Abstract
BackgroundNeuroinflammation is thought to be a cause of Alzheimer’s disease (AD), which is partly caused by inadequate mitophagy. As a receptor of mitophagy, we aimed to reveal the regulatory roles of optineurin (OPTN) on neuroinflammation in the pathogenesis of AD.MethodsBV2 cells and APP/PS1 transgenic (Tg) mice were used as in vitro and in vivo experimental models to determine the regulatory roles of OPTN in neuroinflammation of AD. Sophisticated molecular technologies including quantitative (q) RT-PCR, western blot, enzyme linked immunosorbent assay (ELISA), co-immunoprecipitation (Co-IP) and immunofluorescence (IF) were employed to reveal the inherent mechanisms.ResultsAs a consequence, key roles of OPTN in regulating neuroinflammation were identified by depressing the activity of absent in melanoma 2 (AIM2) inflammasomes and receptor interacting serine/threonine kinase 1 (RIPK1)-mediated NF-κB inflammatory mechanisms. In detail, we found that expression of OPTN was downregulated, which resulted in activation of AIM2 inflammasomes due to a deficiency in mitophagy in APP/PS1 Tg mice. By ectopic expression, OPTN blocks the effects of Aβ oligomer (Aβo) on activating AIM2 inflammasomes by inhibiting mRNA expression of AIM2 and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), leading to a reduction in the active form of caspase-1 and interleukin (IL)-1β in microglial cells. Moreover, RIPK1 was also found to be negatively regulated by OPTN via ubiquitin protease hydrolysis, resulting in the synthesis of IL-1β by activating the transcriptional activity of NF-κB in BV2 cells. As an E3 ligase, the UBAN domain of OPTN binds to the death domain (DD) of RIPK1 to facilitate its ubiquitination. Based on these observations, ectopically expressed OPTN in APP/PS1 Tg mice deactivated microglial cells and astrocytes via the AIM2 inflammasome and RIPK-dependent NF-κB pathways, leading to reduce neuroinflammation.ConclusionsThese results suggest that OPTN can alleviate neuroinflammation through AIM2 and RIPK1 pathways, suggesting that OPTN deficiency may be a potential factor leading to the occurrence of AD.
Highlights
The pathological characteristics of Alzheimer’s disease (AD) are widely believed to be the deposition of extracellular β-amyloid protein (Aβ) and intracellularCao et al Journal of Neuroinflammation (2021) 18:281 hyperphosphorylated tau, which is triggered by the impaired mitochondrial function [1,2,3]
Expression of OPTN is downregulated in the brains of AD patients and APP/PS1 Tg mice With increasing age, cells gradually become senescent, resulting in the disruption of various cell functions, such as overloading the degradation ability of the proteasome, leading to activation of the autophagy system to remove accumulated misfolded proteins, intracellular aggregates and irreparably damaged organelles [55]
The results demonstrated that the mRNA and protein expression of OPTN was downregulated in the cerebral cortex and hippocampus of 9-month-old APP/ PS1 Tg mice compared to that of WT mice (Fig. 1E–G), which is consistent with the transcriptomic sequencing data from AD patients (Fig. 1A–D)
Summary
The pathological characteristics of Alzheimer’s disease (AD) are widely believed to be the deposition of extracellular β-amyloid protein (Aβ) and intracellularCao et al Journal of Neuroinflammation (2021) 18:281 hyperphosphorylated tau, which is triggered by the impaired mitochondrial function [1,2,3]. The biogenesis of mitochondria was impaired via deactivating PGC1α-NRF-TFAM pathway in AD patients [4]. The deposited Aβ in β-amyloid plaques (APs) may cause further mitochondrial dysfunction and impair mitochondrial biogenesis [8]. Except for AD, impaired mitochondria is recruited to mitophagy via a series of mitophagy receptors, such as the ubiquitin-binding receptors optineurin (OPTN) and p62 (SQSTM1) et al [12]. Along these lines, mitophagy impairment has been suggested as a critical event in initiating AD, and restoring the function of mitophagy might be helpful for ameliorating the syndrome of AD [10, 13]. As a receptor of mitophagy, we aimed to reveal the regulatory roles of optineurin (OPTN) on neuroinflammation in the pathogenesis of AD
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