Is It Possible to Improve Memory Function by Upregulation of the Cholesterol 24S-Hydroxylase (CYP46A1) in the Brain?

Maioli, Silvia; Båvner, Ann; Ali, Zeina; Heverin, Maura; Ismail, Muhammad-Al-Mustafa; Puerta, Elena; Olin, Maria; Saeed, Ahmed; Shafaati, Marjan; Parini, Paolo; Cedazo-Minguez, Ángel; Björkhem, Ingemar

doi:10.1371/journal.pone.0068534

Cited by 65 publications

(89 citation statements)

References 26 publications

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“…Although we had previously observed an increase in HMGR activity, our results show that HMGS and HMGR mRNA levels remain unchanged after CYP46A1 overexpression (Fig. 9a) which is consistent with the gene expression profile reported for C46-HA mice [20]. On the other hand, the mRNA levels of the LXR target genes, ABCA1 and APOE, were significantly down-regulated by approximately 30 and 20 %, respectively.…”

Section: Cyp46a1 Overexpression Inhibits the Lxr Pathway As A Consequsupporting

confidence: 92%

“…As previously mentioned, inactivation of Cyp46a1 has been associated with a selective reduction of cholesterol synthesis [13], while a significant increase in the levels of several cholesterol precursors was observed in the brain of CYP46A1 transgenic mice [16,20]. Moreover, herein we have also observed an increase in HMGR activity in CYP46A1 transfected cells.…”

Section: Cyp46a1 Overexpression Inhibits the Lxr Pathway As A Consequsupporting

confidence: 79%

“…Brain cortex tissue was obtained from wild-type and homozygous HA-tagged CYP46A1 transgenic mice, previously described and characterized [20]. Heterozygous mice cross-bred with C57Bl6 mice [16] from the sixth generation were inbred for an additional three generations in order to obtain the homozygous mice [20].…”

Section: Preparation Of Cytosolic and Membrane Fractions From Mice Brmentioning

confidence: 99%

“…Heterozygous mice cross-bred with C57Bl6 mice [16] from the sixth generation were inbred for an additional three generations in order to obtain the homozygous mice [20]. To isolate the cytosolic and membrane fractions of brain cortex tissue, a slice was cut and placed in ice-cold tissue homogenization buffer (250 mM Sucrose, 100 mM potassium phosphate pH 6.7, 5 mM MgCl 2 , 1 mM DTT, and 1× protease inhibitor mixture).…”

Section: Preparation Of Cytosolic and Membrane Fractions From Mice Brmentioning

confidence: 99%

“…Interestingly, these studies with knockout mice are consistent with the possibility that a decrease in cholesterol synthesis may limit the supply of isoprenoid intermediates of the mevalonate pathway, required for learning and synaptic plasticity. Accordingly, transgenic mice overexpressing CYP46A1 exhibit increased brain cholesterol synthesis, increased levels of synaptic proteins in the hippocampus, as well as improved memory function when compared to wild-type controls [16,20].…”

Section: Introductionmentioning

confidence: 99%

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Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells

et al. 2014

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The neuronal-specific cholesterol 24S-hydroxylase (CYP46A1) is important for brain cholesterol elimination. Cyp46a1 null mice exhibit severe deficiencies in learning and hippocampal long-term potentiation, suggested to be caused by a decrease in isoprenoid intermediates of the mevalonate pathway. Conversely, transgenic mice overexpressing CYP46A1 show an improved cognitive function. These results raised the question of whether CYP46A1 expression can modulate the activity of proteins that are crucial for neuronal function, namely of isoprenylated small guanosine triphosphate-binding proteins (sGTPases). Our results show that CYP46A1 overexpression in SH-SY5Y neuroblastoma cells and in primary cultures of rat cortical neurons leads to an increase in 3-hydroxy-3-methyl-glutaryl-CoA reductase activity and to an overall increase in membrane levels of RhoA, Rac1, Cdc42 and Rab8. This increase is accompanied by a specific increase in RhoA activation. Interestingly, treatment with lovastatin or a geranylgeranyltransferase-I inhibitor abolished the CYP46A1 effect. The CYP46A1-mediated increase in sGTPases membrane abundance was confirmed in vivo, in membrane fractions obtained from transgenic mice overexpressing this enzyme. Moreover, CYP46A1 overexpression leads to a decrease in the liver X receptor (LXR) transcriptional activity and in the mRNA levels of ATPbinding cassette transporter 1, sub-family A, member 1 and apolipoprotein E. This effect was abolished by inhibition of prenylation or by co-transfection of a RhoA dominantnegative mutant. Our results suggest a novel regulatory axis in neurons; under conditions of membrane cholesterol reduction by increased CYP46A1 expression, neurons increase isoprenoid synthesis and sGTPase prenylation. This leads to a reduction in LXR activity, and consequently to a decrease in the expression of LXR target genes.

