Nec‐1 alleviates cognitive impairment with reduction of Aβ and tau abnormalities in<scp>APP</scp>/<scp>PS</scp>1 mice

Yang, Seung‐Hoon; Lee, Dongkeun Kenneth; Shin, Jisu; Lee, Se-Jin; Baek, Seungyeop; Kim, Jiyoon; Jung, Hoyong; Hah, Jung Mi; Kim, Young Soo

doi:10.15252/emmm.201606566

Cited by 132 publications

(92 citation statements)

References 70 publications

(85 reference statements)

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“…In conclusion, we have demonstrated that RGC death signaling pathways are active in a regionspecific manner after blunt ocular injury, with necroptotic-dependent mechanisms likely driving a reduction in RGC numbers at the center of the impact site. The inhibition of necroptosis using pharmacological inhibitor, Nec-1s, preserved the number of RBPMS + and BRN3A + RGC compared to In line with our findings, RGC are also protected by the inhibition of necroptosis in other models of RGC death, including glaucoma [62] and retinal ischemia-reperfusion injury [63], and other models of neuronal disease and degeneration, including amyotrophic lateral sclerosis [64][65][66], Alzheimer's disease [26], Niemann-Pick disease [67], traumatic brain injury [28] and spinal cord injury [27]. The abundance of studies across multiple disease indicates the importance of necroptotic signaling in driving neuronal cell death.…”

Section: Discussionsupporting

confidence: 88%

“…RIPK1 expression is elevated in a rat intracerebral hemorrhage model and its inhibition or genetic knockdown reduces brain injury severity [25]. Further, in a mouse model of Alzheimer's disease (APP/PS1 mice) treatment with necroptosis inhibitor Necrostatin-1 (Nec-1) reduces cognitive impairments, β-amyloid and tau abnormalities [26]. Nec-1 also improves histopathology and function in models of traumatic brain and spinal cord injury [27,28].…”

Section: Introductionmentioning

confidence: 99%

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Retinal Ganglion Cells Die by Necroptotic Mechanisms in a Site-Specific Manner in a Rat Blunt Ocular Injury Model

Thomas

Thompson

Ahmed

2019

Cells

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Closed-globe injury can cause visual loss in military and civilian populations, with retinal cell death, including retinal ganglion cell (RGC) degeneration, leading to irreversible blindness. RGC and optic nerve (ON) degeneration after eye or head injury is termed traumatic optic neuropathy (TON). There are currently no treatments for RGC loss, therefore novel therapeutics to prevent RGC death or promote axonal regeneration are a priority. We investigated necroptotic signaling mechanisms in a rat blunt ocular injury model. After bilateral blunt trauma, protein expression and retinal localization of necroptosis pathway members (receptor interacting protein kinase 1, RIPK1; receptor interacting protein kinase 3, RIPK3; and mixed lineage kinase domain like pseudokinase, MLKL) were assessed by Western blot and immunohistochemistry (IHC), and potent necroptosis inhibitor Necrostatin-1s (Nec-1s) was delivered by intravitreal injection to one eye and vehicle to the contralateral eye. RGC and photoreceptor survival were assessed by cell counting and outer nuclear layer (ONL) thickness measurements on histology. The neuroprotective effects of Nec-1s were assessed in primary retinal culture by βIII-tubulin+ RGC cell counts. MLKL protein expression were upregulated at 48 h after injury and MLKL immunolocalised to retinal binding protein with multiple splice (RBPMS)+ RGC, inner nuclear cells and ONL cells, specifically at the retinal injury site. RIPK3 expression did not increase but RIPK3 co-immunolocalised with RBPMS+ RGC in intact and injured retinae. In vitro, a Nec-1s concentration of 0.01 pg/µL was RGC neuroprotective. In the blunt ocular injury rat model, Nec-1s prevented RGC death at the center of the impact site but did not protect against ONL thinning or provide functional restitution. RGC degeneration in our blunt ocular injury model is site-specific, with necroptosis driving death at the center of the focal impact site.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Retinal Ganglion Cells Die by Necroptotic Mechanisms in a Site-Specific Manner in a Rat Blunt Ocular Injury Model

Thomas

Thompson

Ahmed

2019

Cells

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“…47 Moreover, bimolecular binding between RIP kinase and A β was observed. 47 Interaction between these two proteins in the extracellular and luminal regions might be involved in A β -related cell death pathology in AD and therefore might serve as a potential drug target for the disease.…”

