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Cholesterol homeostasis: a key to prevent or slow down neurodegeneration.

Anchisi L, Dessì S, Pani A, Mandas A - Front Physiol (2013)

Bottom Line: Typically human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people, progress slowly, and lead to disability and premature death; however they may occur at all ages.Therefore, since the underlying mechanisms of damage to neurons are similar, in spite of etiology and background heterogeneous, it will be of interest to identify possible trigger point of neurodegeneration enabling development of drugs and/or prevention strategies that target many disorders simultaneously.Among the factors that have been identified so far to cause neurodegeneration, failures in cholesterol homeostasis are indubitably the best investigated.

View Article: PubMed Central - PubMed

Affiliation: Child Neuropsychiatry Unit, Azienda Sanitaria Locale (ASL) n°5 Oristano, Italy ; Department of Clinical and Experimental Medicine and Pharmacology, University of Messina Messina, Italy.

ABSTRACT
Neurodegeneration, a common feature for many brain disorders, has severe consequences on the mental and physical health of an individual. Typically human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people, progress slowly, and lead to disability and premature death; however they may occur at all ages. Despite extensive research and investments, current therapeutic interventions against these disorders treat solely the symptoms. Therefore, since the underlying mechanisms of damage to neurons are similar, in spite of etiology and background heterogeneous, it will be of interest to identify possible trigger point of neurodegeneration enabling development of drugs and/or prevention strategies that target many disorders simultaneously. Among the factors that have been identified so far to cause neurodegeneration, failures in cholesterol homeostasis are indubitably the best investigated. The aim of this review is to critically discuss some of the main results reported in the recent years in this field mainly focusing on the mechanisms that, by recovering perturbations of cholesterol homeostasis in neuronal cells, may correct clinically relevant features occurring in different neurodegenerative disorders and, in this regard, also debate the current potential therapeutic interventions.

No MeSH data available.


Related in: MedlinePlus

Cholesterol homeostasis (neurodegenerative disorders). An imbalance of one or more of finely regulated homeostatic mechanisms that lead to even modest changes in ER-FC pool in neurons can cause a serious and sometimes fatal neurologic disorder. Namely, if a reduction in the transport of cholesterol between ER and PM occurs as a consequence of genetic and/or environmental factors, neuronal ER-FC increases. This increase may cause the activation of ACAT1 leading to an increased CE synthesis while reducing the distribution of FC in raft-domains. If these alterations persist over time the consequences may be: rafts disassembly, demyelination, alterations in synapse formation and function, in other words, neurodegeneration. Beside ACAT1 activation, an increase in ER cholesterol pool of neurons may also activate the CYP46A1 thereby enhancing the levels of circulating 24S-OHC. This is an oxygenated derivative of cholesterol able to cause lipoprotein oxidation (ox-LP). With a mechanism similar to that described for atherosclerosis, ox-Lp might be recognized by scavenger receptors (SR) on the surface of white blood cells, which in turn may be engorged with CE and become foam cells.
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Figure 4: Cholesterol homeostasis (neurodegenerative disorders). An imbalance of one or more of finely regulated homeostatic mechanisms that lead to even modest changes in ER-FC pool in neurons can cause a serious and sometimes fatal neurologic disorder. Namely, if a reduction in the transport of cholesterol between ER and PM occurs as a consequence of genetic and/or environmental factors, neuronal ER-FC increases. This increase may cause the activation of ACAT1 leading to an increased CE synthesis while reducing the distribution of FC in raft-domains. If these alterations persist over time the consequences may be: rafts disassembly, demyelination, alterations in synapse formation and function, in other words, neurodegeneration. Beside ACAT1 activation, an increase in ER cholesterol pool of neurons may also activate the CYP46A1 thereby enhancing the levels of circulating 24S-OHC. This is an oxygenated derivative of cholesterol able to cause lipoprotein oxidation (ox-LP). With a mechanism similar to that described for atherosclerosis, ox-Lp might be recognized by scavenger receptors (SR) on the surface of white blood cells, which in turn may be engorged with CE and become foam cells.

