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[email protected] The overall picture of intracellular cholesterol trafficking is very complex. The transfer of cholesterol within the cell depends on the.
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Mitochondria are cholesterol-poor organelles compared to PM. However, the restricted pool of mitochondrial cholesterol, particularly at IMM, is crucial for the synthesis of neurosteroids in the brain and for physiological GABAergic responses that modulate memory function Stocco et al. As mentioned above, the rate of cholesterol translocation from OMM to IMM controls steroidogenesis, indicating that changes in the levels of cholesterol in IMM has a significant impact in the extramitochondrial functions in specialized tissues mediated by the generation of pregnenolone and subsequent steroids derived from the metabolism of cholesterol in the IMM.

Moreover, pathological conditions leading to unphysiological cholesterol accumulation in mitochondrial membranes can have a profound effect in mitochondrial function, including defective mitochondrial antioxidant defense. The mitochondrial transport of GSH from cytosol where it is synthesized de novo from its constituent aminoacids is dependent on mitochondrial membrane composition and fluidity Ribas et al. These findings are in line with the central role of changes in membrane biophysical properties in AD Yang et al.

Due to the restriction of efficient cytosol GSH transport to mitochondrial imposed by mitochondrial-mediated decrease in membrane dynamics, strategies that increase cytosol GSH levels may not be sufficient to boost mGSH levels. For instance, CAV1 knockout mice, which is characterized by increased mitochondrial cholesterol trafficking via MAM and subsequent mGSH depletion, exhibited increased brain damage caused by 3-nitropropionic acid 3NP treatment Bosch et al. Injection of 3-NP in the striatum of CAV1 null mice caused extensive cell degeneration as revealed by Fluoro-Jade stained serial sections compared to wild type mice.

In addition, there is evidence that the multifunctional htt protein intimately interacts with a variety of lipid membranes, and is essential for the normal development of several perinuclear membrane organelles, including mitochondria and the ER Gao et al. Intriguingly, however, both models of HD knock-in mice treated with olexosime, a cholesterol-like compound, showed decreasing membrane fluidity in brain-isolated mitochondrial membrane fractions and restored HD-specific changes in mitochondrial membranes.

Moreover, BACHD rats treated during months with olexosime showed counteracted the mhtt-induced membrane fluidity increment of brain-isolated mitochondrial membranes. Although, these findings link altered mitochondrial membrane properties with HD and suggest that olexosime may be a potential therapeutic opportunity for HD, whether these effects are mediated by modulating mitochondrial cholesterol levels in OMM o IMM remains to be further investigated.

Selection of latest relevant findings of cholesterol metabolism alterations in Huntington disease models. As mentioned above MAM have emerged as specialized subdomains that play key roles in cholesterol and phospholipids metabolism, calcium signaling, apoptosis, ER stress, autophagy, and mitochondrial dynamics and integrity Vance, ; van Vliet et al. This is quite relevant for neurons, since their morphology and function involve inter-organelle communication via vesicular transport that depends on MAMs to exchange metabolites and signaling molecules.

Importantly, it has been described that the ER portion of MAM is an intracellular lipid-raft domain given its detergent-resistance Area-Gomez et al. However, although there has been recent evidence against the support for the amyloidogenic APP processing in mitochondria from human neuroblastoma cell lines based on an iodixanol centrifugation gradient that separated mitochondria from lysosomes Mamada et al.

The GARP Complex Mediates Cholesterol Transport via Targeting NPC2 to Lysosomes

Moreover, PSEN1-mutant cells and AD fibroblasts exhibited a significant increase in the levels of both phosphatidylserine synthesized at MAM and phosphatidylethanolamine converted at mitochondria; Area-Gomez et al. Indeed, this outcome of increased lipid droplets is consistent with the presence of higher activity of ACAT1, a MAM-resident protein, in both PSEN1-mutant cells and in cells from AD-patients compared with controls, correlating with increased lipid droplets Area-Gomez et al.

For instance, both human fibroblasts and explanted mouse neurons treated with astrocyte-conditioned medium containing ApoE4 show a significant increase of MAM activity measured by both MAM-mediated phospholipid transport and ACAT1-mediated cholesteryl ester synthesis and lipid droplet formation Tambini et al. Using a cytometry-based FRET assay through a rapamycin-inducible fluorescent artificial ER-mitochondria tethering reporters on embryonic fibroblast from wild-type and CAV1-deficient mice, Salas-Vila et al. Importantly, the absence of CAV1 has been related with aging and AD-like neuropathology, since similar to older WT mice, young CAV1-deficient mice exhibit reduction of synapses and degeneration Head et al.

