Tau hyperphosphorylation and increased BACE1 and RAGE levels in the cortex of PPARβ/δ-null mice

Barroso, Emma; Valle, Jaume del; Porquet, David; Santos, Ana M. Vieira; Salvadó, Laia; Rodríguez‐Rodríguez, Rosalía; Gutiérrez, Patrícia; Anglada-Huguet, Marta; Alberch, Jordi; Camins, Antoni; Palomer, Xavier; Pallàs, Mercè; Michalik, Liliane; Wahli, Walter; Vázquez‐Carrera, Manuel

doi:10.1016/j.bbadis.2013.03.006

Cited by 39 publications

(24 citation statements)

References 54 publications

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“…In vitro study discovered that ERK1/ 2 phosphorylation activates RAGE signal via its enhancing the combination with RAGE ligands S100B-or AGEs, as Ab-induced signal transduction in glial cells (Slowik et al 2012). Additional research discovered that tau hyperphosphorylation at Ser199 and enhanced levels of PHF-tau were associated with increased levels of the tau kinases CDK5 and phospho-ERK1/2 (Barroso et al 2013).…”

Section: Rage/erk1/2 Signalingmentioning

confidence: 96%

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Role of RAGE in Alzheimer’s Disease

et al. 2015

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Receptor for advanced glycation end products (RAGE) is a receptor of the immunoglobulin super family that plays various important roles under physiological and pathological conditions. Compelling evidence suggests that RAGE acts as both an inflammatory intermediary and a critical inducer of oxidative stress, underlying RAGE-induced Alzheimer-like pathophysiological changes that drive the process of Alzheimer's disease (AD). A critical role of RAGE in AD includes beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangles, failure of synaptic transmission, and neuronal degeneration. The steady-state level of Aβ depends on the balance between production and clearance. RAGE plays an important role in the Aβ clearance. RAGE acts as an important transporter via regulating influx of circulating Aβ into brain, whereas the efflux of brain-derived Aβ into the circulation via BBB is implemented by LRP1. RAGE could be an important contributor to Aβ generation via enhancing the activity of β- and/or γ-secretases and activating inflammatory response and oxidative stress. However, sRAGE-Aβ interactions could inhibit Aβ neurotoxicity and promote Aβ clearance from brain. Meanwhile, RAGE could be a promoting factor for the synaptic dysfunction and neuronal circuit dysfunction which are both the material structure of cognition, and the physiological and pathological basis of cognition. In addition, RAGE could be a trigger for the pathogenesis of Aβ and tau hyper-phosphorylation which both participate in the process of cognitive impairment. Preclinical and clinical studies have supported that RAGE inhibitors could be useful in the treatment of AD. Thus, an effective measure to inhibit RAGE may be a novel drug target in AD.

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Section: Rage/erk1/2 Signalingmentioning

confidence: 96%

“…Hyperphosphorylated tau and increased RAGE levels have also been detected in the cortex of PPARb/d (peroxisome proliferator-activated receptors b and d) knockout mice (Barroso et al 2013). Therefore, it is expected that the inhibition of RAGE can bring beneficial effects to patients suffering from AD.…”

Section: Rage:a Mediator Role Of Tau Hyperphosphorylation?mentioning

confidence: 97%

Role of RAGE in Alzheimer’s Disease

et al. 2015

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“…PPARδ deficient mice are viable but show several defects in normal CNS biology and exhibit augmented inflammatory reactions. Specifically, PPARδ deficient mice show altered myelination (Peters et al, 2000) and impaired performance in memory tests with associated increases in inflammatory markers, astrogliosis and tau hyperphosphorylation (Barroso et al, 2013). PPARδ deficient mice show increased vulnerability to ischemic insults (Arsenijevic et al, 2006; Pialat et al, 2007) due to defects in antioxidant responses (Arsenijevic et al, 2006).…”

Section: Pparδmentioning

confidence: 99%

“…The protection elicited by PPARδ activation has several possible underlying mechanisms. PPARδ interferes with NFκB signaling, thus leading to a dampened inflammatory milieu and decreased oxidative stress (Paterniti et al, 2010; Barroso et al, 2013). PPARδ activation has been shown to decrease intracellular calcium concentration and reduce ROS production in vitro (Jin et al, 2012).…”

Section: Pparδmentioning

confidence: 99%

Nuclear receptors in neurodegenerative diseases

Skerrett

Malm

Landreth

2014

Neurobiology of Disease

101

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Nuclear receptors have generated substantial interest in the past decade as potential therapeutic targets for the treatment of neurodegenerative disorders. Despite years of effort, effective treatments for progressive neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and ALS remain elusive, making non-classical drug targets such as nuclear receptors an attractive alternative. A substantial literature in mouse models of disease and several clinical trials have investigated the role of nuclear receptors in various neurodegenerative disorders, most prominently AD. These studies have met with mixed results, yet the majority of studies in mouse models report positive outcomes. The mechanisms by which nuclear receptor agonists affect disease pathology remain unclear. Deciphering the complex signaling underlying nuclear receptor action in neurodegenerative diseases is essential for understanding this variability in preclinical studies, and for the successful translation of nuclear receptor agonists into clinical therapies.