Mentions: Taking into account the above and data obtained in our laboratory, a model describing some mechanisms linking cholesterol esterification to neuronal degeneration could tentatively be proposed (Figures 3 and 4). It is well known that cells and tissues, including brain, are protected from the accumulation of potentially toxic FC excess by ACAT1–mediated esterification and by cholesterol efflux (Tabas, 2002), ACAT activity being allosterically activated by the presence of high FC levels in ER (Chang et al., 2001). Cellular cholesterol undergoes a continuous cycle of esterification and ester hydrolysis; net breakdown of CE taking place when ER–FC levels decline. The enzyme responsible for the degradation of CE is neutral cholesterol ester hydrolase (nCEH). Under physiological conditions intracellular CE levels in brains are very low and generally do not exceed the nCEH capacity to re-hydrolize CE to FC and to recycle FC back to PM (Pani and Dessì, 2003). In neurons, if in excess, a part of ER–FC is converted to CE by ACAT1 located at the ER and stored as cytoplasmic lipid droplets, another part leaves the brain (Dietschy, 2009). FC does not across the BBB, therefore before to exit CNS, it is converted into 24S-hydroxycholesterol (24S-OHC) and in this form moves from neurons via the ATP-binding cassette transporter A1 (ABCA1) pathway, through cerebrospinal fluid (CSF), cross the BBB, and is released into the systemic venous circulation. The fate of the 24S-OHC once it reaches the circulation has not yet been defined. An accurate method based on isotope dilution-mass spectrometry showed that in blood compartment 24S-OHC is mainly associated with HDL and LDL (Babiker and Diczfalusy, 1998), suggesting that steady-state plasma 24S-OHC levels follows the metabolic fate of cholesterol in HDL and LDL (i.e., uptake by the liver). Since most of the circulating 24S-OHC arises from brain cholesterol, its levels are considered a measure of cholesterol turnover in the CNS (Orth and Bellosta, 2012). Cells in the CNS synthesize all of their own cholesterol in the ER from acetyl CoA through the mevalonate pathway. The rate-limiting step of the mevalonate pathway is the conversion of hydroxyl-methyl-glutaryl-CoA (HMG-CoA) to mevalonate by HMG-CoA reductase. Both these and several other enzymes that function in later steps of cholesterol synthesis are integral ER membrane proteins. In the ER, FC levels fluctuate much more than that in PMs and are considered the major regulators of the cellular cholesterol homeostatic machinery. Once synthesized, FC leaves the ER, thereby helping to maintain low ER sterol content and is rapidly targeted to PMs where, depending on the type of CNS cells is utilized for membrane turnover and axonal growth or become available for extracellular apoprotein E (Apo E) acceptors (astrocytes) (Dietschy, 2009; Orth and Bellosta, 2012). In summary, the ER, where many critical enzymatic reactions of cholesterol metabolism take place, is relatively cholesterol poor, thus maintenance of cellular cholesterol homeostasis necessitates the transport of cholesterol between subcellular membranes and PMs and eventually its exchange with Apo E and/or ABCA1 for efflux. These findings imply that an imbalance of one or more of these finely regulated homeostatic mechanisms capable of causing even modest changes in ER–FC pool, may contribute to serious and sometimes fatal conditions. In this way, it is plausible to suppose that, if a reduction in the transport of cholesterol between ER and PMs occurs as a consequence of genetic and/or environmental factors, ER–FC in neurons may increase. This increase activates ACAT1 leading to abnormal CE accumulation while membrane cholesterol and its distribution in raft-domains are reduced. If this altered transport persists over time the consequences will be: rafts disassembly, demyelination, alterations in synapsis formation and function (neurodegenerative disorders). Considering that caveolin-1 (Cav-1) is a cholesterol-binding protein that delivers newly synthesized cholesterol at the ER to the PMs (Smart et al., 1996), the fact that embryonic fibroblasts and peritoneal macrophages from Cav-1 mice were found enriched in CEs but depleted of FC membranes compared with their wild-type counterparts (Chang et al., 2006), supports these conclusions. Signs of premature neuronal aging and degeneration, increased Aβ, decreased cerebrovascular volume and reduction in synapses were also observed in brains of young Cav-1 mice compared to young WT mice (Head et al., 2010). Very low mRNA levels of Cav-1 and particularly nCEH were found by us in skin fibroblasts and in PBMCs from patients with AD (Pani et al., 2009a,b). Interestingly, neuron-targeted re-expression of Cav-1 in Cav-1 neurons in vitro decreased Aβ expression (Head et al., 2010).


