Alterations in Apolipoprotein E Expression During Aging and Neurodegeneration

Masliah, Eliezer; Mallory, Margaret; Veinbergs, Isaac; Miller, Aida; Samuel, William

doi:10.1016/s0301-0082(96)00038-x

Cited by 81 publications

(51 citation statements)

References 71 publications

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“…Total RNA (40 g) was hybridized with 32 P-labeled riboprobes. Following RNase digestion, the mRNA-protected 32 P-labeled probes were separated by electrophoresis, and the radioactivity in each band was quantified using a PhosphorImaging system (44). In a third series of experiments, levels of CYP46A1, ATP binding cassette transporter A1 (ABCA1), SR-BI, sterol regulatory element binding protein-1c (SREBP-1c), and SREBP-2 mRNAs were determined by real-time polymerase chain reactions using an Applied Biosystems PRISM 7900HT machine.…”

Section: Measurement Of Mrna Expression In Tissuesmentioning

confidence: 99%

Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration

Xie

Lund

Turley

et al. 2003

Journal of Lipid Research

141

147

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Although the pool of cholesterol in the adult central nervous system (CNS) is large and of constant size, little is known of the process(es) involved in regulation of sterol turnover in this pool. In 7-week-old mice, net excretion of cholesterol from the brain equaled 1.4 mg/day/kg body weight, and from the whole animal was 179 mg/day/kg. Deletion of cholesterol 24-hydroxylase, an enzyme highly expressed in the CNS, did not alter brain growth or myelination, but reduced sterol excretion from the CNS 64% to 0.5 mg/day/kg. In mice with a mutation in the Niemann-Pick C gene that had ongoing neurodegeneration, sterol excretion from the CNS was increased to 2.3 mg/day/kg. Deletion of cholesterol 24-hydroxylase activity in these animals reduced net excretion only 22% to 1. The cells of all extrahepatic tissues outside of the central nervous system (CNS) continuously acquire cholesterol from two sources, de novo synthesis and the uptake of sterol carried in LDLs. In the mouse, as in other species (1), the predominant source for this sterol is de novo synthesis ( ‫ف‬ 100 mg/day/kg body weight), while cellular uptake of LDL cholesterol through the clathrin-coated pit/ lysosomal pathway contributes only a small amount ( ‫ف‬ 5-10 mg/day/kg) to this acquisition process (2-4). Within the cells of these tissues, this newly acquired sterol is transported outwardly to the cell surface, where it apparently continuously replaces cholesterol within the bulk phase and sphingolipid-rich microdomains of the plasma membrane (5, 6). Because the pool of cholesterol in these extrahepatic tissues remains constant ( ‫ف‬ 2,200 mg/kg), each day an amount of sterol equal to that newly acquired must be removed from these cells and carried by lipoproteins back to the liver for excretion from the body as either neutral, i.e., cholesterol or acidic, i.e., bile acid, sterols. While it is not entirely clear why the integrity of these cells depends upon this continuous flow of sterol from the endoplasmic reticulum and lysosomes to the plasma membrane, several lines of evidence suggest this movement may be involved in the regulation of certain proteins and in the function of a number of specific transporters on the cell surface (7-11). Because of this continuous replacement, in a species with a very high metabolic rate like the mouse, ‫ف‬ 7-9% of the total body pool of cholesterol is turned over each day (2, 4).Much less is understood about cholesterol turnover in the brain. As in most of the other extrahepatic organs, sterol in the brain is essentially all unesterified, but unlike in these other tissues, this cholesterol is present in two functionally distinct pools, the plasma membranes of glial and nerve cells, and the multi-layered myelin sheaths elaborated by support cells that surround the processes of neurons. While the concentration of unesterified cholesterol in most organs varies from ‫ف‬ 1.4 mg/g wet weight (muscle) to ‫ف‬ 5.0 mg/g (lung) (2), in the brain, these concentrations vary from ‫ف‬ 8 mg/g (gray matter) to ‫ف‬ 40 mg/g (sp...