In addition to the regulation of lipid droplets, MAMs play a key role in transferring stress signals from the ER to mitochondria emerging as a central site involved in the upregulation of ER chaperones during the early adaptive phases of ER stress and in the regulation of steroidognesis van Vliet and Agostinis, Thus, based on these findings, it is conceivable that GRP78 acts as an acute regulator of mitochondrial cholesterol loading and steroidogenesis at the MAM by regulating StAR folding.

Cholesterol is a vital component of membrane bilayers that plays both structural and functional roles, regulating a wide range of signaling pathways and cell functions. Given these key biological functions, it seems evident that cholesterol homeostasis dysregulations have been associated with the onset of hereditary brain disorders and major neurodegenerative diseases. However, in the case of AD, it is unclear whether increased or decreased brain cholesterol levels are involved in brain dysfunction and disease progression.

These findings suggest that the distribution may be more important than the alterations in total cholesterol levels for neurodegeneration. Indeed, cholesterol trafficking and accumulation in PM, endolysosomes and mitochondria via MAM may be more relevant to disease progression by regulating specific signaling pathways and intracellular compartment function. This premise has been recently well-illustrated with the case of mitochondrial cholesterol accumulation in NPC disease and AD disease.

Although, the pathogenesis of both diseases is markedly different, both exhibit a common feature of increased cholesterol accumulation, which exceeds its metabolism within mitochondria. The accumulation of mitochondrial cholesterol involved an ER stress-mitochondrial cross-talk resulting in the increased expression of StARD1-mediated trafficking of cholesterol to IMM. A better understanding of the functional consequences and mechanisms of mitochondrial or endolysosomal enrichment in cholesterol may provide further insight in the pathogenesis of major neurodegenerative diseases and in the design of novel and improved therapies for treatment.

Among these approaches, improving mitochondrial antioxidant defense in a specific fashion may stand as a novel approach of relevance for neurodegeneration, such as AD, and lysosomal disorders like NPC. In this regard, the boost of cytosolic GSH levels may be insufficient to guarantee mitochondrial GSH levels due to the restriction of increased mitochondrial cholesterol accumulation, which is bypassed by GSH permeable prodrugs that diffuse into mitochondria.

The combination of this approach with other chemically modified scavengers targeted to mitochondria may be a promising approach for the treatment of neurodegenerative diseases. Selected latest brain cholesterol homeostasis factors therapeutically targeted in Alzheimer disease. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

National Center for Biotechnology Information , U. Journal List Front Mol Neurosci v. Published online Nov Author information Article notes Copyright and License information Disclaimer. Received Jul 25; Accepted Nov 2. The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

This article has been cited by other articles in PMC. Abstract Cholesterol is a critical component of membrane bilayers where it plays key structural and functional roles by regulating the activity of diverse signaling platforms and pathways. Introduction As amphipathic sterol, cholesterol exerts key structural and physiological functions in all cells. Cholesterol metabolism in the CNS Biosynthesis, homeostasis, and turnover Although, all mammalian cells have the capacity to biosynthesize cholesterol de novo , this process is crucial for the CNS since cholesterol's metabolism in the brain occurs isolated to the rest of the organism due to the BBB.

Open in a separate window. Cholesterol transport The requirement of neurons for cholesterol is very high, as it is used in neurite formation, maintenance, and synaptic connectivity. Intracellular cholesterol distribution and trafficking between organelles Once synthesized in the ER, cholesterol is then distributed to different membrane bilayers in the cell. Mitochondrial cholesterol trafficking Given the fact that the ER makes extensive MCS with other organelles such as PM, Golgi, and mitochondria, it is likely that cholesterol can move from ER to these downstream destinations. Role of intracellular cholesterol in neurodegeneration The ups and downs of cholesterol in neurodegeneration: Table 1 Selected findings of cholesterol metabolism alterations in Alzheimer disease models.

Alterations in cholesterol homeostasis Event associated Experimental model References Increased plasma cholesterol levels Increased amyloidogenesis compared to control Rabbits cholesterol-rich diet Sparks et al. Table 2 Significant observations relating cholesterol metabolism alterations and Parkinson disease. Probable increase N-glycosylation of proteins by dolichol Plausible increasing phospholipid degradation and defective membrane formation. Table 3 Selection of latest relevant findings of cholesterol metabolism alterations in Huntington disease models. Increased mitochondrial conjugated dienes 2.