Cholesterol homeostasis: a key to prevent or slow down neurodegeneration.

Anchisi L, Dessì S, Pani A, Mandas A - Front Physiol (2013)

Cholesterol homeostasis (neurodegenerative disorders). An imbalance of one or more of finely regulated homeostatic mechanisms that lead to even modest changes in ER-FC pool in neurons can cause a serious and sometimes fatal neurologic disorder. Namely, if a reduction in the transport of cholesterol between ER and PM occurs as a consequence of genetic and/or environmental factors, neuronal ER-FC increases. This increase may cause the activation of ACAT1 leading to an increased CE synthesis while reducing the distribution of FC in raft-domains. If these alterations persist over time the consequences may be: rafts disassembly, demyelination, alterations in synapse formation and function, in other words, neurodegeneration. Beside ACAT1 activation, an increase in ER cholesterol pool of neurons may also activate the CYP46A1 thereby enhancing the levels of circulating 24S-OHC. This is an oxygenated derivative of cholesterol able to cause lipoprotein oxidation (ox-LP). With a mechanism similar to that described for atherosclerosis, ox-Lp might be recognized by scavenger receptors (SR) on the surface of white blood cells, which in turn may be engorged with CE and become foam cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539713&req=5

Figure 4: Cholesterol homeostasis (neurodegenerative disorders). An imbalance of one or more of finely regulated homeostatic mechanisms that lead to even modest changes in ER-FC pool in neurons can cause a serious and sometimes fatal neurologic disorder. Namely, if a reduction in the transport of cholesterol between ER and PM occurs as a consequence of genetic and/or environmental factors, neuronal ER-FC increases. This increase may cause the activation of ACAT1 leading to an increased CE synthesis while reducing the distribution of FC in raft-domains. If these alterations persist over time the consequences may be: rafts disassembly, demyelination, alterations in synapse formation and function, in other words, neurodegeneration. Beside ACAT1 activation, an increase in ER cholesterol pool of neurons may also activate the CYP46A1 thereby enhancing the levels of circulating 24S-OHC. This is an oxygenated derivative of cholesterol able to cause lipoprotein oxidation (ox-LP). With a mechanism similar to that described for atherosclerosis, ox-Lp might be recognized by scavenger receptors (SR) on the surface of white blood cells, which in turn may be engorged with CE and become foam cells.
Mentions: Taking into account the above and data obtained in our laboratory, a model describing some mechanisms linking cholesterol esterification to neuronal degeneration could tentatively be proposed (Figures 3 and 4). It is well known that cells and tissues, including brain, are protected from the accumulation of potentially toxic FC excess by ACAT1–mediated esterification and by cholesterol efflux (Tabas, 2002), ACAT activity being allosterically activated by the presence of high FC levels in ER (Chang et al., 2001). Cellular cholesterol undergoes a continuous cycle of esterification and ester hydrolysis; net breakdown of CE taking place when ER–FC levels decline. The enzyme responsible for the degradation of CE is neutral cholesterol ester hydrolase (nCEH). Under physiological conditions intracellular CE levels in brains are very low and generally do not exceed the nCEH capacity to re-hydrolize CE to FC and to recycle FC back to PM (Pani and Dessì, 2003). In neurons, if in excess, a part of ER–FC is converted to CE by ACAT1 located at the ER and stored as cytoplasmic lipid droplets, another part leaves the brain (Dietschy, 2009). FC does not across the BBB, therefore before to exit CNS, it is converted into 24S-hydroxycholesterol (24S-OHC) and in this form moves from neurons via the ATP-binding cassette transporter A1 (ABCA1) pathway, through cerebrospinal fluid (CSF), cross the BBB, and is released into the systemic venous circulation. The fate of the 24S-OHC once it reaches the circulation has not yet been defined. An accurate method based on isotope dilution-mass spectrometry showed that in blood compartment 24S-OHC is mainly associated with HDL and LDL (Babiker and Diczfalusy, 1998), suggesting that steady-state plasma 24S-OHC levels follows the metabolic fate of cholesterol in HDL and LDL (i.e., uptake by the liver). Since most of the circulating 24S-OHC arises from brain cholesterol, its levels are considered a measure of cholesterol turnover in the CNS (Orth and Bellosta, 2012). Cells in the CNS synthesize all of their own cholesterol in the ER from acetyl CoA through the mevalonate pathway. The rate-limiting step of the mevalonate pathway is the conversion of hydroxyl-methyl-glutaryl-CoA (HMG-CoA) to mevalonate by HMG-CoA reductase. Both these and several other enzymes that function in later steps of cholesterol synthesis are integral ER membrane proteins. In the ER, FC levels fluctuate much more than that in PMs and are considered the major regulators of the cellular cholesterol homeostatic machinery. Once synthesized, FC leaves the ER, thereby helping to maintain low ER sterol content and is rapidly targeted to PMs where, depending on the type of CNS cells is utilized for membrane turnover and axonal growth or become available for extracellular apoprotein E (Apo E) acceptors (astrocytes) (Dietschy, 2009; Orth and Bellosta, 2012). In summary, the ER, where many critical enzymatic reactions of cholesterol metabolism take place, is relatively cholesterol poor, thus maintenance of cellular cholesterol homeostasis necessitates the transport of cholesterol between subcellular membranes and PMs and eventually its exchange with Apo E and/or ABCA1 for efflux. These findings imply that an imbalance of one or more of these finely regulated homeostatic mechanisms capable of causing even modest changes in ER–FC pool, may contribute to serious and sometimes fatal conditions. In this way, it is plausible to suppose that, if a reduction in the transport of cholesterol between ER and PMs occurs as a consequence of genetic and/or environmental factors, ER–FC in neurons may increase. This increase activates ACAT1 leading to abnormal CE accumulation while membrane cholesterol and its distribution in raft-domains are reduced. If this altered transport persists over time the consequences will be: rafts disassembly, demyelination, alterations in synapsis formation and function (neurodegenerative disorders). Considering that caveolin-1 (Cav-1) is a cholesterol-binding protein that delivers newly synthesized cholesterol at the ER to the PMs (Smart et al., 1996), the fact that embryonic fibroblasts and peritoneal macrophages from Cav-1 mice were found enriched in CEs but depleted of FC membranes compared with their wild-type counterparts (Chang et al., 2006), supports these conclusions. Signs of premature neuronal aging and degeneration, increased Aβ, decreased cerebrovascular volume and reduction in synapses were also observed in brains of young Cav-1 mice compared to young WT mice (Head et al., 2010). Very low mRNA levels of Cav-1 and particularly nCEH were found by us in skin fibroblasts and in PBMCs from patients with AD (Pani et al., 2009a,b). Interestingly, neuron-targeted re-expression of Cav-1 in Cav-1 neurons in vitro decreased Aβ expression (Head et al., 2010).

