Brainstem Concentrations of Cholesterol are not Influenced by Genetic Ablation of the Low-Density Lipoprotein Receptor

Taha, Ameer Y.; Chen, Chuck T.; Liu, Zhen; Kim, Jung Hyun; Mount, Howard T.J.; Bazinet, Richard P.

doi:10.1007/s11064-008-9777-7

Cited by 11 publications

(11 citation statements)

References 23 publications

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“…Although LDLR deficiency significantly increased murine brain apoE levels by ~50%, it did not alter brain cholesterol levels (Elder et al, 2007; Fryer et al, 2005; Quan et al, 2003; Taha et al, 2008). Previously, we demonstrated that there was no significant change in brain Aβ levels both before and after the onset of amyloid deposition in PDAPP transgenic mice on a LDLR-deficient background (Fryer et al, 2005).…”

Section: Discussionmentioning

confidence: 88%

Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance

Kim

Castellano

Jiang

et al. 2009

Neuron

230

231

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Summary Apolipoprotein E (APOE) is the strongest genetic risk factor for Alzheimer’s disease (AD). Previous studies suggest that the effect of apoE on amyloid-β (Aβ) accumulation plays a major role in AD pathogenesis. Therefore, understanding proteins that control apoE metabolism may provide new targets for regulating Aβ levels. LDLR, a member of the LDL receptor family, binds to apoE, yet its potential role in AD pathogenesis remains unclear. We hypothesized that LDLR overexpression in the brain would decrease apoE levels, enhance Aβ clearance and decrease Aβ deposition. To test our hypothesis, we created several transgenic mice that overexpress LDLR in the brain and found that apoE levels in these mice decreased by 50–90%. Furthermore, LDLR overexpression dramatically reduced Aβ aggregation and enhanced Aβ clearance from the brain extracellular space. Plaque-associated neuroinflammatory responses were attenuated in LDLR transgenic mice. These findings suggest that increasing LDLR levels may represent a novel AD treatment strategy.

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Section: Discussionmentioning

confidence: 88%

Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance

Kim

Castellano

Jiang

et al. 2009

Neuron

230

231

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“…Although cholesterol crystals were observed in the white matter of the control tissue, the IR results suggest that this fraction is significant in the white matter of mice with atherosclerosis. [42][43][44] The observed changes in the lipid fraction of the brains of 6-month-old atherosclerotic mice on a standard diet could be connected to the use of the ApoE/LDLR −/− mouse model, which demonstrates severe hypercholesterolemia (>500 mg dL −1 ) and the development of advanced atherosclerotic lesions. It has an important role in the normal development and function of the nervous system, as it is one of the components of the myelin sheath.…”

Section: Discussionmentioning

confidence: 99%

IR and Raman imaging of murine brains from control and ApoE/LDLR^−/−mice with advanced atherosclerosis

Kochan

Chrabąszcz

Szczur

et al. 2016

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Confocal Raman mapping and FT-IR imaging combined with chemometric analysis was used to study the alterations in murine brain tissue induced by the development of atherosclerosis. FT-IR imaging allowed us to obtain lower spatial resolution data (∼5.5 μm) from large, representative cross-sectional brain areas, while Raman mapping provided a more detailed insight into chosen regions of interest with high spatial resolution (∼0.4 μm). A comparison of white (WM) and grey matter (GM) from control (C57BL/6J) and ApoE/LDLR(-/-) mice with advanced atherosclerosis revealed disease-induced changes in both: GM and WM. The alterations included an increased lipid to protein ratio and higher total content of cholesterol.

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“…The absence of LDL-R also is related with decreased pre-synaptic bouton density in the hippocampus (Mulder et al 1993), as well as increased locomotor activity (Elder et al 2008). This receptor is found throughout the brain, and although highly enriched in the brainstem, no significant changes in cholesterol content was observed in this region of LDL-R À/À mice (Taha et al 2009).…”

mentioning

confidence: 96%

“…This receptor is found throughout the brain, and although highly enriched in the brainstem, no significant changes in cholesterol content was observed in this region of LDL‐R −/− mice (Taha et al . ).…”

mentioning

confidence: 97%

Brain region‐specific immunolocalization of the lipolysis‐stimulated lipoprotein receptor (LSR) and altered cholesterol distribution in aged LSR^+/− mice

Stenger

Pinçon

Hanse

et al. 2012

Journal of Neurochemistry

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Brain lipid homeostasis is important for maintenance of brain cell function and synaptic communications, and is intimately linked to age-related cognitive decline. Because of the bloodbrain barrier's limiting nature, this tissue relies on a complex system for the synthesis and receptor-mediated uptake of lipids between the different networks of neurons and glial cells. Using immunofluorescence, we describe the region-specific expression of the lipolysis-stimulated lipoprotein receptor (LSR), in the mouse hippocampus, cerebellum Purkinje cells, the ependymal cell interface between brain parenchyma and cerebrospinal fluid, and the choroid plexus. Colocalization with cell-specific markers revealed that LSR was expressed in neurons, but not astrocytes. Age-related cognitive decline associated with higher risk of neurodegenerative disorders has become an important public concern as life expectancy increases in industrially developed countries. Although the molecular mechanisms underlying the decrease in memory and other brain-related functions with age are under active investigation, the processes Address correspondence and reprint requests to Frances T. Yen, Lipidomix, Université de Lorraine, ENSAIA, 2 avenue de la Forêt de Haye, 54501 Vandoeuvre-lès-Nancy, France. E-mail: frances.yen-potin@univ-lorraine.fr 1 CS and AP contributed equally to this work.Abbreviations used: BBB, blood-brain barrier; FFA, free fatty acid; GFAP, glial fibrillary acidic protein; LDL-R, low-density lipoprotein receptor; LpL, lipoprotein lipase; LRP1, low-density lipoprotein receptor-related protein 1; LSR, lipolysis-stimulated lipoprotein receptor; NeuN, neuronal nuclei; PBS, phosphate-buffered saline; PFA, paraformaldehyde. Journal of Neurochemistry

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Brainstem Concentrations of Cholesterol are not Influenced by Genetic Ablation of the Low-Density Lipoprotein Receptor

Abstract: The LDLr is not necessary for maintaining cholesterol concentrations in the cortex or brainstem, suggesting that other mechanisms are sufficient to maintain brain cholesterol concentrations.

Cited by 11 publications

References 23 publications

Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance

Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance

IR and Raman imaging of murine brains from control and ApoE/LDLR^−/−mice with advanced atherosclerosis

Brain region‐specific immunolocalization of the lipolysis‐stimulated lipoprotein receptor (LSR) and altered cholesterol distribution in aged LSR^+/− mice

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Brainstem Concentrations of Cholesterol are not Influenced by Genetic Ablation of the Low-Density Lipoprotein Receptor

Abstract: The LDLr is not necessary for maintaining cholesterol concentrations in the cortex or brainstem, suggesting that other mechanisms are sufficient to maintain brain cholesterol concentrations.

Cited by 11 publications

References 23 publications

Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance

Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance

IR and Raman imaging of murine brains from control and ApoE/LDLR−/−mice with advanced atherosclerosis

Brain region‐specific immunolocalization of the lipolysis‐stimulated lipoprotein receptor (LSR) and altered cholesterol distribution in aged LSR+/− mice

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Product

Resources

About

IR and Raman imaging of murine brains from control and ApoE/LDLR^−/−mice with advanced atherosclerosis

Brain region‐specific immunolocalization of the lipolysis‐stimulated lipoprotein receptor (LSR) and altered cholesterol distribution in aged LSR^+/− mice