Cerebrovascular degradation of TRKB by MMP9 in the diabetic brain

Navaratna, Deepti; Fan, Xiang; Leung, Wendy; Lok, Josephine; Guo, Shuzhen; Xing, Chao; Wang, Xiaoying; Lo, Eng H.

doi:10.1172/jci65767

Cited by 29 publications

(23 citation statements)

References 15 publications

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“…In the normal state, retinal endothelial cells secret BDNF to support RGC, whereas the secretion of MMP9 is suppressed. Navaratna et al (50,51) revealed that endothelial cells of diabetic rats express decreased BDNF levels and increased MMP9 protein. Abnormal expression of MMP9 is associated with glaucomatous alterations (52).…”

Section: Discussionmentioning

confidence: 99%

The effects of endothelium‐specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model

et al. 2019

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Glaucoma is a leading cause of irreversible blindness worldwide. Vascular factors play a substantial role in the pathogenesis of glaucoma. Expressed in the vascular endothelium, cytochrome P450 (CYP) 2J2 is one of the CYP epoxygenases that metabolize arachidonic acid to produce epoxyeicosatrienoic acids and exert pleiotropic protective effects on the vasculature. In the present study, we investigated whether endothelium‐specific over‐expression of CYP2J2 (tie2‐CYP2J2‐Tr) protects against retinal ganglion cell (RGC) loss induced by glaucoma and in what way retinal vessels are involved in this process. We used a glaucoma model of retinal ischemia‐reperfusion (I/R) injury in rats and found that endothelium‐specific overexpression of CYP2J2 attenuated RGC loss induced by retinal I/R. Moreover, retinal I/R triggered retinal vascular senescence, indicated by up‐regulated senescence‐related proteins p53, p16, and β‐galactosidase activity. The senescent endothelial cells resulted in pericyte loss and increased endothelial secretion of matrix metallopeptidase 9, which further contributed to RGC loss. CYP2J2 overexpression alleviated vascular senescence, pericyte loss, and matrix metallopeptidase 9 secretion. CYP2J2 suppressed endothelial senescence by down‐regulating senescence‐associated proteins p53 and p16. These 2 proteins were positively regulated by microRNA‐128‐3p, which was inhibited by CYP2J2. These results suggest that CYP2J2 protects against endothelial senescence and RGC loss in glaucoma, a discovery that may lead to the development of a potential treatment strategy for glaucoma.—Huang, J., Zhao, Q., Li, M., Duan, Q., Zhao, Y., Zhang, H. The effects of endothelium‐specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model. FASEB J. 33, 11194–11209 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

The effects of endothelium‐specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model

et al. 2019

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“…In models of diabetes, advanced glycation end-products lead to MMP9 secretion by endothelial cells and cleavage of the ectodomain of the BDNF receptor TRKB on neurons, reducing neurotrophic signaling (Navaratna et al, 2013). Owing to their trophic support of vascular cells, dysfunction and damage to neurons and glia is associated with endothelial cell atrophy and microvascular rarefaction (Brown and Thore, 2011).…”

Section: Pathogenic Mechanisms Responsible For White Matter Injurymentioning

confidence: 99%

The Pathobiology of Vascular Dementia

Iadecola

2013

Neuron

1,435

1,399

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Vascular cognitive impairment defines alterations in cognition, ranging from subtle deficits to full-blown dementia, attributable to cerebrovascular causes. Often coexisting with Alzheimer’s disease, mixed vascular and neurodegenerative dementia has emerged as the leading cause of age-related cognitive impairment. Central to the disease mechanism is the crucial role that cerebral blood vessels play in brain health, not only for the delivery of oxygen and nutrients, but also for the trophic signaling that links inextricably the well being of neurons and glia to that of cerebrovascular cells. This review will examine how vascular damage disrupts these vital homeostatic interactions, focusing on the hemispheric white matter, a region at heightened risk for vascular damage, and on the interplay between vascular factors and Alzheimer’s disease. Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia.

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“…Antioxidants including vitamin C, free radical scavengers and mimetics of antioxidant enzymes have been shown to attenuate the deleterious effects of high glucose [122]. Exposure of HBMECs to AGEs results in increased MMP9 activation, leading to the degradation of TRKB, a BDNF receptor [123]. Decreased viability of endothelial cells is observed following the silencing of SIRT3, a mitochondrial sirtuin that increases the activities of metabolic enzymes by deacetylation [124].…”

Section: Damage To the Blood Brain Barrier (Bbb)mentioning

confidence: 99%

Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease

Pugazhenthi¹,

Qin²,

Reddy³

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

506

325

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Cognitive decline in chronic diabetic patients is a less investigated topic. Diabetes and obesity are among the modifiable risk factors for Alzheimer's disease (AD), the most common form of dementia. Studies have identified several overlapping neurodegenerative mechanisms, including oxidative stress, mitochondrial dysfunction, and inflammation that are observed in these disorders. Advanced glycation end products generated by chronic hyperglycemia and their receptor RAGE provide critical links between diabetes and AD. Peripheral inflammation observed in obesity leads to insulin resistance and type 2 diabetes. Although the brain is an immune-previleged organ, crosstalks between peripheral and central inflammation have been reported. Damage to the blood brain barrier (BBB) as seen with aging can lead to infiltration of immune cells into the brain, leading to the exacerbation of central inflammation.Neuroinflammation, which has emerged as an important cause of cognitive dysfunction, could provide a central mechanism for aging-associated ailments. To further add to these injuries, adult neurogenesis that provides neuronal plasticity is also impaired in the diabetic brain. This review discusses these molecular mechanisms that link obesity, diabetes and AD.

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Cerebrovascular degradation of TRKB by MMP9 in the diabetic brain

Cited by 29 publications

References 15 publications

The effects of endothelium‐specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model

The effects of endothelium‐specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model

The Pathobiology of Vascular Dementia

Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease

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