LRP1 activation attenuates white matter injury by modulating microglial polarization through Shc1/PI3K/Akt pathway after subarachnoid hemorrhage in rats

Abstract

White matter injury (WMI) is associated with motor deficits and cognitive dysfunctions in subarachnoid hemorrhage (SAH) patients. Therapeutic strategy targeting WMI would likely improve the neurological outcomes after SAH. Low-density lipoprotein receptor-related protein-1 (LRP1), a scavenger receptor of apolipoprotein E (apoE), is able to modulate microglia polarization towards anti-inflammatory M2 phenotypes during inflammatory and oxidative insult. In the present study, we investigated the effects of LRP1 activation on WMI and underlying mechanisms of M2 microglial polarization in a rat model of SAH. Two hundred and seventeen male Sprague Dawley rats (weight 280–330 g) were used. SAH was induced by endovascular perforation. LPR1 ligand, apoE-mimic peptide COG1410 was administered intraperitoneally. Microglial depletion kit liposomal clodronate (CLP), LPR1 siRNA or PI3K inhibitor were administered intracerebroventricularly. Post-SAH assessments included neurobehavioral tests, brain water content, immunohistochemistry, Golgi staining, western blot and co-immunoprecipitation. SAH induced WMI shown as the accumulation of amyloid precursor protein and neurofilament heavy polypeptide as well as myelin loss. Microglial depletion by CLP significantly suppressed WMI after SAH. COG1410 reduced brain water content, increased the anti-inflammatory M2 microglial phenotypes, attenuated WMI and improved neurological function after SAH. LRP1 was bound with endogenous apoE and intracellular adaptor protein Shc1. The benefits of COG1410 were reversed by LPR1 siRNA or PI3K inhibitor. LRP1 activation attenuated WMI and improved neurological function by modulating M2 microglial polarization at least in part through Shc1/PI3K/Akt signaling in a rat model of SAH. The apoE-mimic peptide COG1410 may serve as a promising treatment in the management of SAH patients.

Peroxisomal Dysfunction Contributes to White Matter Injury Following Subarachnoid Hemorrhage in Rats via Thioredoxin-Interacting Protein-Dependent Manner

“…In an experimental SAH model, Egashira et al (2015) have demonstrated that increased secretion of MMP-9 from astrocytes and oligodendrocyte precursors caused disruption of the blood-brain barrier (BBB) and subsequent WMI following SAH. Pang et al (2019) have summarized the pathogenesis and underlying mechanisms of WMI after SAH in their systematic review. In this review, authors have indicated that WMI mainly results from five pathophysiologic changes, including BBB disruption, physical and mechanical damage, neuroinflammation, ischemia, and oxidative stress, underlining the importance of targeting WMI in the treatment of SAH.…”

“…Previous studies have mainly focused on studying the injuries of the cortex or hippocampus following SAH; however, white matter injury (WMI) after SAH has not been well addressed. More than half of the central nervous system is composed of white matter, which is more vulnerable to ischemia/hemorrhagic stroke than gray matter (Pang et al, 2019). In our previous study, we found that WMI occurred in the early stage of SAH, which is characterized by amyloid precursor protein (APP) accumulation, myelin basic protein (MBP) degradation, and white matter edema (Peng et al, 2019).…”

“…More than half of the central nervous system is composed of white matter, which is more vulnerable to ischemia/hemorrhagic stroke than gray matter (Pang et al, 2019). In our previous study, we found that WMI occurred in the early stage of SAH, which is characterized by amyloid precursor protein (APP) accumulation, myelin basic protein (MBP) degradation, and white matter edema (Peng et al, 2019). However, the underlying mechanisms of WMI following SAH are still unclear.…”

Biglycan regulates neuroinflammation by promoting M1 microglial activation in early brain injury after experimental subarachnoid hemorrhage

“…M1 microglia release destructive pro‐inflammatory cytokines, such as TNF‐α, IL‐1β, IL‐6, iNOS, and CD16/32 (Huang et al, ; Pang et al, ), while M2 microglia promote arginase‐1 (Arg1), IL‐10, and CD206 expression (Martinez, Helming, & Gordon, ). We previously demonstrated that suppressing M1 microglial activation ultimately resulted in the attenuation of neuronal and white matter injury as well as brain edema during EBI after SAH (Pang et al, ; Peng et al, ). All these data suggest that biglycan promotes M1 microglial activation.…”

“…The modified Garcia and beam balance tests were conducted to evaluate the neurobehavioral function (SAH mice were assessed prior to sham group) at 48 h after SAH by an investigator who was blinded to experimental groups as previously described (Peng et al, ). The modified Garcia test (maximum score = 18) included spontaneous activity (scores 0–3), spontaneous movement of the four limbs (scores 0–3), forelimbs outstretching (scores 0–3), climbing capacity (scores 1–3), trunk touch (scores 1–3), and vibrissae touch (scores 1–3).…”