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Section: Measurement Of Mrna Expression In Tissuesmentioning

confidence: 99%

Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration

Xie

Lund

Turley

et al. 2003

Journal of Lipid Research

141

147

View full text Add to dashboard Cite

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“…ApoE genotype of the litters were verified by PCR and confirmed by immunoblotting using anti-apoE (1:1000; Calbiochem, San Diego, CA) as described [9]. Two-to four-month-old male KO and WT mice were lesioned as previously described [7,18,24].…”

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confidence: 99%

Impact of apoE deficiency during synaptic remodeling in the mouse olfactory bulb

Nwosu

Gairhe

Struble

et al. 2008

Neuroscience Letters

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In this study we examined the role of apoE on the rate of synaptic recovery in the olfactory bulb (OB) following olfactory epithelium (OE) lesioning in mice. We used both immunoblotting and immunohistochemical techniques to compare the density of OB synaptophysin (Syn, a synaptic marker) in apoE-gene deficient/knockout (KO) mice and wild-type (WT) mice following OE lesion. We found that the whole bulb concentrations of Syn, measured by immunoblotting, declined sharply following injury in both WT and KO mice during the degenerative phase (3-7 days). After this initial decline, the Syn concentration gradually increased to normal levels by 56 days in WT mice. In contrast, Syn concentration in KO mice did not recover by day 56 when Syn density in WT was essentially normal. Glomerular Syn density, measured by immunohistochemistry, found a lower density in KO mice at all time points post lesion. This lower concentration of whole bulb Syn parallels the slower recovery of glomerular area in KO mice. The data indicate that apoE deficiency in KO mice is associated with a delayed recovery of the glomerular area and a slower recovery in Syn concentration in the OB. Keywords apoE; synaptophysin; olfactory bulb; glia; olfactory nerve; glial proteins; transgenic mice Apolipoprotein E (apoE), a lipid transporting protein, is widely expressed in the primary olfactory pathway [6,12,13,23,25]. Previous studies from our laboratories and others have shown apoE expression in the olfactory nerve and around the glomeruli in the OB of adult mice [12,23]. ApoE levels in the OB were two fold higher than normal immediately following OE lesion, and remained elevated over a 3-week period when axons from the newly differentiated olfactory receptor neurons (ORN) grew to reestablish the synaptic connections with cells in the glomeruli [13]. The precise function of apoE in the olfactory system during normal and injury-induced remodeling is unclear; however, studies suggest a role for apoE in the synaptogenesis of the CNS [2,8,20,27].

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“…ApoE knockout mice, although neuropathologically normal, show numerous CNS defects including impaired memory and learning deficits, some of which are age-dependent. 24,31,40,41,77 They also show cholinergic changes 24 and age-related disruption in the dendritic cytoskeleton and reduced synaptophysin and microtubule-associated protein-2 immunoreactivity in the hippocampus 37 (reviewed in Ref. 40).…”

mentioning

confidence: 99%

“…24,31,40,41,77 They also show cholinergic changes 24 and age-related disruption in the dendritic cytoskeleton and reduced synaptophysin and microtubule-associated protein-2 immunoreactivity in the hippocampus 37 (reviewed in Ref. 40). ApoE-KO mice also show defects in responses to injury, including cerebral ischemia, 13,32 and impaired synaptic regeneration (recovery of synaptophysin-IR) in the outer molecular layer (OML) after EC lesion (ECL).…”

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confidence: 99%

Role of apolipoprotein E and estrogen in mossy fiber sprouting in hippocampal slice cultures

et al. 1999

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Abstract-A role for apolipoprotein E is implicated in regeneration of synaptic circuitry after neural injury. The in vitro mouse organotypic hippocampal slice culture system shows Timm's stained mossy fiber sprouting into the dentate gyrus molecular layer in response to deafferentation of the entorhinal cortex. We show that cultures derived from apolipoprotein E knockout mice are defective in this sprouting response; specifically, they show no sprouting in the dorsal region of the dentate gyrus, yet retain sprouting in the ventral region. Dorsal but not ventral sprouting in cultures from C57Bl/6J mice is increased 75% by treatment with 100 pM 17b-estradiol; this response is blocked by both progesterone and tamoxifen.These results show that neuronal sprouting is increased by estrogen in the same region where sprouting is dependent on apolipoprotein E. Sprouting may be stimulated by estrogen through its up-regulation of apolipoprotein E expression leading to increased recycling of membrane lipids for use by sprouting neurons. Estrogen and apolipoprotein E may therefore interact in their modulation of both Alzheimer's disease risk and recovery from CNS injury.

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Alterations in Apolipoprotein E Expression During Aging and Neurodegeneration

Cited by 81 publications

References 71 publications

Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration

Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration

Impact of apoE deficiency during synaptic remodeling in the mouse olfactory bulb

Role of apolipoprotein E and estrogen in mossy fiber sprouting in hippocampal slice cultures

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