Abstract
Alteration in cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative disorders. Apolipoprotein E (ApoE) is the major component of brain lipoproteins supporting cholesterol transport. We previously reported that the acute-phase protein Haptoglobin (Hpt) binds ApoE, and influences its function in blood cholesterol homeostasis. Major aim of this study was to investigate whether Hpt influences the mechanisms by which cholesterol is shuttled from astrocytes to neurons. In detail it was studied Hpt effect on ApoE-dependent cholesterol efflux from astrocytes and ApoE-mediated cholesterol incorporation in neurons. We report here that Hpt impairs ApoE-mediated cholesterol uptake in human neuroblastoma cell line SH-SY5Y, and limits the toxicity of a massive concentration of cholesterol for these cells, while it does not affect cholesterol efflux from the human glioblastoma-astrocytoma cell line U-87 MG. As aging is the most important non-genetic risk factor for various neurodegenerative disorders, and our results suggest that Hpt modulates ApoE functions, we evaluated the Hpt and ApoE expression profiles in cerebral cortex and hippocampus of adolescent (2 months), adult (5 and 8 months), and middle-aged (16 months) rats. Hpt mRNA level was higher in hippocampus of 8 and 16 month-old than in 2-month old rats (p < 0.05), and Hpt concentration increased with the age from adolescence to middle-age (p < 0.001). ApoE concentration, in hippocampus, was higher (p < 0.001) in 5 month-old rats compared to 2 month but did not further change with aging. No age-related changes of Hpt (protein and mRNA) were found in the cortex. Our results suggest that aging is associated with changes, particularly in the hippocampus, in the Hpt/ApoE ratio. Age-related changes in the concentration of Hpt were also found in human cerebrospinal fluids. The age-related changes might affect neuronal function and survival in brain, and have important implications in brain pathophysiology.
Highlights
Cholesterol is a key component of biological membranes, participates in the modulation of their fluidity, and is the precursor of several signaling molecules, including steroid hormones (Tabas, 1997; Simons and Ikonen, 2000)
These results suggest that Hpt binding to Apolipoprotein E (ApoE) does not interfere with cholesterol efflux from astrocytes, and that ApoE retains the ability to stimulate this process when the Hpt/ApoE molar ratio increases
As ApoE plays a key role in modulating brain cholesterol trafficking, and dysregulation of cholesterol balance in brain is increasingly being correlated to Alzheimer’s disease (AD) (Vance, 2012), the evaluation of inflammatory- and non-inflammatory players, able to influence ApoE key activity in cholesterol or Aβ metabolism might represent an alternative approach to elucidate the link among AD pathogenesis, ApoE, and cholesterol metabolism
Summary
Cholesterol is a key component of biological membranes, participates in the modulation of their fluidity, and is the precursor of several signaling molecules, including steroid hormones (Tabas, 1997; Simons and Ikonen, 2000). As intracellular synthesis is down regulated in the mature brain, neurons meet their cholesterol requirements essentially via uptake of cholesterol carried in Apolipoprotein E (ApoE)-containing lipoproteins secreted by glial cells (Pfrieger, 2003). This specific brain lipoprotein transport system very efficiently recycles cholesterol, and mainly depends on the presence of ApoE (Verghese et al, 2011). Astrocytes release cholesterol and ApoE that are assembled with phospholipids into lipoprotein particles, which are similar in size to plasma HDL (Boyles et al, 1985; DeMattos et al, 2001; Pfrieger and Ungerer, 2011). These lipoproteins interact, via ApoE, with the low-density lipoprotein receptor (LDLR) and with the lowdensity lipoprotein receptor-related protein 1 (LRP1), expressed in neurons (Boyles et al, 1989; Posse de Chaves et al, 2000; Herz, 2009), delivering cholesterol for growth, repair, and Frontiers in Cellular Neuroscience www.frontiersin.org
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