Significant reduction of mitochondrial phospholipids in striatum Decreased mitochondrial membrane fluidity. MAM in cholesterol trafficking and neurodegeneration As mentioned above MAM have emerged as specialized subdomains that play key roles in cholesterol and phospholipids metabolism, calcium signaling, apoptosis, ER stress, autophagy, and mitochondrial dynamics and integrity Vance, ; van Vliet et al.

Concluding remarks Cholesterol is a vital component of membrane bilayers that plays both structural and functional roles, regulating a wide range of signaling pathways and cell functions. Table 4 Selected latest brain cholesterol homeostasis factors therapeutically targeted in Alzheimer disease. Conflict of interest statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The steroidogenic acute regulatory protein homolog MLN64, a late endosomal cholesterol-binding protein.

Amyloid-beta Alzheimer targets - protein processing, lipid rafts, and amyloid-beta pores. Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. Mitochondria-associated ER membranes and Alzheimer disease. On the pathogenesis of Alzheimer's disease: How the Wnt signaling pathway protects from neurodegeneration: MLN64 induces mitochondrial dysfunction associated with increased mitochondrial cholesterol content.

Endoplasmic reticulum stress mediates amyloid beta neurotoxicity via mitochondrial cholesterol trafficking. Function of lipid droplet-organelle interactions in lipid homeostasis. Acta , — Brain neutral lipids mass is increased in alpha-synuclein gene-ablated mice. The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science , — Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature , — Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene.


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Traffic 12 , — Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization. Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. Fatty acid incorporation is decreased in astrocytes cultured from alpha-synuclein gene-ablated mice. MLN64 mediates egress of cholesterol from endosomes to mitochondria in the absence of functional Niemann-Pick Type C1 protein.

Cholesteryl ester transfer protein polymorphism DG associated with a potential decreased risk for Alzheimer's disease as a modifier for APOE epsilon4 in Chinese. Regulation of alpha-synuclein expression by liver X receptor ligands in vitro. Neuroreport 19 , — Cell 24 , — Lipid droplet binding and oligomerization properties of the Parkinson's disease protein alpha-synuclein. Membrane raft domains and remodeling in aging brain. Biochimie , — Neuron 79 , — Localization and processing of the amyloid-beta protein precursor in mitochondria-associated membranes.

Positive correlation between elevated plasma cholesterol levels and cognitive impairments in LDL receptor knockout mice: Neuroscience , 99— ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism. Brain , — Linking lipids to Alzheimer's disease: Cholesterol modulates the membrane-disordering effects of beta-amyloid peptides in the hippocampus: Mitochondrial membrane fluidity is consistently increased in different models of Huntington disease: Membrane lipid rafts and neurobiology: Convergent signaling pathways controlled by LRP1 receptor-related protein 1 cytoplasmic and extracellular domains limit cellular cholesterol accumulation.

Alzheimer's disease risk genes and lipid regulators. Acta , 90— Impact of high cholesterol in a Parkinson's disease model: Mitochondrial cholesterol loading exacerbates amyloid beta peptide-induced inflammation and neurotoxicity. ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading. Intravenous treatment with human recombinant ApoA-I Milano reduces beta amyloid cerebral deposition in the APPtransgenic mouse model of Alzheimer's disease.

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Aging 60 , — The role of lipids interacting with alpha-synuclein in the pathogenesis of Parkinson's disease. Oxidized cholesterol as the driving force behind the development of Alzheimer's disease. Cholesterol modifies huntingtin binding to, disruption of, and aggregation on lipid membranes. Biochemistry 55 , 92— Mitochondrial cholesterol in health and disease.

Human mitochondrial DNA-protein complexes attach to a cholesterol-rich membrane structure. Oxysterol-binding protein activation at endoplasmic reticulum-golgi contact sites reorganizes phosphatidylinositol 4-phosphate pools. Role of serum cholesterol in Parkinson's disease: HIG1, a novel regulator of mitochondrial gamma-secretase, maintains normal mitochondrial function. Loss of caveolin-1 accelerates neurodegeneration and aging. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease.