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“…[7][8][9] However, there is less information about the role and mechanism of PPARβ/δ in SAH. It is reported that PPARβ/δ may play a role in brain protection by regulating nuclear factor-κB (NF-κB) or matrix metalloproteinase-9 (MMP-9) expression in cerebral ischemia, spinal cord injury, and Parkinson's disease.…”

mentioning

confidence: 99%

Peroxisome Proliferator–Activated Receptor β/δ Alleviates Early Brain Injury After Subarachnoid Hemorrhage in Rats

Teng

Jiang

et al. 2016

Stroke

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S ubarachnoid hemorrhage (SAH) is a devastating disease with high mortality and disability. Traditionally, cerebral vasospasm, which develops in large cerebral arteries 3 to 7 days after SAH, was considered the most crucial cause of serious consequences after SAH. However, recent studies have shown that there is little advance in improving the outcome of SAH by prevention of vasospasm. It is reported that 12% of SAH patients die before receiving medical attention and 33% within 48 hours of SAH and 50% survivors havepermanent disability.1 The primary determinant of poor outcome in SAH patients was proposed to be early brain injury (EBI).2,3 EBI was described as the immediate injury of the brain after SAH, including elevation of intracranial pressure, disruption of bloodbrain barrier (BBB), neuronal cell death, brain edema, and other pathophysiologic changes. 4,5 Several recent studies have indicated apoptosis might play an important role in the pathogenesis of EBI after SAH. 6Background and Purpose-Early brain injury is proposed to be the primary cause of the poor outcome after subarachnoid hemorrhage (SAH), which is closely related to the neural apoptosis. To date, the relationship between peroxisome proliferator-activated receptor β/δ (PPARβ/δ) and nuclear factor-κB/matrix metalloproteinase-9 (NF-κB/MMP-9) pathway, both of which are closely related to apoptotic effects, has been poorly studied in SAH. The present study was undertaken to evaluate the effects of PPARβ/δ on early brain injury and NF-κB/MMP-9 pathway after SAH in rats. Methods-SAH model was established by injecting nonheparinized autologous arterial blood into the prechiasmatic cistern in male Sprague-Dawley rats. Adenoviruses or small interfering RNAs were injected into the right lateral cerebral ventricle to, respectively, up-or downregulate PPARβ/δ expression before SAH. All animals were assessed with a neurological score and then killed at 24 hours after SAH surgery. The indexes of brain water content, blood-brain barrier permeability, and apoptosis were used to detect brain injury. The expression of PPARβ/δ, NF-κB, and MMP-9 were measured by immunohistochemistry, gelatin zymography, and Western Blot methods, respectively. In addition, GW0742, a specific agonist of PPARβ/δ, was used to treat SAH in rats, the effects of which were evaluated by neurological scoring and Evans blue extravasation. Results-Overexpression of PPARβ/δ by adenoviruses treatment significantly ameliorated brain injury with improvement in neurological deficits, brain edema, blood-brain barrier impairment, and neural cell apoptosis at 24 hours after SAH in rats, whereas downregulation of PPARβ/δ by small interfering RNAs administration resulted in the reverse effects of the above. The expression levels of NF-κB and MMP-9 were markedly downregulated when PPARβ/δ increased after PPARβ/δ adenovirus transfection and upregulated when PPARβ/δ decreased by PPARβ/δ small interfering RNAs treatment. Moreover, GW0742 improved neurological deficits and reduced Evans blue extravasation ...

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Tau hyperphosphorylation and increased BACE1 and RAGE levels in the cortex of PPARβ/δ-null mice

Cited by 39 publications

References 54 publications

Role of RAGE in Alzheimer’s Disease

Role of RAGE in Alzheimer’s Disease

Nuclear receptors in neurodegenerative diseases

Peroxisome Proliferator–Activated Receptor β/δ Alleviates Early Brain Injury After Subarachnoid Hemorrhage in Rats

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