Modulation of Amyloid β-Induced Microglia Activation and Neuronal Cell Death by Curcumin and Analogues

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is not restricted to the neuronal compartment but includes important interactions with immune cells, including microglia. Protein aggregates, common pathological hallmarks of AD, bind to pattern recognition receptors on microglia and trigger an inflammatory response, which contributes to disease progression and severity. In this context, curcumin is emerging as a potential drug candidate able to affect multiple key pathways implicated in AD, including neuroinflammation. Therefore, we studied the effect of curcumin and its structurally related analogues cur6 and cur16 on amyloid-β (Aβ)-induced microglia activation and neuronal cell death, as well as their effect on the modulation of Aβ aggregation. Primary cortical microglia and neurons were exposed to two different populations of Aβ42 oligomers (Aβ42Os) where the oligomeric state had been assigned by capillary electrophoresis and ultrafiltration. When stimulated with high molecular weight Aβ42Os, microglia released proinflammatory cytokines that led to early neuronal cell death. The studied compounds exerted an anti-inflammatory effect on high molecular weight Aβ42O-stimulated microglia and possibly inhibited microglia-mediated neuronal cell toxicity. Furthermore, the tested compounds demonstrated antioligomeric activity during the process of in vitro Aβ42 aggregation. These findings could be investigated further and used for the optimization of multipotent candidate molecules for AD treatment

Molecular interplay between phytoconstituents of Ficus Racemosa and neurodegenerative diseases

“…F. racemosa , a plant abundant in these phytoconstituents, holds significant promise as a therapeutic resource for treating NDs (Yadav et al, 2015). These pharmacologically active phytoconstituents exhibit multifaceted actions, collectively contributing to regulating key pathological events, including oxidative stress, apoptosis, neuroinflammation, Aβ accumulation, and tau‐related neuropathology (de Lorenzi et al, 2022; Sotolongo et al, 2020). F. racemosa , having a series of numerous phytochemicals including polyphenols, glycosides, terpenoids, and furocoumarin, is well known to possess antiapoptotic, anti‐inflammatory, antioxidant effects, and neuroprotective potential (Ahmed & Urooj, 2010).…”

“…Toxic Aβ monomers and oligomers have been shown to induce microglial activation and proliferation. Activated microglia secrete proinflammatory cytokines such as IL‐1β and IL‐6 (de Lorenzi et al, 2022). Terpenoids are natural compounds that show promising potential to mitigate these cellular disruptions.…”

Pharmacological intervention of curcumin via the NLRP3 inflammasome in ischemic stroke

“…Several studies have suggested that microglia activation may prevent chronic inflammation ( Qin et al, 2019 ). Curcumin may alter microglia from M 1 to M 2 , which then protects against neurological damage by blocking the ERK1/2 pathway and attenuating the formation of TNF-β, IL-1β, and IL-6 and NF-κB pathway activation in microglia ( De Lorenzi et al, 2022 ). Microglia, as the immune cell in the brain, participates in the inflammation and release factors that determine the microglia phenotype ( Ramírez-Carreto et al, 2023 ).…”

Selected Plant-Derived Polyphenols as Potential Therapeutic Agents for Peripheral Artery Disease: Molecular Mechanisms, Efficacy and Safety

“…Curcumin has been widely evaluated with respect to the modulation of endothelial function [ 102 ]. Curcumin also presents a neuroprotective potential in the pathogenesis of Alzheimer’s disease [ 103 , 104 , 105 ]. The many described biological activities of curcumin have been linked to its chemical instability that leads to the rapid autoxidation responsible for its antioxidant behavior.…”