In the central nervous system
cholesterol is involved in membrane structure and function. Since the blood-brain barrier efficiently prevents
cholesterol uptake from the circulation, de novo synthesis is responsible for almost all
cholesterol present there. In mature brain neurons down regulate their
cholesterol synthesis and rely on delivery from
ApoE lipoproteins secreted by astrocytes.
ApoE transcription is regulated by
24S-hydroxycholesterol (24OHC) released by neurons, via LXR. In order to maintain homeostasis, excess of
cholesterol is converted into 24OHC by the neuronal specific
cholesterol 24-hydroxylase (
CYP46A1). The brain is the major source of circulating 24OHC. Plasma levels of 24OHC reflect the number of metabolically active neurons in the brain and thus, the volume of the grey matter structures. In
neurodegenerative disorders such as
Multiple Sclerosis, Alzheimer and
Huntington disease, plasma 24OHC was found reduced proportionally to the degree of brain
atrophy as measured by MRI. Less than 1% of the total excretion of 24OHC occurs via the cerebrospinal fluid (CSF). This small fraction appears to reflect neuronal damage and rate of neuronal loss rather than the total number of metabolically active neuronal cells. In CSF form patients affected by
neurodegenerative diseases, increased levels of 24OHC were found. In case of
Mild Cognitive Impairment and AD patients, the CSF concentration of 24OHC was correlated with CSF
ApoE,
cholesterol and Tau. CSF tau is considered related to the neurodegenerative process in AD,
ApoE and
cholesterol are involved in the β-
amyloid deposition. It is likely that during process of neurodegeneration, the excess of
cholesterol converted into 24OHC in neurons up-regulate the expression of
ApoE proportionally to the amount of neurodegeneration.
27-Hydroxycholesterol (27OHC), formed outside the brain, cross the blood-brain barrier proportionally to the barrier dysfunction. There is a positive correlation between levels of
cholesterol and 27OHC in the circulation. This
oxysterol antagonizes the preventive effect of 24OHC on generation of β-
amyloid. A rare
hereditary disease, SPG5, due to mutation at CYP7B1, is characterized by massive neurodegeneration associated to high plasma and CSF 27OHC. Since its CSF levels were found higher in MCI and AD patients, 27OHC may be the link between
hypercholesterolemia and AD. In conclusion the analysis of
oxysterols in plasma and CSF seems to contribute to investigate the role of
cholesterol metabolism in pathogenesis of neurodegeneration and is helpful in the study of patients affected by
neurodegenerative diseases.