The Liver X Receptor Agonist GW3965 Improves Recovery from Mild Repetitive Traumatic Brain Injury in Mice Partly through Apolipoprotein E

Namjoshi, Dhananjay; Martin, Georgina; Donkin, James; Wilkinson, Anna; Stukas, Sophie; Fan, Jianjia; Carr, Michael; Tabarestani, Sanaz; Wuerth, Kelli; Hancock, Robert E. W.; Wellington, Cheryl L.

doi:10.1371/journal.pone.0053529

Cited by 45 publications

(40 citation statements)

References 63 publications

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“…[65][66][67][68][69] Increasing amounts of head movement have also been incorporated, [70][71][72] to more closely approximate human head kinematics following mTBI. 73 As such, WD models are increasingly utilized to model repeated mTBI.…”

Section: Closed-head Models Of Tbimentioning

confidence: 99%

“…241 Following 2 closed-head mTBIs incorporating rotational acceleration, given on consecutive days, the liver X receptor agonist GW3965 improves cognition, axonal integrity, and Ab clearance in an Apolipoprotein E (ApoE)-dependent manner. 67 Preventing tauopathy or decreasing the risk of developing neurodegenerative disease has been attempted using various models and treatment targets. Vitamin E, a potent exogenous antioxidant, was administered for 12 wk to aged transgenic mice, exhibiting Alzheimer's disease-like amyloidosis.…”

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confidence: 99%

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Repeated mild traumatic brain injury: potential mechanisms of damage

2016

Cell Transplant

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Mild traumatic brain injury (mTBI) represents a significant public healthcare concern, accounting for the majority of all head injuries. While symptoms are generally transient, some patients go on to experience long-term cognitive impairments and additional mild impacts can result in exacerbated and persisting negative outcomes. To date, studies using a range of experimental models have reported chronic behavioral deficits in the presence of axonal injury and inflammation following repeated mTBI; assessments of oxidative stress and myelin pathology have thus far been limited. However, some models employed induced acute focal damage more suggestive of moderate-severe brain injury and are therefore not relevant to repeated mTBI. Given that the nature of mechanical loading in TBI is implicated in downstream pathophysiological changes, the mechanisms of damage and chronic consequences of single and repeated closed-head mTBI remain to be fully elucidated. This review covers literature on potential mechanisms of damage following repeated mTBI, integrating known mechanisms of pathology underlying moderate-severe TBIs, with recent studies on adult rodent models relevant to direct impact injuries rather than blast-induced damage. Pathology associated with excitotoxicity and cerebral blood flow-metabolism uncoupling, oxidative stress, cell death, blood-brain barrier dysfunction, astrocyte reactivity, microglial activation, diffuse axonal injury, and dysmyelination is discussed, followed by a summary of functional deficits and preclinical assessments of therapeutic strategies. Comprehensive characterization of the pathology underlying delayed and persisting deficits following repeated mTBI is likely to facilitate further development of therapeutic strategies to limit long-term sequelae.

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Section: Closed-head Models Of Tbimentioning

confidence: 99%

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confidence: 99%

Repeated mild traumatic brain injury: potential mechanisms of damage

2016

Cell Transplant

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“…As apoEcontaining lipoproteins are the major source by which adult neurons acquire the lipids necessary for the maintenance and repair of membranes, it is possible that the impact of LCAT defi ciency may be most evident when apoE is required for lipid transport, such as under acute conditions of neuronal damage. Traumatic brain injury in humans, for example, leads to a signifi cant decrease in CSF apoE levels but not of CSF apoA-I levels ( 57 ), and loss of apoE impairs recovery after traumatic brain injury in mice ( 58 ). Future studies may reveal a role for CNS LCAT to facilitate lipid transport in response to acute neuronal damage.…”