Bottom Line: Typically human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people, progress slowly, and lead to disability and premature death; however they may occur at all ages.Therefore, since the underlying mechanisms of damage to neurons are similar, in spite of etiology and background heterogeneous, it will be of interest to identify possible trigger point of neurodegeneration enabling development of drugs and/or prevention strategies that target many disorders simultaneously.Among the factors that have been identified so far to cause neurodegeneration, failures in cholesterol homeostasis are indubitably the best investigated.

View Article: PubMed Central - PubMed

Affiliation: Child Neuropsychiatry Unit, Azienda Sanitaria Locale (ASL) n°5 Oristano, Italy ; Department of Clinical and Experimental Medicine and Pharmacology, University of Messina Messina, Italy.

ABSTRACT
Neurodegeneration, a common feature for many brain disorders, has severe consequences on the mental and physical health of an individual. Typically human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people, progress slowly, and lead to disability and premature death; however they may occur at all ages. Despite extensive research and investments, current therapeutic interventions against these disorders treat solely the symptoms. Therefore, since the underlying mechanisms of damage to neurons are similar, in spite of etiology and background heterogeneous, it will be of interest to identify possible trigger point of neurodegeneration enabling development of drugs and/or prevention strategies that target many disorders simultaneously. Among the factors that have been identified so far to cause neurodegeneration, failures in cholesterol homeostasis are indubitably the best investigated. The aim of this review is to critically discuss some of the main results reported in the recent years in this field mainly focusing on the mechanisms that, by recovering perturbations of cholesterol homeostasis in neuronal cells, may correct clinically relevant features occurring in different neurodegenerative disorders and, in this regard, also debate the current potential therapeutic interventions.

No MeSH data available.


Related in: MedlinePlus