Activation of the unfolded protein response is an early event in Alzheimer's and Parkinson's disease. Total cholesterol and the risk of Parkinson disease. Neurology 70 , — Serum cholesterol and the progression of Parkinson's disease: A genome-wide expression profile of adrenocortical cells in knockout mice lacking steroidogenic acute regulatory protein. Endocrinology , — Increased expression of the lysosomal cholesterol transporter NPC1 in Alzheimer's disease. Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance.

Neuron 64 , — Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha -secretase ADAM ATP-binding cassette transporter A1: Mitochondria-associated membranes as hubs for neurodegeneration. Hypothalamic digoxin-mediated model for Parkinson's disease. The impairment of cholesterol metabolism in Huntington disease. Non-vesicular lipid transport by lipid-transfer proteins and beyond. An update on type 2 diabetes mellitus as a risk factor for Dementia. Anti-ApoE antibody given after plaque onset decreases Abeta accumulation and improves brain function in a mouse model of Abeta amyloidosis.

Lanosterol induces mitochondrial uncoupling and protects dopaminergic neurons from cell death in a model for Parkinson's disease. Alzheimer's APP mangles mitochondria. SNARE-mediated cholesterol movement to mitochondria supports steroidogenesis in rodent cells. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell , — Routes and mechanisms of post-endosomal cholesterol trafficking: Traffic 18 , — Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: Bidirectional links between Alzheimer's disease and Niemann-Pick type C disease.

Niemann-Pick type C cells show cholesterol dependent decrease of APP expression at the cell surface and its increased processing through the beta-secretase pathway. Mitochondria are devoid of amyloid beta-protein Abeta -producing secretases: Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cholesterol in brain disease: Cholesterol metabolism and transport in the pathogenesis of Alzheimer's disease. Evidence for changes in the Alzheimer's disease brain cortical membrane structure mediated by cholesterol. Aging 13 , — Cholesterol-metabolizing enzyme cytochrome P 46A1 as a pharmacologic target for Alzheimer's disease.

Neuropharmacology , — Mitochondrial modulators improve lipid composition and attenuate memory deficits in experimental model of Huntington's disease. Insights into the mechanisms of sterol transport between organelles.

Intracellular cholesterol trafficking.

Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss. Endocrinology , 89— Acta 12 Pt A , — Acat1 knockdown gene therapy decreases amyloid-beta in a mouse model of Alzheimer's disease. Decreased cholesterol biosynthesis in fibroblasts from patients with Parkinson disease.

Rab GTPases and their roles in brain neurons and glia. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Neuroepidemiology 17 , 14— Altered cholesterol ester cycle in skin fibroblasts from patients with Alzheimer's disease. Cholesterol - A putative endogenous contributor towards Parkinson's disease.

Apolipoprotein E4 elicits lysosomal cathepsin D release, decreased thioredoxin-1 levels, and apoptosis. Changes in apolipoprotein E expression in response to dietary and pharmacological modulation of cholesterol. The role of endoplasmic reticulum in amyloid precursor protein processing and trafficking: Mitochondria-associated endoplasmic reticulum membrane MAM regulates steroidogenic activity via steroidogenic acute regulatory protein StAR -voltage-dependent anion channel 2 VDAC2 interaction. Mitochondrial metabolic regulation by GRP Role of acyl-coenzyme a: Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer's disease: Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model.

Current insights into pathogenesis of Parkinson's disease: Interplay between hepatic mitochondria-associated membranes, lipid metabolism and caveolin-1 in mice. Desmosterolosis-phenotypic and molecular characterization of a third case and review of the literature. A A , — Metabolic characterization of intact cells reveals intracellular amyloid beta but not its precursor protein to reduce mitochondrial respiration. Mitochondria-associated ER membranes in Alzheimer disease. Lysosome and endoplasmic reticulum quality control pathways in Niemann-Pick type C disease.

Review ARTICLE

Processing of endogenous AbetaPP in blood-brain barrier endothelial cells is modulated by liver-X receptor agonists and altered cellular cholesterol homeostasis. Cholesterol homeostasis failure in the brain: Current status and future perspectives: TSPO in steroid neuroendocrinology. Early and brain region-specific decrease of de novo cholesterol biosynthesis in Huntington's disease: Diet-induced hypercholesterolemia enhances brain A beta accumulation in transgenic mice.

