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Pilitsis, Julie G.; Díaz, Fernando G.; Wellwood, Jody; O’Regan, Michael H.; Fairfax, Marilynn R.; Phillis, John W.; Coplin, William M.

doi:10.1023/a:1014227231130

Cited by 33 publications

(10 citation statements)

References 30 publications

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“…Further supporting reports demonstrated that in traumatic brain injury, free fatty acid (FFA) levels increase significantly in the cerebrospinal fluid (CSF), and are recognized as markers of brain injury. In particular, the concentration of palmitate almost doubled as compared to control, above 1100 μg/L in the CSF of traumatic brain injury versus around 600 μg/L in control (Pilitsis et al, 2003; Pilitsis et al, 2001; Zamir et al, 1991). FFAs in plasma can cross the blood-brain barrier (Dhopeshwarkar and Mead, 1973; Smith and Nagura, 2001), and high fat diets increase the uptake of fatty acids by the brain from the plasma (Karmi et al, 2010; Wang et al, 1994).…”

Section: Discussionmentioning

confidence: 86%

Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes

Liu

Martin

Kohler

et al. 2013

Experimental Neurology

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Deregulation of calcium has been implicated in neurodegenerative diseases, including Alzheimer’s disease (AD). Previously, we showed that saturated free-fatty acid, palmitate, causes AD-like changes in primary cortical neurons mediated by astrocytes. However, the molecular mechanisms by which conditioned media from astrocytes cultured in palmitate induces AD-like changes in neurons are unknown. This study demonstrates that this condition media from astrocytes elevates calcium level in the neurons, which subsequently increases calpain activity, a calcium-dependent protease, leading to enhance p25/Cdk5 activity and phosphorylation and activation of the STAT3 (signal transducer and activator of transcription) transcription factor. Inhibiting calpain or Cdk5 significantly reduces the upregulation in nuclear level of pSTAT3, which we found to transcriptionally regulate both BACE1 and presenilin-1, the latter is a catalytic subunit of γ-secretase. Decreasing pSTAT3 levels reduced the mRNA levels of both BACE1 and presenilin-1 to near control levels. These data demonstrate a signal pathway leading to the activation of STAT3, and the generation of the amyloid peptide. Thus, our results suggest that STAT3 is an important potential therapeutic target of AD pathogenesis.

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Section: Discussionmentioning

confidence: 86%

Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes

Liu

Martin

Kohler

et al. 2013

Experimental Neurology

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“…69 FFA increases have also been observed in the rat brain following CCI 21 as well as in the CSF of TBI patients. 70,71 An increase in FFAs is known to accompany cellular injury events such as uncoupling of oxidative phosphorylation, exacerbating the disruption of ion balance and aggregation of oxidative metabolites. 72 The disruption of calcium ion homeostasis in combination with energy depletion in the brain following injury leads to the activation of phospholipases A 2 and C, which causes the release of FFAs from membrane phospholipids.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Lipidome Alterations Following Traumatic Brain Injury via High-Resolution Metabolomics

et al. 2018

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Traumatic brain injury (TBI) can occur across wide segments of the population, presenting in a heterogeneous manner that makes diagnosis inconsistent and management challenging. Biomarkers offer the potential to objectively identify injury status, severity, and phenotype by measuring the relative concentrations of endogenous molecules in readily accessible biofluids. Through a data-driven, discovery approach, novel biomarker candidates for TBI were identified in the serum lipidome of adult male Sprague-Dawley rats in the first week following moderate controlled cortical impact (CCI). Serum samples were analyzed in positive and negative modes by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). A predictive panel for the classification of injured and uninjured sera samples, consisting of 26 dysregulated species belonging to a variety of lipid classes, was developed with a cross-validated accuracy of 85.3% using omniClassifier software to optimize feature selection. Polyunsaturated fatty acids (PUFAs) and PUFA-containing diacylglycerols were found to be upregulated in sera from injured rats, while changes in sphingolipids and other membrane phospholipids were also observed, many of which map to known secondary injury pathways. Overall, the identified biomarker panel offers viable molecular candidates representing lipids that may readily cross the blood-brain barrier (BBB) and aid in the understanding of TBI pathophysiology.

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“…Alternatively, Hashimoto and colleagues suggested that DHA’s effects on Aβ oligomerization might be independent of micelle formation (since they occur below critical micelle concentration) and revolve around the disruption of hydrophobic intra- and inter-chain amino acid interactions (Hashimoto et al, 2009; Hashimoto et al, 2008; Hossain et al, 2009). However, directly extrapolating these in vitro findings to in vivo settings remains challenging given that the free DHA concentrations necessary to modulate Aβ aggregation in vitro (10 μM to 50 μM) (Hashimoto et al, 2009; Hashimoto et al, 2008; Hossain et al, 2009; Johansson et al, 2007) are far higher than those measured from human CSF (185 nM; Pilitsis et al, 2001). …”

Section: Discussionmentioning

confidence: 99%

Dietary DHA supplementation in an APP/PS1 transgenic rat model of AD reduces behavioral and Aβ pathology and modulates Aβ oligomerization

Teng

Taylor

Bilousova

et al. 2015

Neurobiology of Disease

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Increased dietary consumption of docosahexaenoic acid (DHA) is associated with decreased risk for Alzheimer’s disease (AD). These effects have been postulated to arise from DHA’s pleiotropic effects on AD pathophysiology, including its effects on β-amyloid (Aβ) production, aggregation, and toxicity. While in vitro studies suggest DHA may inhibit and reverse the formation of toxic Aβ oligomers, it remains uncertain whether these mechanisms operate in vivo at the physiological concentrations of DHA attainable through dietary supplementation. We sought to clarify the effects of dietary DHA supplementation on Aβ indices in a transgenic APP/PS1 rat model of AD. Animals maintained on a DHA-supplemented diet exhibited reductions in hippocampal Aβ plaque density and modest improvements on behavioral testing relative to those maintained on a DHA-depleted diet. However, DHA supplementation also increased overall soluble Aβ oligomer levels in the hippocampus. Further quantification of specific conformational populations of Aβ oligomers indicated that DHA supplementation increased fibrillar (i.e. putatively less toxic) Aβ oligomers and decreased prefibrillar (i.e. putatively more toxic) Aβ oligomers. These results provide in vivo evidence suggesting that DHA can modulate Aβ aggregation by stabilizing soluble fibrillar Aβ oligomers and thus reduce the formation of both Aβ plaques and prefibrillar Aβ oligomers. However, since fibrillar Aβ oligomers still retain inherent neurotoxicity, DHA may need to be combined with other interventions that can additionally reduce fibrillar Aβ oligomer levels for more effective prevention of AD in clinical settings.

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Cited by 33 publications

References 30 publications

Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes

Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes

Discovery of Lipidome Alterations Following Traumatic Brain Injury via High-Resolution Metabolomics

Dietary DHA supplementation in an APP/PS1 transgenic rat model of AD reduces behavioral and Aβ pathology and modulates Aβ oligomerization

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