Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

Coronavirus disease 2019 (COVID19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originating in Wuhan China in 2019. The disease in notably severe in elderly and those with underlying chronic conditions. The molecular mechanism as to why the elderly are vulnerable and why children are resistant is largely unknown. Understanding these differences is critical for safeguarding the vulnerable and guiding effective policy and treatments. Here we show loading cells with cholesterol from blood serum using the cholesterol transport protein apolipoprotein E (apoE) enhances the endocytic entry of pseudotyped SARS-CoV-2. Super resolution imaging of the SARS-CoV-2 entry point with high cholesterol showed markedly increased apparent diameter (~10% to 100 nm) and almost twice the total number of viral entry points. The cholesterol concomitantly traffics angiotensinogen converting enzyme (ACE2) to the viral entry site where SARS-CoV-2 docks to properly exploit entry into the cell. Furthermore, we show cholesterol enhances binding of SARS-CoV-2 to the cell surface which increases association with the endocytic pathway. Decreasing cellular cholesterol has the opposite effect. Based on these findings and known loading of cholesterol into peripheral tissue during aging and inflammation, we build a cholesterol dependent model for COVID19 lethality in elderly and the chronically ill. As cholesterol increases with age and inflammation (e.g. smoking and diabetes), the cell surface is coated with viral entry points and optimally assembled viral entry proteins. Importantly our model suggests high levels of cholesterol is most alarming in the tissue, not the blood. In fact, rapidly dropping cholesterol in the blood may indicate severe loading of cholesterol in peripheral tissue and a dangerous situation for escalated SARS-CoV-2 infectivity. Polyunsaturated fatty acids (PUFAs) oppose the effects of cholesterol and provide a molecular basis for eating healthy diets to avoid severe cases of COVID19.

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“…with apoE. We adapted the technique from our studies of cholesterol loading in the central nervous system 49 .…”

Section: Resultsmentioning

confidence: 99%

The role of high cholesterol in age-related COVID19 lethality

Wang

Yuan

Pavel

et al. 2020

Preprint

Self Cite

132

177

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“…Interestingly, genetically lowering cholesterol esterification in triple-transgenic AD mice (3xTg-AD) mice also lowered pathological Tau accumulation ( Shibuya et al, 2015 ). In addition, in vivo , genetic inhibition of ApoE-mediated cholesterol transport from astrocytes to neurons also reduced neuronal pTau levels in mice ( Wang et al, 2020 ). While the exact mechanism underlying cholesterol-dependent regulation of Tau needs to be further established, these findings do further implicate cholesterol as a central player in AD pathogenesis upstream of Aβ and Tau pathology ( Kant et al, 2019 ).…”

Section: Cholesterol and Ad A Dual Driver Of Aβ And Tau Pathology In Neuronsmentioning

confidence: 99%

Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

Feringa

Kant

2021

Front. Aging Neurosci.

150

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While the central nervous system compromises 2% of our body weight, it harbors up to 25% of the body’s cholesterol. Cholesterol levels in the brain are tightly regulated for physiological brain function, but mounting evidence indicates that excessive cholesterol accumulates in Alzheimer’s disease (AD), where it may drive AD-associated pathological changes. This seems especially relevant for late-onset AD, as several of the major genetic risk factors are functionally associated with cholesterol metabolism. In this review we discuss the different systems that maintain brain cholesterol metabolism in the healthy brain, and how dysregulation of these processes can lead, or contribute to, Alzheimer’s disease. We will also discuss how AD-risk genes might impact cholesterol metabolism and downstream AD pathology. Finally, we will address the major outstanding questions in the field and how recent technical advances in CRISPR/Cas9-gene editing and induced pluripotent stem cell (iPSC)-technology can aid to study these problems.

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“…Cholesterol and raft integrity are of great importance to the modulation of both innate and acquired immune responses 37 . Amyloid-beta (Ab) has been demonstrated to protect against microbial infection as a host defense peptide and the production of Aβ is regulated by lipid raft integrity 38 , 39 ( Fig. S1C ).…”

Section: Resultsmentioning

confidence: 99%

“…prior to viral infection. We adapted cholesterol loading from our previous studies in primary neurons 37 .…”

Section: Resultsmentioning

confidence: 99%

Hydroxychloroquine: mechanism of action inhibiting SARS-CoV2 entry

Yuan

Pavel

Wang

et al. 2020

Preprint

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Background: SARS-coronavirus 2 (SARS-CoV-2) is currently causing a worldwide pandemic. Potential drugs identified for the treatment of SARS-CoV-2 infection include chloroquine (CQ), its derivative hydroxychloroquine (HCQ), and the anesthetic propofol. Their mechanism of action in SARS-CoV-2 infection is poorly understood. Recently, anesthetics, both general and local, were shown to disrupt ordered lipid domains. These same lipid domains recruit the SARS-CoV-2 surface receptor angiotensin converting enzyme 2 (ACE2) to an endocytic entry point and their disruption by cholesterol depletion decreases ACE2 recruitment and viral entry. Methods: Viral entry was determined using a SARS-CoV-2 pseudovirus (SARS2-PV) and a luciferase reporter gene expressed by the virus after treatment of the cells with 50 micromolar propofol, tetracaine, HCQ, and erythromycin. HCQ disruption of monosialotetrahexosylganglioside1 (GM1) lipid rafts, phosphatidylinositol 4,5-bisphosphate (PIP2) domains, and ACE2 receptor at nanoscale distances was monitored by direct stochastic reconstruction microscopy (dSTORM). Cells were fixed, permeabilized, and then labeled with either fluorescent cholera toxin B (CTxB) or antibody and then fixed again prior to imaging. Cluster analysis of dSTORM images was used to determine size and number and cross pair correlation was used to determine trafficking of endogenously expressed ACE2 in and out of lipid domains. Results: Propofol, tetracaine, and HCQ inhibit SARS2-PV viral entry. HCQ directly perturbs both GM1 lipid rafts and PIP2 domains. GM1 rafts increased in size and number similar to anesthetic disruption of lipid rafts; PIP2 domains decreased in size and number. HCQ blocked both GM1 and PIP2 domains ability to attract and cluster ACE2. Conclusions: We conclude HCQ is an anesthetic-like compound that disrupts GM1 lipid rafts similar to propofol and other local or general anesthetics. Furthermore, we conclude disruption of GM1 raft function, and not the concentration of GM1 raft molecules, governs the antiviral properties of HCQ. HCQ disruption of the membrane appears to also disrupt the production of host defense peptide, hence an antimicrobial such as erythromycin could be an important combined treatment. Nonetheless erythromycin has anti-SARS-CoV-2 activity and may combine with HCQ to reduce infection.

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Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

Cited by 36 publications

References 84 publications

The role of high cholesterol in age-related COVID19 lethality

The role of high cholesterol in age-related COVID19 lethality

Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

Hydroxychloroquine: mechanism of action inhibiting SARS-CoV2 entry

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