However, although there has been recent evidence against the support for the amyloidogenic APP processing in mitochondria from human neuroblastoma cell lines based on an iodixanol centrifugation gradient that separated mitochondria from lysosomes Mamada et al. Moreover, PSEN1-mutant cells and AD fibroblasts exhibited a significant increase in the levels of both phosphatidylserine synthesized at MAM and phosphatidylethanolamine converted at mitochondria; Area-Gomez et al. Indeed, this outcome of increased lipid droplets is consistent with the presence of higher activity of ACAT1, a MAM-resident protein, in both PSEN1-mutant cells and in cells from AD-patients compared with controls, correlating with increased lipid droplets Area-Gomez et al.

For instance, both human fibroblasts and explanted mouse neurons treated with astrocyte-conditioned medium containing ApoE4 show a significant increase of MAM activity measured by both MAM-mediated phospholipid transport and ACAT1-mediated cholesteryl ester synthesis and lipid droplet formation Tambini et al. Using a cytometry-based FRET assay through a rapamycin-inducible fluorescent artificial ER-mitochondria tethering reporters on embryonic fibroblast from wild-type and CAV1-deficient mice, Salas-Vila et al. Importantly, the absence of CAV1 has been related with aging and AD-like neuropathology, since similar to older WT mice, young CAV1-deficient mice exhibit reduction of synapses and degeneration Head et al.

In addition to the regulation of lipid droplets, MAMs play a key role in transferring stress signals from the ER to mitochondria emerging as a central site involved in the upregulation of ER chaperones during the early adaptive phases of ER stress and in the regulation of steroidognesis van Vliet and Agostinis, Thus, based on these findings, it is conceivable that GRP78 acts as an acute regulator of mitochondrial cholesterol loading and steroidogenesis at the MAM by regulating StAR folding.

Together, all these observations not only support the concept that MAMs emerge as intracellular sites for amyloidogenic APP processing, but also that MAM agglutinates several other biochemical and morphological features typically observed at early stages of AD Figure 2B , especially mitochondrial dysfunction as a common feature in many neurodegenerative diseases, defining the so called MAM hypothesis as a key event for AD pathogenesis Area-Gomez and Schon, Cholesterol is a vital component of membrane bilayers that plays both structural and functional roles, regulating a wide range of signaling pathways and cell functions.

Given these key biological functions, it seems evident that cholesterol homeostasis dysregulations have been associated with the onset of hereditary brain disorders and major neurodegenerative diseases. However, in the case of AD, it is unclear whether increased or decreased brain cholesterol levels are involved in brain dysfunction and disease progression. These findings suggest that the distribution may be more important than the alterations in total cholesterol levels for neurodegeneration. Indeed, cholesterol trafficking and accumulation in PM, endolysosomes and mitochondria via MAM may be more relevant to disease progression by regulating specific signaling pathways and intracellular compartment function.

This premise has been recently well-illustrated with the case of mitochondrial cholesterol accumulation in NPC disease and AD disease. Although, the pathogenesis of both diseases is markedly different, both exhibit a common feature of increased cholesterol accumulation, which exceeds its metabolism within mitochondria. The accumulation of mitochondrial cholesterol involved an ER stress-mitochondrial cross-talk resulting in the increased expression of StARD1-mediated trafficking of cholesterol to IMM. A better understanding of the functional consequences and mechanisms of mitochondrial or endolysosomal enrichment in cholesterol may provide further insight in the pathogenesis of major neurodegenerative diseases and in the design of novel and improved therapies for treatment.

Among these approaches, improving mitochondrial antioxidant defense in a specific fashion may stand as a novel approach of relevance for neurodegeneration, such as AD, and lysosomal disorders like NPC. In this regard, the boost of cytosolic GSH levels may be insufficient to guarantee mitochondrial GSH levels due to the restriction of increased mitochondrial cholesterol accumulation, which is bypassed by GSH permeable prodrugs that diffuse into mitochondria. The combination of this approach with other chemically modified scavengers targeted to mitochondria may be a promising approach for the treatment of neurodegenerative diseases.

Selected latest brain cholesterol homeostasis factors therapeutically targeted in Alzheimer disease. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The steroidogenic acute regulatory protein homolog MLN64, a late endosomal cholesterol-binding protein. Amyloid-beta Alzheimer targets - protein processing, lipid rafts, and amyloid-beta pores.

Intracellular cholesterol trafficking.

