such as structural target convergence of antibodies and simple organic molecules

Cited by 28 publications

References 111 publications

Kaempferol as a potential neuroprotector in Alzheimer's disease

Kaempferol as a potential neuroprotector in Alzheimer's disease

In vitro enzymatic evaluation of some pyrazolo[1,5‐a]pyrimidine derivatives: Design, synthesis, antioxidant, anti‐diabetic, anti‐Alzheimer, and anti‐arthritic activities with molecular modeling simulation

Preclinical Models for Alzheimer’s Disease: Past, Present, and Future Approaches

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