Section: Alzheimer's Diseasementioning

confidence: 98%

Necroptosis in neurodegenerative diseases: a potential therapeutic target

et al. 2017

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Neurodegenerative diseases are a group of chronic progressive disorders characterized by neuronal loss. Necroptosis, a recently discovered form of programmed cell death, is a cell death mechanism that has necrosis-like morphological characteristics. Necroptosis activation relies on the receptor-interacting protein (RIP) homology interaction motif (RHIM). A variety of RHIM-containing proteins transduce necroptotic signals from the cell trigger to the cell death mediators RIP3 and mixed lineage kinase domain-like protein (MLKL). RIP1 plays a particularly important and complex role in necroptotic cell death regulation ranging from cell death activation to inhibition, and these functions are often cell type and context dependent. Increasing evidence suggests that necroptosis plays an important role in the pathogenesis of neurodegenerative diseases. Moreover, small molecules such as necrostatin-1 are thought inhibit necroptotic signaling pathway. Understanding the precise mechanisms underlying necroptosis and its interactions with other cell death pathways in neurodegenerative diseases could provide significant therapeutic insights. The present review is aimed at summarizing the molecular mechanisms of necroptosis and highlighting the emerging evidence on necroptosis as a major driver of neuron cell death in neurodegenerative diseases.

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“…The stock solution was diluted 40 times with sterile PBS before use in order to obtain 2.5% DMSO and 0.625 μg/μl necrostatin-1. Subsequently, necrostatin-1 was administered by intraperitoneal injection (6.25 mg/kg) during the stress period, once every 3 days ( Yang et al, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

Inhibiting RIP1 Improves Chronic Stress-Induced Cognitive Impairments in D-Galactose-Induced Aging Mice

Wang

et al. 2018

Front. Behav. Neurosci.

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Mounting evidence shows that chronic stress can affect both the structure and function of the brain resulting in decreased synaptic plasticity and cognitive dysfunction. Although several studies have indicated that aged brains are more vulnerable to chronic stress, it remains unknown how to prevent stress-induced memory deficits in aged animals. Neuroinflammation plays an important role in the pathogenesis of chronic stress-related brain dysfunction. Receptor-interacting protein 1 (RIP1) is a key molecule that can modulate inflammation, apoptosis, and necroptosis. Here, we investigated whether inhibiting RIP1 using necrostatin-1 during chronic stress could improve chronic stress-related brain dysfunction in D-galactose-induced aging mice. The stressed mice underwent restraint stress for 14 days. Necrostatin-1 (6.25 mg/kg) or vehicle was administered intraperitoneally once every 3 days during the stress period. Locomotor activity was tested using the open field test and cognitive function was assessed using the novel object recognition and Barnes maze tests. The hippocampus was collected to assess neuroinflammation (Iba1, IL-1α, IL-1β, TNF-α, and C1q), necroptosis [RIP1, RIP3, mixed lineage kinase domain-like (MLKL), and NF-κB], neuroplasticity (doublecortin, NR1, NR2A, NR2B, GluA1, and GluA2), and the expression of glucocorticoid and mineralocorticoid receptors. Blood samples were collected to quantify the levels of corticosterone. We found that chronic stress induced obvious memory impairment and neuroinflammation, decreased neurogenesis and GluA2 expression, and increased the expression of RIP1 and NF-κB. Inhibiting RIP1 by necrostatin-1 during chronic stress rescued the memory impairment and alleviated the pathological changes induced by stress. These suggest that inhibiting RIP1 using necrostatin-1 improves chronic stress-related brain dysfunction in D-galactose-induced aging mice. The potential mechanisms include limitation of neuroinflammation and the rescue of neurogenesis and GluA2 expression.

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Nec‐1 alleviates cognitive impairment with reduction of Aβ and tau abnormalities inAPP/PS1 mice

Cited by 132 publications

References 70 publications

Retinal Ganglion Cells Die by Necroptotic Mechanisms in a Site-Specific Manner in a Rat Blunt Ocular Injury Model

Retinal Ganglion Cells Die by Necroptotic Mechanisms in a Site-Specific Manner in a Rat Blunt Ocular Injury Model

Necroptosis in neurodegenerative diseases: a potential therapeutic target

Inhibiting RIP1 Improves Chronic Stress-Induced Cognitive Impairments in D-Galactose-Induced Aging Mice

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