Ferulic acid amide derivatives with varying inhibition of amyloid-β oligomerization and fibrillization

Kolaj, Igri; Wang, Yanfei; Ye, Kailin; Meek, Autumn; Liyanage, S. Imindu; Santos, Carlos Honorato Schuch; Weaver, Donald F.

doi:10.1016/j.bmc.2021.116247

Cited by 4 publications

(3 citation statements)

References 29 publications

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“…To demonstrate their utility as a molecular platform, 30 analogues of ferulate were synthesized and demonstrated varying Aβ 1‐40 anti‐aggregant activities (Table S5 in supporting information). 40 Ferulate has also been shown to inhibit IDO‐1 enzymatic activity. 41 …”

Section: Resultsmentioning

confidence: 99%

“…In ThT and CD anti‐aggregation assays, salicylate, ferulate, sinapate, 4‐coumarate, caffeiate, tannate, and resveratrol exhibited Aβ anti‐aggregant activities. To demonstrate their utility as a molecular platform, 30 analogues of ferulate were synthesized and demonstrated varying Aβ 1‐40 anti‐aggregant activities (Table S5 in supporting information) 40 . Ferulate has also been shown to inhibit IDO‐1 enzymatic activity 41 …”

Section: Resultsmentioning

confidence: 99%

“…As an alternative to synthetic tryptophan metabolite analogues, we next performed an in silico screen of 2950 natural products (BioCyc/MetaCyc database; 38 S5 in supporting information). 40 Ferulate has also been shown to inhibit IDO-1 enzymatic activity. 41 Additionally, these plant-based hits support the concept of AD as an innate autoimmune disorder.…”

Section: Alternative Platforms For Therapeutics Discoverymentioning

confidence: 99%

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Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites

Meier-Stephenson

Carter

et al. 2022

A&D Transl Res & Clin Interv

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Introduction Alzheimer's disease (AD) is characterized by neurotoxic immuno‐inflammation concomitant with cytotoxic oligomerization of amyloid beta (Aβ) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. Methods We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic–molecular mechanisms of cytokine‐mediated and Aβ‐mediated neurotoxicities in AD. Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small‐molecule therapeutics for AD. Results In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon “self” neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane‐penetrating attack by antimicrobial peptides (AMPs) such as Aβ. After this self‐attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic self‐perpetuating autoimmune cycle. AD thus emerges as a brain‐centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti‐AD molecules capable of chemical modification into multi‐site therapeutic modulators targeting AD's complex immunopathic–proteopathic pathogenesis. Discussion Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug‐like analogues of these endogenous regulators represents a novel therapeutic approach for AD.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Alternative Platforms For Therapeutics Discoverymentioning

confidence: 99%

See 1 more Smart Citation

Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites

Meier-Stephenson

Carter

et al. 2022

A&D Transl Res & Clin Interv

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Screening the extraction process of phenolic compounds from pressed grape seed residue: Towards an integrated and sustainable management of viticultural waste

Gómez-Mejía

Vicente-Zurdo²,

Rosales-Conrado³

et al. 2022

LWT

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Ferulic Acid reduces amyloid beta mediated neuroinflammation through modulation of Nurr1 expression in microglial cells

Moghimi-Khorasgani,

Homayouni Moghadam,

Nasr-Esfahani

2023

PLoS ONE

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Microglial cells (MGCs) serve as the resident macrophages in the brain and spinal cord, acting as the first line of immune defense against pathological changes. With various phenotypes, they can shift from a homeostatic state to a reactive state or transit from a reactive to a non-inflammatory reactive state (alternative homeostatic). A well-timed transit is crucial in limiting excessive microglial reaction and promoting the healing process. Studies indicate that increased Nurr1 expression promotes anti-neuroinflammatory responses in the brain. In this study, we investigated the possible role of ferulic acid (FA) in facilitating microglia transition due to its anti-inflammatory and Nurr1-inducing effects. MGCs were extracted from the brains of male NMRI mice at postnatal day 2 (P2) and cultured with or without FA and beta-amyloid (Aβ). Real-time qRT-PCR was conducted to measure the expressions of Nurr1, IL-1β, and IL-10 genes. Immunostaining was performed to determine the number of NURR1-positive cells, and the ramification index (RI) of MGCs was calculated using Image J software. Treating MGCs with FA (50 μg/ml) induced Nurr1 and IL-10 expressions, while reducing the level of IL-1β in the absence of Aβ-stress. Further assessments on cells under Aβ-stress showed that FA treatment restored the IL-10 and Nurr1 levels, increased the RI of cells, and the number of NURR1-positive cells. Morphological assessments and measurements of the RI revealed that FA treatment reversed amoeboid and rod-like cells to a ramified state, which is specific morphology for non-inflammatory reactive microglia. To conclude, FA can provide potential alternative homeostatic transition in Aβ-reactive microglia by recruiting the NURR1 dependent anti-inflammatory responses. This makes it a promising therapeutic candidate for suppressing Aβ-induced neuroinflammatory responses in MGCs. Furthermore, given that FA has the ability to increase NURR1 levels in homeostatic microglia, it could be utilized as a preventative medication.

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Ferulic acid amide derivatives with varying inhibition of amyloid-β oligomerization and fibrillization

Cited by 4 publications

References 29 publications

Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites

Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites

Screening the extraction process of phenolic compounds from pressed grape seed residue: Towards an integrated and sustainable management of viticultural waste

Ferulic Acid reduces amyloid beta mediated neuroinflammation through modulation of Nurr1 expression in microglial cells

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