Section: Discussionmentioning

confidence: 99%

LCAT deficiency does not impair amyloid metabolism in APP/PS1 mice

Stukas

Freeman

Lee

et al. 2014

Journal of Lipid Research

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Journal of Lipid Research Volume 55, 20141721 of the apoE4 allele increases risk and decreases the age of onset of late-onset AD ( 2 ), the putative roles of apoE in AD pathogenesis have been a topic of intensive focus. apoE is the primary apolipoprotein secreted by astrocytes and microglia in the CNS, and lipidation of nascent apoEcontaining discoidal particles eventually leads to the formation of mature CNS HDL-like particles in cerebrospinal fl uid (CSF) ( 1, 3 ). It is well-established that amyloid burden in humans follows an isoform-dependent pattern of apoE4>apoE3>apoE2 ( 4-6 ). In contrast to human apoE, murine apoE exists in only one isoform with limited homology to human apoE. Amyloid burden is robust in AD mice expressing murine apoE and nearly abrogated in apoE-defi cient mice ( 7-11 ). Reconstitution of human apoE isoforms into AD mice greatly delays amyloid deposition relative to murine apoE, but retains the human isoform-specifi c infl uence on amyloid accumulation (12)(13)(14)(15)(16)(17). Taken together, the relative amyloid burden across murine and human apoE is: murine apoE>>apoE4>apoE3>apoE2>>apoE Ϫ / Ϫ . These observations clearly show that apoE affects amyloid burden in vivo. In vivo, neither apoE isoform nor gene dose significantly affects the rate of ␤ -amyloid (A ␤ ) production from amyloid precursor protein ( 16,17 ), leading to the consensus that apoE is largely involved in modulating the clearance of A ␤ peptides from the brain. apoE participates in each of the three known pathways of A ␤ clearance, including proteolytic degradation, egress across the blood-brain barrier, and interstitial fl uid drainage, although many details remain poorly understood ( 18,19 ). It is important to note, however, that apoE isoforms, levels, and lipidation status are all important variables.Abstract A key step in plasma HDL maturation from discoidal to spherical particles is the esterifi cation of cholesterol to cholesteryl ester, which is catalyzed by LCAT. HDL-like lipoproteins in cerebrospinal fl uid (CSF) are also spherical, whereas nascent lipoprotein particles secreted from astrocytes are discoidal, suggesting that LCAT may play a similar role in the CNS. In plasma, apoA-I is the main LCAT activator, while in the CNS, it is believed to be apoE. apoE is directly involved in the pathological progression of Alzheimer's disease, including facilitating ␤ -amyloid (A ␤ ) clearance from the brain, a function that requires its lipidation by ABCA1. However, whether apoE particle maturation by LCAT is also required for A ␤ clearance is unknown. Here we characterized the impact of LCAT defi ciency on CNS lipoprotein metabolism and amyloid pathology. Deletion of LCAT from APP/PS1 mice resulted in a pronounced decrease of apoA-I in plasma that was paralleled by decreased apoA-I levels in CSF and brain tissue, whereas apoE levels were unaffected. Furthermore, LCAT defi ciency did not increase A ␤ or amyloid in APP/PS1 LCAT ؊ / ؊ mice. Finally, LCAT expression and plasma activity were unaffected by age or the ons...

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“…The combined sample showed five absorbance peaks at 280 nm by gel-filtration chromatography, and relatively high fluorescence intensities to the elastase substrate were detected in the fractions of peak 2 Absorbance at 280 nm 6 (fractions 20-24) and peak 3 (fractions [25][26][27][28]. Peak 2 showed the highest intensity of 30,293 RFU, peak 3 had an intensity of 7426 RFU, while no fluorescence was observed for peaks 1, 4, and 5 (Fig.…”

Section: Partial Purification Of Elastase-like Activity In the Extracmentioning

confidence: 91%

“…The burden of extracellular Aβ induces an increase in intraneuronal Aβ accumulation [5] that is derived from internalized Aβ by neurons from the extracellular space. This occurs through ApoE-dependent and ApoE-independent pathways [6] and from intrinsic Aβ that escapes exocytosis after APP processing in the endocytic compartment [7].…”

Section: Introductionmentioning

confidence: 99%