https://pmc.ncbi.nlm.nih.gov/articles/PMC4636982/
. Author manuscript; available in PMC: 2016 Dec 1.
Published in final edited form as: Neurochem Res. 2015 May 7;40(12):2583–2599. doi: 10.1007/s11064-015-1581-6
onsdag 28 januari 2026
Kolesterolin kierrätys hermokudoksessa aivoissa. GLYMFAATTINEN SYSTEEMI.
https://pubmed.ncbi.nlm.nih.gov/?term=recirculation+of+cholesterol+in+brain
https://pubmed.ncbi.nlm.nih.gov/28188218/
The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid β. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain.
The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau.
...findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation
ACAT1 , ACAT2 kolesteroli-asyylitransferaasit, kolesteroliestereiden muodostajaentsyymit
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Review Article
Acyl coenzyme A : cholesterol acyltransferase types 1 and 2: structure and function in atherosclerosis
Rudel, Lawrence L.; Lee, Richard G.; Cockman, Terri L.
Author Information
Current Opinion in Lipidology 12(2):p 121-127, April 2001.
Abstract
Two enzymes are responsible for cholesterol ester formation in tissues, acyl coenzyme A : cholesterol acyltransferase types 1 and 2 (ACAT1 and ACAT2). The available evidence suggests different cell locations, membrane orientations, and metabolic functions for each enzyme. ACAT1 and ACAT2 gene disruption experiments in mice have shown complementary results, with ACAT1 being responsible for cholesterol homeostasis in the brain, skin, adrenal, and macrophages. ACAT1 −/− mice have less atherosclerosis than their ACAT1 +/+ counterparts, presumably because of the decreased ACAT activity in the macrophages.
By contrast, ACAT2 −/− mice have limited cholesterol absorption in the intestine, and decreased cholesterol ester content in the liver and plasma lipoproteins. Almost no cholesterol esterification was found when liver and intestinal microsomes from ACAT2 −/− mice were assayed.
Studies in non-human primates have shown the presence of ACAT1 primarily in the Kupffer cells of the liver, in non-mucosal cell types in the intestine, and in kidney and adrenal cortical cells, whereas ACAT2 is present only in hepatocytes and in intestinal mucosal cells.
The membrane topology for ACAT1 and ACAT2 is also apparently different, with ACAT1 having a serine essential for activity on the cytoplasmic side of the endoplasmic reticulum membrane, whereas the analogous serine is present on the lumenal side of the endoplasmic reticulum for ACAT2.
Taken together, the data suggest that cholesterol ester formation by ACAT1 supports separate functions compared with cholesterol esterification by ACAT2. The latter enzyme appears to be responsible for cholesterol ester formation and secretion in lipoproteins, whereas ACAT1 appears to function to maintain appropriate cholesterol availability in cell membranes.
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)
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.
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).
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