Aivot ja kolesteroli

 https://pmc.ncbi.nlm.nih.gov/articles/PMC3484857/

Although the brain makes up only 2–5% of body mass, approximately 25% of total body cholesterol resides in the brain (Dietschy and Turley, 2001). Thus, the brain is highly enriched in cholesterol compared with other mammalian tissues: whereas the cholesterol concentration in most animal tissues is ∼2 mg/g tissue, the cholesterol concentration in the CNS is 15–20 mg/g tissue (Dietschy and Turley, 2004).

 The majority (70–90%) of cholesterol in the CNS is in the myelin that surrounds axons and facilitates the transmission of electrical signals. 

Consequently, cholesterol synthesis in the brain is highest in oligodendrocytes during active myelination and decreases by ∼90% in adults after myelination has been completed (Dietschy and Turley, 2004; Quan et al., 2003).

 Nevertheless, cholesterol synthesis continues at a low rate in the mature brain, particularly in astrocytes; in the adult brain, the rate of cholesterol biosynthesis is higher in astrocytes than in neurons (Nieweg et al., 2009).

Transport

The brain operates its own lipoprotein transport system, independent of that in the peripheral circulation (Fig. 2). 

Astrocytes produce cholesterol and apolipoprotein E (APOE) that, together with phospholipids, generate lipoproteins that are similar in size to plasma high-density lipoproteins (Boyles et al., 1985). 

The secreted APOE acquires cholesterol and phospholipids via the efflux of cellular lipid in a process mediated by one or more of the ATP-binding cassette (ABC) transporters such as ABCA1, ABCG1 and/or ABCG4 

The uptake of these lipoproteins by neurons is mediated by receptors of the low-density lipoprotein (LDL) receptor family, such as the LDL receptor, LDL-receptor-related protein (LRP) and APOE receptor 2 (APOER2), that are expressed in neurons and can endocytose the astrocyte-derived APOE-containing lipoprotein particles (Boyles et al., 1989; Herz, 2001b; Posse de Chaves et al., 2000) (Fig. 2). 

In this manner, cholesterol is shuttled from astrocytes to neurons (Mauch et al., 2001; Michikawa et al., 2000; Vance and Hayashi, 2010). 

The interaction between APOE-containing lipoproteins and these neuronal receptors seems to be crucial for normal neuronal function:

 the APOE-containing lipoproteins stimulate synaptogenesis (Mauch et al., 2001), enhance axonal growth (Hayashi et al., 2004) and
 prevent neuron death (Hayashi et al., 2009; Hayashi et al., 2007)

 Moreover, a role for APOE in nerve repair has been indicated, because APOE synthesis in glial cells increases by up to 150-fold after a nerve injury (Ignatius et al., 1986). APOE therefore seems to be a key player in regulating cholesterol homeostasis and distribution among cells of the brain.

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APOE-containing lipoproteins transport cholesterol from astrocytes to neurons. Glial cells, primarily astrocytes, but also microglia, secrete APOE, which acquires cholesterol and phospholipids, thereby forming APOE-containing lipoproteins. These are delivered to neurons where they are endocytosed via cell surface receptors (members of the LDL receptor family). Consequently, cholesterol is delivered to the neurons. Some APOE receptors also function as signaling receptors.

Cholesterol has a remarkably long half-life in the brain (4–6 months in rodents and up to 5 years in humans) (Dietschy and Turley, 2001). 

There is a low rate of cholesterol synthesis in the adult brain, and cholesterol cannot be degraded in the CNS, but a steady-state level of cholesterol is maintained in the CNS because a small fraction (0.02–0.4%) of the cholesterol pool is excreted from the brain each day (Dietschy and Turley, 2004).

 The conversion of cholesterol to 24-hydroxycholesterol (Fig. 1), by the enzyme cholesterol 24-hydroxylase (CYP46) that is expressed in a subset of neurons (but not in astrocytes) (Russell et al., 2009), represents a major mechanism by which excess cholesterol is eliminated from the brain. 

In contrast to cholesterol, 24-hydroxycholesterol can cross the blood-brain barrier, enter the peripheral circulation and be eliminated from the body in bile (Russell et al., 2009).

 Studies in CYP46-deficient mice show that at least 40% of the cholesterol that is excreted from the brain is in the form of 24-hydroxycholesterol. Interestingly, however, in CYP46-deficient mice, cholesterol does not accumulate because cholesterol synthesis is reduced by ∼40% as a compensatory mechanism (Russell et al., 2009).