Abstract: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 th… Show more
“…Also possible is that CYP46A1 activation by EFV allowed the enzyme to compete more efficiently with CYP27A1 for cholesterol in the cells where both enzymes were expressed, thus contributing to a decrease in the retinal 27HC levels as compared to control Apoj −/− mice. A decrease in the retinal 27HC levels was likely a beneficial EFV effect as 27HC was shown to be toxic to immature oligodendrocytes in the brain, favor the oligodendrocyte progenitor cell maturation, and modify protein levels in myelin [ 101 ] Fig. 11 Ocular effects of EFV treatment.…”
Apolipoprotein J (APOJ) is a multifunctional protein with genetic evidence suggesting an association between APOJ polymorphisms and Alzheimer’s disease as well as exfoliation glaucoma. Herein we conducted ocular characterizations of Apoj−/− mice and found that their retinal cholesterol levels were decreased and that this genotype had several risk factors for glaucoma: increased intraocular pressure and cup-to-disk ratio and impaired retinal ganglion cell (RGC) function. The latter was not due to RGC degeneration or activation of retinal Muller cells and microglia/macrophages. There was also a decrease in retinal levels of 24-hydroxycholesterol, a suggested neuroprotectant under glaucomatous conditions and a positive allosteric modulator of N-methyl-d-aspartate receptors mediating the light-evoked response of the RGC. Therefore, Apoj−/− mice were treated with low-dose efavirenz, an allosteric activator of CYP46A1 which converts cholesterol into 24-hydroxycholesterol. Efavirenz treatment increased retinal cholesterol and 24-hydroxycholesterol levels, normalized intraocular pressure and cup-to-disk ratio, and rescued in part RGC function. Retinal expression of Abcg1 (a cholesterol efflux transporter), Apoa1 (a constituent of lipoprotein particles), and Scarb1 (a lipoprotein particle receptor) was increased in EVF-treated Apoj−/− mice, indicating increased retinal cholesterol transport on lipoprotein particles. Ocular characterizations of Cyp46a1−/− mice supported the beneficial efavirenz treatment effects via CYP46A1 activation. The data obtained demonstrate an important APOJ role in retinal cholesterol homeostasis and link this apolipoprotein to the glaucoma risk factors and retinal 24-hydroxycholesterol production by CYP46A1. As the CYP46A1 activator efavirenz is an FDA-approved anti-HIV drug, our studies suggest a new therapeutic approach for treatment of glaucomatous conditions.
“…Also possible is that CYP46A1 activation by EFV allowed the enzyme to compete more efficiently with CYP27A1 for cholesterol in the cells where both enzymes were expressed, thus contributing to a decrease in the retinal 27HC levels as compared to control Apoj −/− mice. A decrease in the retinal 27HC levels was likely a beneficial EFV effect as 27HC was shown to be toxic to immature oligodendrocytes in the brain, favor the oligodendrocyte progenitor cell maturation, and modify protein levels in myelin [ 101 ] Fig. 11 Ocular effects of EFV treatment.…”
Apolipoprotein J (APOJ) is a multifunctional protein with genetic evidence suggesting an association between APOJ polymorphisms and Alzheimer’s disease as well as exfoliation glaucoma. Herein we conducted ocular characterizations of Apoj−/− mice and found that their retinal cholesterol levels were decreased and that this genotype had several risk factors for glaucoma: increased intraocular pressure and cup-to-disk ratio and impaired retinal ganglion cell (RGC) function. The latter was not due to RGC degeneration or activation of retinal Muller cells and microglia/macrophages. There was also a decrease in retinal levels of 24-hydroxycholesterol, a suggested neuroprotectant under glaucomatous conditions and a positive allosteric modulator of N-methyl-d-aspartate receptors mediating the light-evoked response of the RGC. Therefore, Apoj−/− mice were treated with low-dose efavirenz, an allosteric activator of CYP46A1 which converts cholesterol into 24-hydroxycholesterol. Efavirenz treatment increased retinal cholesterol and 24-hydroxycholesterol levels, normalized intraocular pressure and cup-to-disk ratio, and rescued in part RGC function. Retinal expression of Abcg1 (a cholesterol efflux transporter), Apoa1 (a constituent of lipoprotein particles), and Scarb1 (a lipoprotein particle receptor) was increased in EVF-treated Apoj−/− mice, indicating increased retinal cholesterol transport on lipoprotein particles. Ocular characterizations of Cyp46a1−/− mice supported the beneficial efavirenz treatment effects via CYP46A1 activation. The data obtained demonstrate an important APOJ role in retinal cholesterol homeostasis and link this apolipoprotein to the glaucoma risk factors and retinal 24-hydroxycholesterol production by CYP46A1. As the CYP46A1 activator efavirenz is an FDA-approved anti-HIV drug, our studies suggest a new therapeutic approach for treatment of glaucomatous conditions.