PubMed Abstract Google Scholar. Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. Mitochondria-associated ER membranes and Alzheimer disease. On the pathogenesis of Alzheimer's disease: How the Wnt signaling pathway protects from neurodegeneration: MLN64 induces mitochondrial dysfunction associated with increased mitochondrial cholesterol content. Endoplasmic reticulum stress mediates amyloid beta neurotoxicity via mitochondrial cholesterol trafficking. Function of lipid droplet-organelle interactions in lipid homeostasis. Brain neutral lipids mass is increased in alpha-synuclein gene-ablated mice.

The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene. Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization.

Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. Fatty acid incorporation is decreased in astrocytes cultured from alpha-synuclein gene-ablated mice. MLN64 mediates egress of cholesterol from endosomes to mitochondria in the absence of functional Niemann-Pick Type C1 protein. Cholesteryl ester transfer protein polymorphism DG associated with a potential decreased risk for Alzheimer's disease as a modifier for APOE epsilon4 in Chinese.

Regulation of alpha-synuclein expression by liver X receptor ligands in vitro. Lipid droplet binding and oligomerization properties of the Parkinson's disease protein alpha-synuclein. Membrane raft domains and remodeling in aging brain. Localization and processing of the amyloid-beta protein precursor in mitochondria-associated membranes. Positive correlation between elevated plasma cholesterol levels and cognitive impairments in LDL receptor knockout mice: ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.

Linking lipids to Alzheimer's disease: Cholesterol modulates the membrane-disordering effects of beta-amyloid peptides in the hippocampus: Mitochondrial membrane fluidity is consistently increased in different models of Huntington disease: Membrane lipid rafts and neurobiology: Convergent signaling pathways controlled by LRP1 receptor-related protein 1 cytoplasmic and extracellular domains limit cellular cholesterol accumulation. Alzheimer's disease risk genes and lipid regulators.

Impact of high cholesterol in a Parkinson's disease model: Mitochondrial cholesterol loading exacerbates amyloid beta peptide-induced inflammation and neurotoxicity. ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading. Intravenous treatment with human recombinant ApoA-I Milano reduces beta amyloid cerebral deposition in the APPtransgenic mouse model of Alzheimer's disease.

The role of lipids interacting with alpha-synuclein in the pathogenesis of Parkinson's disease. Oxidized cholesterol as the driving force behind the development of Alzheimer's disease. Cholesterol modifies huntingtin binding to, disruption of, and aggregation on lipid membranes. Mitochondrial cholesterol in health and disease. Human mitochondrial DNA-protein complexes attach to a cholesterol-rich membrane structure. Oxysterol-binding protein activation at endoplasmic reticulum-golgi contact sites reorganizes phosphatidylinositol 4-phosphate pools. Role of serum cholesterol in Parkinson's disease: HIG1, a novel regulator of mitochondrial gamma-secretase, maintains normal mitochondrial function.

Loss of caveolin-1 accelerates neurodegeneration and aging. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease. Activation of the unfolded protein response is an early event in Alzheimer's and Parkinson's disease. Total cholesterol and the risk of Parkinson disease. Serum cholesterol and the progression of Parkinson's disease: A genome-wide expression profile of adrenocortical cells in knockout mice lacking steroidogenic acute regulatory protein. Increased expression of the lysosomal cholesterol transporter NPC1 in Alzheimer's disease.

Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha -secretase ADAM ATP-binding cassette transporter A1: Mitochondria-associated membranes as hubs for neurodegeneration. Hypothalamic digoxin-mediated model for Parkinson's disease. The impairment of cholesterol metabolism in Huntington disease. Non-vesicular lipid transport by lipid-transfer proteins and beyond.

An update on type 2 diabetes mellitus as a risk factor for Dementia. Anti-ApoE antibody given after plaque onset decreases Abeta accumulation and improves brain function in a mouse model of Abeta amyloidosis. Lanosterol induces mitochondrial uncoupling and protects dopaminergic neurons from cell death in a model for Parkinson's disease.

Alzheimer's APP mangles mitochondria. SNARE-mediated cholesterol movement to mitochondria supports steroidogenesis in rodent cells. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Routes and mechanisms of post-endosomal cholesterol trafficking: Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: Bidirectional links between Alzheimer's disease and Niemann-Pick type C disease.

Niemann-Pick type C cells show cholesterol dependent decrease of APP expression at the cell surface and its increased processing through the beta-secretase pathway. Mitochondria are devoid of amyloid beta-protein Abeta -producing secretases: Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cholesterol in brain disease: Cholesterol metabolism and transport in the pathogenesis of Alzheimer's disease. Evidence for changes in the Alzheimer's disease brain cortical membrane structure mediated by cholesterol.

