Combating amyloid-induced cellular toxicity and stiffness by designer peptidomimetics

Konar, Mouli; Ghosh, Debasis; Samanta, Sourav; Govindaraju, T.

doi:10.1039/d1cb00235j

Cited by 13 publications

(19 citation statements)

References 48 publications

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“…We have adopted indirect immunofluorescence imaging for molecular characterization and AFM for morphological and mechanical analysis using integrated Bio-AFM instrumentation. We have imaged the protein marker Iba1 for microglia activation and actin for the cytoskeletal network using confocal microscopy, and the morphological and mechanical changes, viz., shape, height, stiffness, and adhesive forces, were assessed using AFM. , This novel approach enabled us to analyze the microglial activation and the effect of M3 by correlating molecular-level events and mechanical properties. We have used C6 microglial cells as the model and Aβ42 as stimuli for microglial activation that mimics AD conditions.…”

Section: Resultsmentioning

confidence: 99%

Rationally Designed Molecules Synergistically Modulate Multifaceted Aβ Toxicity, Microglial Activation, and Neuroinflammation

Ramesh

Balachandra

Andhare

et al. 2022

ACS Chem. Neurosci.

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Synergistic modulation of multifaceted toxicity is the key to tackle multifactorial Alzheimer’s disease (AD). The etiology of AD includes amyloid β (Aβ) amyloidosis, metal ion dyshomeostasis, reactive oxygen species (ROS), oxidative stress, mitochondrial damage, and neuroinflammation. We rationally designed multifunctional modulators by integrating pharmacophores for metal chelation, antioxidant and anti-inflammatory properties, and modulation of Aβ42 aggregation on the naphthalene monoimide (NMI) scaffold. The in vitro and cellular studies of NMIs revealed that M3 synergistically modulates metal-independent and -dependent amyloid toxicity, scavenges ROS, alleviates oxidative stress, and emulates Nrf2-mediated stress response in neuronal cells. M3 effectively reduced structural and functional damage of mitochondria, reduced Cyt c levels, and rescued cells from apoptosis. The biological atomic force microscopy and Western blot analysis revealed the ability of M3 to suppress microglial activation and neuroinflammation through inhibition of the NF-κβ pathway. The synergistic action of M3 is in agreement with our design strategy to develop a multifunctional therapeutic candidate by integrating multiple pharmacophores with distinct structural and functional elements to ameliorate the multifaceted toxicity of AD.

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Section: Resultsmentioning

confidence: 99%

Rationally Designed Molecules Synergistically Modulate Multifaceted Aβ Toxicity, Microglial Activation, and Neuroinflammation

Ramesh

Balachandra

Andhare

et al. 2022

ACS Chem. Neurosci.

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“…146 We have designed peptidomimetics derived from Aβ14-23 (I) by incorporating cyclo(Lys-Asp)-based CDP (kd) molecule at various positions to develop potent aggregation modulators with biocompatibility and stability. [147][148][149] Incorporation of rigid, proteolytically stable unnatural CDP amino acid (kd) with exceptional intermolecular hydrogen bonding ability overcome the limitations of large linear and cyclic peptides. Peptides II to V were designed by incorporating Kd at the middle (Akd M /II), C-terminal (Akd C /III), N-terminal (Akd N /IV), and at all three positions (Akd NMC /V), respectively (Fig.…”

Section: Aβ Aggregation Modulatorsmentioning

confidence: 99%

Multipronged diagnostic and therapeutic strategies for Alzheimer's disease

Ramesh

Govindaraju

2022

Chem. Sci.

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“…23−25 We have reported a variety of CDP-based molecular systems and material architectures with exceptional mechanical properties, ambidextrous supergelators, antioxidants, sensing, drug delivery applications, and anti-amyloidogenic properties, among others. 26,27 CDPs are known for their remarkable molecular assembly through multiple hydrogenbonding-guided molecular chains and layers. These exceptional properties have motivated us to develop a CDP-based copolymer (CP) and study its interaction with nanoparticles for modulating Aβ42 aggregation.…”

Section: Introductionmentioning

confidence: 99%

Multifunctional Architectures of Cyclic Dipeptide Copolymers and Composites, and Modulation of Multifaceted Amyloid-β Toxicity

Moorthy

Datta

Samanta

et al. 2022

ACS Appl. Mater. Interfaces

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Alzheimer's disease (AD) is a major neurodegenerative disorder primarily characterized by the β-amyloid (Aβ42) misfolding and aggregation-associated multifaceted amyloid toxicity encompassing oxidative stress, neuronal death, and severe cognitive impairment. Modulation of Aβ42 aggregation via various structurally anisotropic macromolecular systems is considered effective in protecting neuronal cells. In this regard, we have developed a cyclic dipeptide (CDP)-based copolymer (CP) and explored its material and biomedical properties. Owing to the structural versatility, CDP-CP forms solvent-dependent anisotropic architectures ranging from dense fibers and mesosheets to vesicles, which are shown to interact with dyes and nanoparticles and mimic synthetic protocells, providing a conceptually new approach to achieve advanced functional materials with the hierarchical organization. CP upon interaction with gold nanoparticles (GNP) and polyoxometalate (POM) generated faceted architectures (CP-GNP) and the nanocomposite (CP-POM), respectively. CP-GNP and CP-POM have shown remarkable ability to inhibit Aβ42 aggregation, dissolve the preformed aggregates, and scavenge reactive oxygen species (ROS) to ameliorate multifaceted amyloid toxicity. In cellulo studies show that CP-GNP and CP-POM protect neuronal cells from Aβ42-induced toxicity and reduce lipopolysaccharide (LPS)-activated neuroinflammation at sub-micromolar concentration. To our knowledge, this is the first report on the hierarchical organization of CDP-CP into 1D-to-2D architectures and their organic−inorganic hybrid nanocomposites to combat the multifaceted amyloid toxicity.

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Combating amyloid-induced cellular toxicity and stiffness by designer peptidomimetics

Abstract: Amyloid beta (Aβ) aggregation species-associated cellular stress instigates cytotoxicity and adverse cellular stiffness to neuronal cells. The study and modulation of these adverse effects demand immediate attention to tackle Alzheimer’s...

Cited by 13 publications

References 48 publications

Rationally Designed Molecules Synergistically Modulate Multifaceted Aβ Toxicity, Microglial Activation, and Neuroinflammation

Rationally Designed Molecules Synergistically Modulate Multifaceted Aβ Toxicity, Microglial Activation, and Neuroinflammation

Multipronged diagnostic and therapeutic strategies for Alzheimer's disease

Multifunctional Architectures of Cyclic Dipeptide Copolymers and Composites, and Modulation of Multifaceted Amyloid-β Toxicity

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