“…Comparing the effects of 2D primary astrocytes alone with the phenotype found in the 3D co-cultures, we can hypothesize that the effects of 27-OH in the brain are not cell-specific, and the interaction between several cell types could generate the detrimental effects observed in neurons and astrocytes and, as a limitation to this study, those interactions are present in our 3D cultures but not characterized. Previous study from our laboratory suggests that 27-OH might influence oligodendrocyte maturation ( Alanko et al, 2023 ), and single-cell sequencing data show key enzymes for oxysterol metabolism expressed in different brain cell types ( Zeisel et al, 2015 ; Swartzlander et al, 2018 ), but functional studies are yet to be performed to unravel the interaction between other cells types than neurons and astrocytes under elevated 27-OH levels.…”
Astrocytes represent the most abundant cell type in the brain, where they play critical roles in synaptic transmission, cognition, and behavior. Recent discoveries show astrocytes are involved in synaptic dysfunction during Alzheimer’s disease (AD). AD patients have imbalanced cholesterol metabolism, demonstrated by high levels of side-chain oxidized cholesterol known as 27-hydroxycholesterol (27-OH). Evidence from our laboratory has shown that elevated 27-OH can abolish synaptic connectivity during neuromaturation, but its effect on astrocyte function is currently unclear. Our results suggest that elevated 27-OH decreases the astrocyte function in vivo in Cyp27Tg, a mouse model of brain oxysterol imbalance. Here, we report a downregulation of glutamate transporters in the hippocampus of CYP27Tg mice together with increased GFAP. GLT-1 downregulation was also observed when WT mice were fed with high-cholesterol diets. To study the relationship between astrocytes and neurons, we have developed a 3D co-culture system that allows all the cell types from mice embryos to differentiate in vitro. We report that our 3D co-cultures reproduce the effects of 27-OH observed in 2D neurons and in vivo. Moreover, we found novel degenerative effects in astrocytes that do not appear in 2D cultures, together with the downregulation of glutamate transporters GLT-1 and GLAST. We propose that this transporter dysregulation leads to neuronal hyperexcitability and synaptic dysfunction based on the effects of 27-OH on astrocytes. Taken together, these results report a new mechanism linking oxysterol imbalance in the brain and synaptic dysfunction through effects on astrocyte function.
“…Cholesterol plays a key role in regulation of myelin biosynthesis and deterioration [ 48 , 49 ] and aberrant cholesterol deposition coincides with reduced myelination in the brains of APOE4 carrier mice, whereas pharmacological facilitation of its transport can recover myelination [ 50 ]. In addition, some of cholesterol forms such as the 27-hydroxycholesterol are transported across the blood-brain barrier, are toxic to immature oligodendrocytes, and alter myelin composition [ 51 ]. Thus, our results suggest that myelin health may be a candidate link between MetS and cognitive decline, yet the metabolic mechanisms, which could be targeted by lipid-based therapy and dietary interventions, remain to be identified.…”
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