Cholesterol-metabolizing enzyme cytochrome P 46A1 as a pharmacologic target for Alzheimer's disease. Mitochondrial modulators improve lipid composition and attenuate memory deficits in experimental model of Huntington's disease. Insights into the mechanisms of sterol transport between organelles. Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss. Acta 12 Pt A , — Acat1 knockdown gene therapy decreases amyloid-beta in a mouse model of Alzheimer's disease. Decreased cholesterol biosynthesis in fibroblasts from patients with Parkinson disease.

Rab GTPases and their roles in brain neurons and glia. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Altered cholesterol ester cycle in skin fibroblasts from patients with Alzheimer's disease. Cholesterol - A putative endogenous contributor towards Parkinson's disease. Apolipoprotein E4 elicits lysosomal cathepsin D release, decreased thioredoxin-1 levels, and apoptosis.

Changes in apolipoprotein E expression in response to dietary and pharmacological modulation of cholesterol. The role of endoplasmic reticulum in amyloid precursor protein processing and trafficking: Mitochondria-associated endoplasmic reticulum membrane MAM regulates steroidogenic activity via steroidogenic acute regulatory protein StAR -voltage-dependent anion channel 2 VDAC2 interaction.

Mitochondrial metabolic regulation by GRP Role of acyl-coenzyme a: Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer's disease: Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Current insights into pathogenesis of Parkinson's disease: Interplay between hepatic mitochondria-associated membranes, lipid metabolism and caveolin-1 in mice. Desmosterolosis-phenotypic and molecular characterization of a third case and review of the literature.

Introduction

Metabolic characterization of intact cells reveals intracellular amyloid beta but not its precursor protein to reduce mitochondrial respiration. Mitochondria-associated ER membranes in Alzheimer disease. Lysosome and endoplasmic reticulum quality control pathways in Niemann-Pick type C disease.

Processing of endogenous AbetaPP in blood-brain barrier endothelial cells is modulated by liver-X receptor agonists and altered cellular cholesterol homeostasis. Cholesterol homeostasis failure in the brain: Current status and future perspectives: TSPO in steroid neuroendocrinology. Early and brain region-specific decrease of de novo cholesterol biosynthesis in Huntington's disease: Diet-induced hypercholesterolemia enhances brain A beta accumulation in transgenic mice.

The role of oxidized cholesterol in diabetes-induced lysosomal dysfunction in the brain. Intracellular cholesterol transport proteins: Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. A brief history of the search for the protein s involved in the acute regulation of steroidogenesis. ApoE4 upregulates the activity of mitochondria-associated ER membranes. Dietary cholesterol, fats and risk of Parkinson's disease in the Singapore chinese health study. Direct transcriptional effects of apolipoprotein E. High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice.

Blood-brain barrier permeability precedes senile plaque formation in an Alzheimer disease model. Dysregulation of cholesterol balance in the brain: MAM mitochondria-associated membranes in mammalian cells: Regulation of cholesterol homeostasis. New functions of mitochondria associated membranes in cellular signaling. Steroidogenic acute regulatory protein StAR: Decreased prevalence of Alzheimer disease associated with 3-hydroxymethyglutaryl coenzyme A reductase inhibitors.

Peroxisome-proliferator-activated receptor gamma coactivator 1 alpha contributes to dysmyelination in experimental models of Huntington's disease. Induction of apoptosis and necroptosis by 24 S -hydroxycholesterol is dependent on activity of acyl-CoA: Cyclodextrin has conflicting actions on autophagy flux in vivo in brains of normal and Alzheimer model mice. Cellular membrane fluidity in amyloid precursor protein processing. Altered cholesterol metabolism in Niemann-Pick type C1 mouse brains affects mitochondrial function. Novel S-acyl glutathione derivatives prevent amyloid oxidative stress and cholinergic dysfunction in Alzheimer disease models.

Regulatory effects of simvastatin and apoJ on APP processing and amyloid-beta clearance in blood-brain barrier endothelial cells. Cholesterol metabolism and homeostasis in the brain. Protein Cell 6, — NCEH-1 modulates cholesterol metabolism and protects against alpha-synuclein toxicity in a C. Cathepsin D-mediated proteolysis of apolipoprotein E: ACAT1 regulates the dynamics of free cholesterols in plasma membrane which leads to the APP-alpha-processing alteration.

Neurodegeneration and the neurovascular unit. The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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