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Section: Cyp46a1 Overexpression Inhibits the Lxr Pathway As A Consequsupporting

confidence: 92%

Section: Cyp46a1 Overexpression Inhibits the Lxr Pathway As A Consequsupporting

confidence: 79%

Section: Preparation Of Cytosolic and Membrane Fractions From Mice Brmentioning

confidence: 99%

Section: Preparation Of Cytosolic and Membrane Fractions From Mice Brmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells

et al. 2014

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Myelination, oligodendrocytes, and serious mental illness

Haroutunian

Katsel

Roussos

et al. 2014

Glia

222

174

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Historically, the human brain has been conceptually segregated from the periphery and further dichotomized into gray matter (GM) and white matter (WM) based on the whitish appearance of the exceptionally high lipid content of the myelin sheaths encasing neuronal axons. These simplistic dichotomies were unfortunately extended to conceptually segregate neurons from glia, cognition from behavior, and have been codified in the separation of clinical and scientific fields into medicine, psychiatry, neurology, pathology, etc. The discrete classifications have helped obscure the importance of continual dynamic communication between all brain cell types (neurons, astrocytes, microglia, oligodendrocytes, and precursor (NG2) cells) as well as between brain and periphery through multiple signaling systems. The signaling systems range from neurotransmitters to insulin, angiotensin, and multiple kinases such a glycogen synthase kinase 3 (GSK-3) that together help integrate metabolism, inflammation, and myelination processes and orchestrate the development, plasticity, maintenance, and repair that continually optimize function of neural networks. A more comprehensive, evolution-based, systems biology approach that integrates brain, body, and environmental interactions may ultimately prove more fruitful in elucidating the complexities of human brain function. The historic focus on neurons/GM is rebalanced herein by highlighting the importance of a systems-level understanding of the interdependent age-related shifts in both central and peripheral homeostatic mechanisms that can lead to remarkably prevalent and devastating neuropsychiatric diseases. Herein we highlight the role of glia, especially the most recently evolved oligodendrocytes and the myelin they produce, in achieving and maintaining optimal brain function. The human brain undergoes exceptionally protracted and pervasive myelination (even throughout its GM) and can thus achieve and maintain the rapid conduction and synchronous timing of neural networks on which optimal function depends. The continuum of increasing myelin vulnerability resulting from the human brain's protracted myelination underlies underappreciated communalities between different disease phenotypes ranging from developmental ones such as schizophrenia (SZ) and bipolar disorder (BD) to degenerative ones such as Alzheimer's disease (AD). These shared vulnerabilities also expose significant yet underexplored opportunities for novel treatment and prevention approaches that have the potential to considerably reduce the tremendous burden of neuropsychiatric disease.

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27‐hydroxycholesterol promotes oligodendrocyte maturation: Implications for hypercholesterolemia‐associated brain white matter changes

Alanko

Gaminde-Blasco

Quintela-López

et al. 2023

Glia

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Oxidized cholesterol metabolite 27‐hydroxycholesterol (27‐OH) is a potential link between hypercholesterolemia and neurodegenerative diseases since unlike peripheral cholesterol, 27‐OH is transported across the blood–brain barrier. However, the effects of high 27‐OH levels on oligodendrocyte function remain unexplored. We hypothesize that during hypercholesterolemia 27‐OH may impact oligodendrocytes and myelin and thus contribute to the disconnection of neural networks in neurodegenerative diseases. To test this idea, we first investigated the effects of 27‐OH in cultured oligodendrocytes and found that it induces cell death of immature O4+/GalC+ oligodendrocytes along with stimulating differentiation of PDGFR+ oligodendrocyte progenitors (OPCs). Next, transgenic mice with increased systemic 27‐OH levels (Cyp27Tg) underwent behavioral testing and their brains were immunohistochemically stained and lysed for immunoblotting. Chronic exposure to 27‐OH in mice resulted in increased myelin basic protein (MBP) but not 2′,3′‐cyclic‐nucleotide 3′‐phosphodiesterase (CNPase) or myelin oligodendrocyte glycoprotein (MOG) levels in the corpus callosum and cerebral cortex. Intriguingly, we also found impairment of spatial learning suggesting that subtle changes in myelinated axons of vulnerable areas like the hippocampus caused by 27‐OH may contribute to impaired cognition. Finally, we found that 27‐OH levels in cerebrospinal fluid from memory clinic patients were associated with levels of the myelination regulating CNPase, independently of Alzheimer's disease markers. Thus, 27‐OH promotes OPC differentiation and is toxic to immature oligodendrocytes as well as it subtly alters myelin by targeting oligodendroglia. Taken together, these data indicate that hypercholesterolemia‐derived higher 27‐OH levels change the oligodendrocytic capacity for appropriate myelin remodeling which is a crucial factor in neurodegeneration and aging.

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Is It Possible to Improve Memory Function by Upregulation of the Cholesterol 24S-Hydroxylase (CYP46A1) in the Brain?

Cited by 65 publications

References 26 publications

Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells

Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells

Myelination, oligodendrocytes, and serious mental illness

27‐hydroxycholesterol promotes oligodendrocyte maturation: Implications for hypercholesterolemia‐associated brain white matter changes

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