Microglial activation in Alzheimer's disease: The role of flavonoids and microRNAs

Abstract

Alzheimer's disease (AD) is the most common form of senile dementia and is characterized by progressive cognitive impairment and neuronal degeneration. Microglial activation is an important pathologic hallmark of AD. During disease progression, microglial cells switch from an alternative or anti-inflammatory and neuroprotective profile (M2) to a classic or proinflammatory and neurotoxic profile (M1). Phenotypically, M1 microglia is characterized by the activation of inflammatory signaling pathways that cause increased expression of proinflammatory genes, including those coding for cytokines and chemokines. This microglia-mediated neuroinflammation contributes to neuronal cell death. Recent studies in microglial cells have shown that a group of plant-derived compounds, known as flavonoids, possess anti-inflammatory properties and therefore exert a neuroprotective effect through regulating microglia activation. Here, we discuss how flavonoids can promote the switch from an inflammatory M1 phenotype to an anti-inflammatory M2 phenotype in microglia and how this represents a valuable opportunity for the development of novel therapeutic strategies to blunt neuroinflammation and boost neuronal recovery in AD. We also review how

The Phytochemical Agathisflavone Modulates miR146a and miR155 in Activated Microglia Involving STAT3 Signaling

“…In AD, it has been shown that microglia recognize soluble Aβ oligomers through different cell surface receptors, including CD36 and TLRs, such as TLR2, TLR4, TLR6, and TLR9. The recognition by these receptors contributes to the activation of NF-κB, and consequent microglial activation and release of proinflammatory mediators, such as NO, IL-6, and IL-1β [ 3 , 4 ]. Also shown in studies with models of neuroinflammation using LPS, IL-1β, or Aβ oligomers is the effect of agathisflavone and other flavonoids in negatively regulating the expression of NF-κB and, consequently, of the inflammatory cytokines IL-6, IL-1β, TNF, and NOS2, contributing to the reduction of neuroinflammation [ 3 , 24 , 25 , 26 ].…”

“…The recognition by these receptors contributes to the activation of NF-κB, and consequent microglial activation and release of proinflammatory mediators, such as NO, IL-6, and IL-1β [ 3 , 4 ]. Also shown in studies with models of neuroinflammation using LPS, IL-1β, or Aβ oligomers is the effect of agathisflavone and other flavonoids in negatively regulating the expression of NF-κB and, consequently, of the inflammatory cytokines IL-6, IL-1β, TNF, and NOS2, contributing to the reduction of neuroinflammation [ 3 , 24 , 25 , 26 ]. Moreover, we also demonstrated that agathisflavone protected neurons against the cytodestructive and proinflammatory effects of IL-1β, a key cytokine that is released by activated microglia via downregulation of NF-κB expression, an effect not observed in combined treatment with α and β estrogen receptor (ER) antagonists [ 24 ].…”

“…Proinflammatory microglia express cytokines, chemokines, and other mediators involved in the regulation of neuroinflammation, such as microRNAs [ 1 , 2 ]. MicroRNAs (miRNAs) are endogenous, short, noncoding RNA molecules that act as important post-transcriptional regulators of gene expression by base-pairing with target mRNA [ 3 , 4 ]. Multiple studies have demonstrated miRNAs as important regulators and risk factors for the development of neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases [ 5 , 6 , 7 ].…”

“…Flavonoids are a group of polyphenolic compounds from different plant species with varied biological effects, such as anti-inflammatory, antioxidant, antitumor, antimicrobial, and antiviral actions [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. The neuroprotective effects of flavonoids may be related to their action on the expression of miRNAs and their proinflammatory properties in microglial cells [ 3 , 20 , 21 ]. Our previous studies have demonstrated that the biflavonoid agathisflavone, purified from the leaves of Cenostigma pyramidale (Tul.)…”

Flavonoids as Promising Neuroprotectants and Their Therapeutic Potential against Alzheimer’s Disease

“…Flavonoids are of huge interest in numerous nutraceutical, pharmacological, medical, and cosmetic applications; they are a crucial ingredient. This is explained by their ability to control important cellular enzyme functions as well as their antioxidative [40], anti-inflammatory [41,42], antimutagenic [43], and anticarcinogenic capabilities [44][45][46]. According to numerous researches, flavonoids possess bio-logical properties such as antiallergenic, antiviral, antiinflammatory, and vasodilation effects.…”