Apolipoprotein E-Mimetic COG1410 Reduces Acute Vasogenic Edema following Traumatic Brain Injury

Cao, Fang; Jiang, Yong; Wu, Yue; Zhong, Jian; Liu, Jieshi; Qin, Xinghu; Chen, Ligang; Vitek, Michael P.; Li, Fengqiao; Xu, Li; Sun, Xiaochuan

doi:10.1089/neu.2015.3887

Cited by 57 publications

(38 citation statements)

References 47 publications

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“…Of potential relevance, the injection of apoE N-terminal fragment (residues 1-191) into rabbits indicated a clearance rate from the circulation that is consistent with a receptor mediated process, for example, via hepatic LRP1 (66), even though the fragment was not associated with lipoprotein particles (67). In addition, apoEderived mimetic peptides that span the LDL receptor binding region have been used successfully as neuroprotective agents in mice (49,50,68,69).…”

Section: Discussionmentioning

confidence: 99%

The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis

Muñoz

Liu

Ruberu

et al. 2018

Journal of Biological Chemistry

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Apolipoprotein-E (apoE) is a glycoprotein highly expressed in the brain, where it appears to play a role in lipid transport, b-amyloid clearance, and neuronal signaling. ApoE proteolytic fragments are also present in the brain, but the enzymes responsible for apoE fragmentation are unknown, and the biological activity of specific apoE fragments remains to be determined. Here we utilised SK-N-SH neuroblastoma cells differentiated into neurons with all-trans retinoic acid (ATRA) to study extracellular apoE proteolysis. ApoE fragments were detectable in culture supernatants after 3 days, and their levels were increased for up to 9 days in the presence of ATRA. The concentration of apoE fragments was positively correlated with levels of the neuronal maturation markers (PSD95 and SMI32). The most abundant apoE fragments were 25 kDa and 28 kDa N-terminal fragments that both contained sialylated glycosylation and bound to heparin. We detected apoE fragments only in the extracellular milieu and not in cell lysates, suggesting that an extracellular protease contributes to apoE fragmentation.Of note, siRNA-mediated knockdown of high-temperature requirement serine peptidase A1 (HtrA1) and a specific HtrA1 inhibitor reduced apoE 25 kDa fragment formation by 41% and 86%, respectively. Recombinant 25-kDa fragment apoE and full-length apoE both stimulated neuritogenesis in vitro, increasing neuroblastoma neurite growth by more than 2-fold over a 6-day period. This study provides a cellular model for assessing apoE proteolysis, indicates that HtrA1 regulates apoE 25-kDa fragment formation under physiological conditions, and reveals a new neurotrophic function for the apoE 25-kDa fragment. ________________________________________

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Section: Discussionmentioning

confidence: 99%

The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis

Muñoz

Liu

Ruberu

et al. 2018

Journal of Biological Chemistry

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“…Overall, APOE tends to maintain BBB integrity and promote neurological recovery. While APOE-deficiency provokes BBB dysfunction, exogenously administered APOE or its mimetic peptides preserve BBB integrity in experimental studies [197][198][199][200][201][202][203].…”

Section: The Bbb Integrity-promoting Effects Of Astrocytesmentioning

confidence: 99%

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

et al. 2020

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Traumatic brain injury (TBI) is one of the leading causes of fatality and disability worldwide. Despite its high prevalence, effective treatment strategies for TBI are limited. Traumatic brain injury induces structural and functional alterations of astrocytes, the most abundant cell type in the brain. As a way of coping with the trauma, astrocytes respond in diverse mechanisms that result in reactive astrogliosis. Astrocytes are involved in the physiopathologic mechanisms of TBI in an extensive and sophisticated manner. Notably, astrocytes have dual roles in TBI, and some astrocyte-derived factors have double and opposite properties. Thus, the suppression or promotion of reactive astrogliosis does not have a substantial curative effect. In contrast, selective stimulation of the beneficial astrocytederived molecules and simultaneous attenuation of the deleterious factors based on the spatiotemporalenvironment can provide a promising astrocyte-targeting therapeutic strategy. In the current review, we describe for the first time the specific dual roles of astrocytes in neuronal plasticity and reconstruction, including neurogenesis, synaptogenesis, angiogenesis, repair of the blood-brain barrier, and glial scar formation after TBI. We have also classified astrocyte-derived factors depending on their neuroprotective and neurotoxic roles to design more appropriate targeted therapies.

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“…In closed head injury paradigms, apoE −/− mice have decreased levels of antioxidant compounds (Lomnitski et al, 1999a; Lomnitski et al, 1997) and impaired functional recovery and neuronal loss (Chen et al, 1997a; Han and Chung, 2000). Notably, treatment with exogenous apoE decrease the anatomical and functional deficits in the animal models of several neurological diseases, such as ischemic stroke (Horsburgh et al, 2000; Tu et al, 2017), of Alzheimer's disease (Sarantseva et al, 2009), traumatic brain injury (Wang et al, 2007; Lynch et al, 2005; Laskowitz et al, 2010; Kaufman et al, 2010; Hoane et al, 2009; Laskowitz et al, 2017; Cao et al, 2016), or EAE (Li et al, 2006). These studies suggest that apoE plays important roles in neuroprotection after neurological diseases and injuries.…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

Cheng

Zheng

et al. 2018

Experimental Neurology

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Apolipoprotein E (apoE), a plasma lipoprotein well known for its important role in lipid and cholesterol metabolism, has also been implicated in many neurological diseases. In this study, we examined the effect of apoE on the pathophysiology of traumatic spinal cord injury (SCI). ApoE-deficient mutant (apoE−/−) and wild-type mice received a T9 moderate contusion SCI and were evaluated using histological and behavioral analyses after injury. At 3 days after injury, the permeability of spinal cord-blood-barrier, measured by extravasation of Evans blue dye, was significantly increased in apoE−/− mice compared to wild type. The inflammation and spared white matter was also significantly increased and decreased, respectively, in apoE−/− mice compared to the wild type ones. The apoptosis of both neurons and oligodendrocytes was also significantly increased in apoE−/− mice. At 42 days after injury, the inflammation was still robust in the injured spinal cord in apoE−/− but not wild type mice. CD45+ leukocytes from peripheral blood persisted in the injured spinal cord of apoE−/− mice. The spared white matter was significantly decreased in apoE−/− mice compared to wild type ones. Locomotor function was significantly decreased in apoE−/− mice compared to wild type ones from week 1 to week 8 after contusion. Treatment of exogenous apoE mimetic peptides partially restored the permeability of spinal cord-blood-barrier in apoE−/− mice after SCI. Importantly, the exogenous apoE peptides decreased inflammation, increased spared white matter and promoted locomotor recovery in apoE−/− mice after SCI. Our results indicate that endogenous apoE plays important roles in maintaining the spinal cord-blood-barrier and decreasing inflammation and spinal cord tissue loss after SCI, suggesting its important neuroprotective function after SCI. Our results further suggest that exogenous apoE mimetic peptides could be a novel and promising neuroprotective reagent for SCI.

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Apolipoprotein E-Mimetic COG1410 Reduces Acute Vasogenic Edema following Traumatic Brain Injury

Cited by 57 publications

References 47 publications

The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis

The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

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