Cholesterol and Neurodegenerative Diseases: Pressing Questions and How to Address Them

The maintenance of balanced cholesterol homeostasis is an important aspect of Central Nervous System functions including brain development, myelination, neuronal signalling and survival. Cholesterol also interacts with numerous sterol transport proteins that facilitate cholesterol trafficking and regulate its subcellular distribution. The importance of brain cholesterol homeostasis is highlighted by the negative impact of genetic mutations affecting enzymes of this metabolic pathway, as observed in several neurodevelopmental and neurodegenerative diseases. Brain cells are cut off from cholesterol blood supply as the blood-brain barrier (BBB) prevents entry of lipoproteins. As a consequence, the cholesterol present in the brain is formed by de novo synthesis. All types of neural cells, including glial and neuronal cell types, synthesize cholesterol during development. As adulthood is reached, neurons are believed to down-regulate cholesterol synthesis and to entirely rely on cholesterol delivered by astrocytes. The major pathway for cholesterol catabolism is achieved by the neuronal enzyme, cholesterol 24- hydroxylase, leading to the conversion of cholesterol into 24(S)- hydroxycholesterol (24S-OHC), a metabolite that can cross the BBB, but also acts locally as a ligand of Liver X receptors -target genes. As adulthood is reached, neurons are believed to down-regulate cholesterol synthesis and to entirely rely on cholesterol delivered by astrocytes. Importantly, the dysregulation of cholesterol metabolism has been implicated in several Neurodegenerative diseases: i) in Alzheimer's disease, cholesterol turnover is involved in amyloid precursor protein processing at the membrane and modification of cholesterol levels can influence Aβ formation, ii) in Parkinson's disease, α-synuclein aggregation may be linked to cholesterol levels, and in patients, 24S-OHC levels in cerebrospinal fluid is correlated with disease duration, iii) in Huntington's disease the last decade research emphasized alteration of cholesterol synthesis and metabolism as a pathological mechanism. In this research topic we wish to review the knowledge of key molecular pathways involved in each major aspect of cellular cholesterol metabolism, and its role on the pathogenesis of neurodegenerative diseases. We will also discuss the specific methodology requirement to quantify and monitor sterols and oxysterols within the brain and the different structures of the brain. The final goal is to address the spatio-temporal intervention for cholesterol manipulation to delay the age of onset of the disease and slow-down progression before brain cells may undergo irreversible damage. All article types of the Journal are welcome for submission.