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.