The Role of Aldose Reductase in Beta-Amyloid-Induced Microglia Activation

Abstract

The occurrence of Alzheimer’s disease has been associated with the accumulation of beta-amyloid (β-amyloid) plaques. These plaques activate microglia to secrete inflammatory molecules, which damage neurons in the brain. Thus, understanding the underlying mechanism of microglia activation can provide a therapeutic strategy for alleviating microglia-induced neuroinflammation. The aldose reductase (AR) enzyme catalyzes the reduction of glucose to sorbitol in the polyol pathway. In addition to mediating diabetic complications in hyperglycemic environments, AR also helps regulate inflammation in microglia. However, little is known about the role of AR in β-amyloid-induced inflammation in microglia and subsequent neuronal death. In this study, we confirmed that AR inhibition attenuates increased β-amyloid-induced reactive oxygen species and tumor necrosis factor α secretion by suppressing ERK signaling in BV2 cells. In addition, we are the first to report that AR inhibition reduced the phagocytotic capability and cell migration of BV2 cells in response to β-amyloid. To further investigate the protective role of the AR inhibitor sorbinil in neurons, we co-cultured β-amyloid-induced microglia with stem cell-induced neurons. sorbinil ameliorated neuronal damage in both cells in the co-culture system. In summary, our findings reveal AR regulation of microglia activation as a novel therapeutic target for Alzheimer’s disease.

Aldose reductase inhibition decelerates optic nerve degeneration by alleviating retinal microglia activation

“…Furthermore, inflammation results in increased accumulation of ROS production which contributes to inflammatory cytokine secretion 68 . AR inhibition can alleviate oxidative stress by attenuating ROS and phagocytotic activity in microglial cells as recently reported by our group 67 . Published studies showed that activated microglia migrate into the inner nuclear or outer nuclear layer of the retina 9 , 69 , where the major neuronal cells reside.…”

“…1 D) 38 , 63 . Additionally, Sorbinil has been previously reported to attenuate secretion of IL-1β in macrophages and activation of JNK and p38 66 , 67 . As Sorbinil does not affect BV2 cell viability, the attenuation of microglial distribution is unlikely caused by the cytotoxicity of Sorbinil (Fig.…”

Inflammatory Processes in Alzheimer’s Disease—Pathomechanism, Diagnosis and Treatment: A Review

“…In addition to highlighting the role of potential therapeutic candidates for neuroinflammation in AD patients, the study has opened the way to an even broader understanding of the role of microglia as an inflammation inducer in AD; however, a full understanding of the role of microglia as a cellular inflammatory factor requires detailed research [ 86 ]. Huang et al, came to similar conclusions, identifying microglia as a factor for which understanding its function and activation can help determine how to neutralize inflammation in Alzheimer’s patients [ 87 ]. The excessive phagocytosis of amyloid plaques by microglia cells has been shown to play an important role in the penetration of β-amyloid into healthy brain regions of AD patients.…”

“…The excessive phagocytosis of amyloid plaques by microglia cells has been shown to play an important role in the penetration of β-amyloid into healthy brain regions of AD patients. In vitro studies conducted by the authors showed that, along with the penetration of β-amyloid into healthy regions of neural tissue, microglia furthermore produce a large amount of pro-inflammatory cytokines such as IL-6, which further causes the inflammatory involvement of healthy neurons in AD patients [ 87 ].…”

Diabetic vascular diseases: molecular mechanisms and therapeutic strategies

“… 81 , 82 Aldose reductase activity is significantly and systemically increased with hyperactivation of the sorbitol pathway in diabetes. 83 This leads to insulin resistance, resulting in widespread oxidative stress and increased inflammatory cytokines. The insulin receptor signaling system plays an important role in maintaining normal brain and cognitive functions 84 by regulating GLP-1 receptors, 84 , 85 insulin receptor substrate (IRS) receptors.…”