Cholesterol Dysmetabolism in Alzheimer’s Disease: A Starring Role for Astrocytes?

Staurenghi, Erica; Giannelli, Serena; Testa, Gabriella; Sottero, Barbara; Leonarduzzi, Gabriella; Gamba, Paola

doi:10.3390/antiox10121890

Cited by 28 publications

(21 citation statements)

References 201 publications

(268 reference statements)

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“…In that sense, 27-HC is synthesized by CYP27A1, representing the major cholesterol metabolite in the circulation. Its expression takes place in most of the organs and tissues [ 75 ] and can be transported by diffusion from the circulation into the brain [ 76 ]. Recent works support the idea that the pool of 27-HC contributes to cholesterol-related metabolite uptake in neurons [ 77 ].…”

Section: Hdl-mediated Cholesterol Trafficking In the Cnsmentioning

confidence: 99%

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

Borràs

Mercer

Sirisi

et al. 2022

IJMS

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The main aim of this work is to review the mechanisms via which high-density lipoprotein (HDL)-mediated cholesterol trafficking through the central nervous system (CNS) occurs in the context of Alzheimer’s disease (AD). Alzheimer’s disease is characterized by the accumulation of extracellular amyloid beta (Aβ) and abnormally hyperphosphorylated intracellular tau filaments in neurons. Cholesterol metabolism has been extensively implicated in the pathogenesis of AD through biological, epidemiological, and genetic studies, with the APOE gene being the most reproducible genetic risk factor for the development of AD. This manuscript explores how HDL-mediated cholesterol is transported in the CNS, with a special emphasis on its relationship to Aβ peptide accumulation and apolipoprotein E (ApoE)-mediated cholesterol transport. Indeed, we reviewed all existing works exploring HDL-like-mediated cholesterol efflux and cholesterol uptake in the context of AD pathogenesis. Existing data seem to point in the direction of decreased cholesterol efflux and the impaired entry of cholesterol into neurons among patients with AD, which could be related to impaired Aβ clearance and tau protein accumulation. However, most of the reviewed studies have been performed in cells that are not physiologically relevant for CNS pathology, representing a major flaw in this field. The ApoE4 genotype seems to be a disruptive element in HDL-like-mediated cholesterol transport through the brain. Overall, further investigations are needed to clarify the role of cholesterol trafficking in AD pathogenesis.

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Section: Hdl-mediated Cholesterol Trafficking In the Cnsmentioning

confidence: 99%

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

Borràs

Mercer

Sirisi

et al. 2022

IJMS

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“…In the developing mammalian brain, cholesterol is abundant and the majority of it is synthesized in oligodendrocytes and utilized in myelination ( Dietschy, 2009 ). In the adult brain, however, most cholesterol is synthesized in astrocytes and it can be transferred to neurons in order to maintain axonal integrity ( Dietschy, 2009 ; Mou et al, 2020 ; Staurenghi et al, 2021 ). In mouse models of Alzheimer’s disease, brain CEs—as well as TAGs—are elevated and LDs accumulate in forebrain ependymal cells of the neural stem cell niche ( Chan et al, 2012 ; Yang et al, 2014 ; Hamilton et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Functions of Stress-Induced Lipid Droplets in the Nervous System

Islimye

Girard

Gould

2022

Front. Cell Dev. Biol.

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Lipid droplets are highly dynamic intracellular organelles that store neutral lipids such as cholesteryl esters and triacylglycerols. They have recently emerged as key stress response components in many different cell types. Lipid droplets in the nervous system are mostly observed in vivo in glia, ependymal cells and microglia. They tend to become more numerous in these cell types and can also form in neurons as a consequence of ageing or stresses involving redox imbalance and lipotoxicity. Abundant lipid droplets are also a characteristic feature of several neurodegenerative diseases. In this minireview, we take a cell-type perspective on recent advances in our understanding of lipid droplet metabolism in glia, neurons and neural stem cells during health and disease. We highlight that a given lipid droplet subfunction, such as triacylglycerol lipolysis, can be physiologically beneficial or harmful to the functions of the nervous system depending upon cellular context. The mechanistic understanding of context-dependent lipid droplet functions in the nervous system is progressing apace, aided by new technologies for probing the lipid droplet proteome and lipidome with single-cell type precision.

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Section: Introductionmentioning

confidence: 99%

“…Astrocytes are important for cholesterol synthesis in brain and are a major source of ApoE-containing lipoprotein particles central to cholesterol transport between astrocytes, neurons, and other cells (22). APOE is the most important risk factor for AD and contributes significantly to the risk of developing several other neurological and non-neurological disorders (23).…”

Section: Introductionmentioning

confidence: 99%

Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol

Cashikar

Rios

Timm

et al. 2022

Preprint

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Neuroinflammation is a major hallmark of Alzheimer disease and several other neurological and psychiatric disorders and is often associated with dysregulated cholesterol metabolism. Relative to homeostatic microglia, activated microglia express higher levels of Ch25h, an enzyme that hydroxylates cholesterol to produce 25-hydroxycholesterol (25HC). 25HC is an oxysterol with interesting immune roles stemming from its ability to regulate cholesterol biosynthesis. Since astrocytes synthesize cholesterol in the brain and transport it to other cells via apolipoprotein E (ApoE)-containing lipoproteins, we hypothesized that secreted 25HC from microglia may influence lipid metabolism as well as extracellular ApoE derived from astrocytes. Here we show that astrocytes take up externally added 25HC and respond with altered lipid metabolism. 25HC increased extracellular levels of ApoE lipoprotein particles without altering Apoe mRNA expression, due to elevated Abca1 expression via activation of LXRs and decreased ApoE reuptake due to suppressed Ldlr expression via inhibition of SREBP. Astrocytes metabolized 25HC to limit its effects on lipid metabolism via Cyp7b1, an enzyme responsible for 7alpha-hydroxylation of 25HC. Knockdown of Cyp7b1 expression with siRNA prolonged the effects of 25HC on astrocyte lipid metabolism. 25HC also suppressed Srebf2 expression to reduce cholesterol synthesis in astrocytes but did not affect fatty acid levels or the genes required for fatty acid synthesis. We further show that 25HC led to a doubling of the amount of cholesterol esters and their concomitant storage in lipid droplets. Our results suggest an important role for 25HC in regulating astrocyte lipid metabolism.

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Cholesterol Dysmetabolism in Alzheimer’s Disease: A Starring Role for Astrocytes?

Cited by 28 publications

References 201 publications

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

Functions of Stress-Induced Lipid Droplets in the Nervous System

Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol

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