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Cited by 302Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsCholesterol and Lipid Metabolism

The DOI matches its Crossref record; 82 of the 82 references it cites were found in a registry or an index; 34 of the 56 sources its claims cite were checked for support.

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

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Wang, Hao, Kulas, Joshua A., Wang, Chao, Holtzman, David M., Ferris, Heather A., Hansen, Scott B.·2021·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2102191118PMC PMC8379952

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Abstract

Significance: The accumulation of amyloid β (Aβ) in the brain appears to be a necessary event in the pathogenesis of Alzheimer’s disease (AD). However, processes linked to the endogenous regulation of Aβ production are still not completely understood. Here, the authors show that Aβ accumulation in neurons is tightly regulated by cholesterol synthesis and apoE transport from astrocytes. The study provides a molecular context for understanding the endogenous regulation of Aβ accumulation and why it correlates with AD. The tight regulation suggests that Aβ may perform an important cellular function. A complete understanding of the mechanism is likely necessary to predict whether the selective removal of Aβ has potential for a therapeutic benefit.

Overview

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TL;DR

Astrocyte-derived cholesterol, transported to neurons by apoE, regulates APP localization to GM1 lipid clusters and thereby shifts APP processing between nonamyloidogenic sAPP-α and amyloidogenic Aβ. Deleting astrocyte SREBP2 in 3xTg-AD mice nearly eliminates insoluble Aβ and plaques, linking astrocyte cholesterol, apoE, and amyloid pathology in one pathway.

Key findings

  • dSTORM imaging showed GM1 domains averaged ∼141 nm in WT mouse cortical tissue, ∼150 nm in primary neurons, and ∼100 nm in N2a cells; astrocyte SREBP2 knockout reduced primary neuron cluster size to 130 nm, and apoE +FBS increased N2a cluster diameter from 100 to 130 nm.
  • APP, β-secretase, and γ-secretase associated with GM1 clusters (pair correlation 10–15), while α-secretase did not (<3); apoE cholesterol loading increased APP–GM1 association almost twofold versus efflux, and in primary cultures apoE decreased APP association >twofold in purified neurons but increased it 2.5-fold when astrocytes were present.
  • In 3xTg-AD × SREBP2fl/fl GFAP-Cre mice at 60 wk, soluble Aβ40 and Aβ42 were reduced twofold, insoluble Aβ40 and Aβ42 were almost entirely eliminated, amyloid plaques were absent, and pTau at T181 was eliminated, with total APP, GFAP, and ApoE unchanged.
  • ApoE4 knock-in brains showed increased APP–GM1 association versus apoE3, but purified apoE3 and apoE4 did not differ significantly in loading or unloading cholesterol in N2a cells.

Methods

  • Superresolution dSTORM imaging in N2a cells, primary cortical neurons, mixed neuron/astrocyte cultures, and mouse brain slices; GM1 lipids were labeled with fluorescent CTxB and APP/secretases with antibodies, followed by pair-correlation and cluster analysis.
  • Mouse genetics included astrocyte-specific SREBP2 knockout via ALDH1L1-Cre or GFAP-Cre, crosses with 3xTg-AD and APOE-KI/APP/PS1 mice, and measurements by ELISA for Aβ40/42, sAPP-α, and pTau, plus Western blot, lipidomics mass spectrometry, and live-cell cholesterol assays.
  • Cell culture used embryonic day 17 cortical neurons, FACS sorting with Thy1.2, astrocyte-conditioned media from WT or APOE−/− astrocytes, and apoE3/apoE4 treatments with or without FBS/cholesterol.

Limitations

  • Stated: all astrocyte-targeting Cre lines also delete to some degree in neural progenitor cells, and the exact mechanisms by which astrocyte cholesterol influences neuronal tau phosphorylation require future investigations.
  • Evident: most mechanistic evidence comes from cultured cells and mouse models, with no human tissue or clinical data; the in vivo apoE4 versus apoE3 cholesterol trend was not statistically significant, and purified apoE3/apoE4 showed no significant functional difference in cholesterol transport.
  • Evident: reduced brain tissue volume was observed in AD × SB2−/− animals, similar to prior astrocyte-specific SB2−/− brains, which could complicate interpretation of pathology endpoints.

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Crossref · 10.1073/pnas.2102191118

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Figures

Fig. 1. Astrocyte cholesterol signals to membrane nanostructure in neurons. (A) dSTORM superresolution imaging on WT brain slices showing lipid cluster nanostructure in cell membrane. (Scale Bar, 2 µm.) (B) Comparison of apparent cluster length in N2a cells; primary neurons cultured with astrocytes with and without (SREBP−/−) cholesterol synthesis and brain slices. Data are expressed as mean ± SEM and n = 1,748 to 6,779 clusters from >3 images. (C) Mass spectrometry analysis showing that the majority of lipids extracted by apoE (a cholesterol transport protein) from N2a cells are cholesterol. Some cluster-associated lipids are also transported by apoE. Abbreviations for lipids: FC, free cholesterol; CE, cholesterol ester; SM, sphingomyelin; dhSM, dihydrosphingomyelin; and Pep, plasmalogen phosphatidylethanolamine. (D) Quantitation of cluster lengths in N2a cells indicates changes in cluster structure after apoE treatment with and without a source of cholesterol (± chol). Data are expressed as mean ± SEM and n = 1,911 to 6,779 clusters from four to seven cells. (E) Quantitation of GM1 clusters in N2a cells shows that apoE decreased the number of clusters under low-cholesterol conditions, while apoE treatment with high, environmental cholesterol doesn’t affect cluster number. Data are expressed as mean ± SEM and one-way ANOVA. (F) Exposure of N2a cells to apoE removes cholesterol from cellular membranes, as measured by a fluorescent-based live cell cholesterol assay. Cholesterol loading by apoE increases cellular cholesterol level. Data are expressed as mean ± SEM, n = 4 to 7, one-way ANOVA, *P < 0.05, ***P < 0.001, and ****P < 0.0001.
Fig. 1. Astrocyte cholesterol signals to membrane nanostructure in neurons. (A) dSTORM superresolution imaging on WT brain slices showing lipid cluster nanostructure in cell membrane. (Scale Bar, 2 µm.) (B) Comparison of apparent cluster length in N2a cells; primary neurons cultured with astrocytes with and without (SREBP−/−) cholesterol synthesis and brain slices. Data are expressed as mean ± SEM and n = 1,748 to 6,779 clusters from >3 images. (C) Mass spectrometry analysis showing that the majority of lipids extracted by apoE (a cholesterol transport protein) from N2a cells are cholesterol. Some cluster-associated lipids are also transported by apoE. Abbreviations for lipids: FC, free cholesterol; CE, cholesterol ester; SM, sphingomyelin; dhSM, dihydrosphingomyelin; and Pep, plasmalogen phosphatidylethanolamine. (D) Quantitation of cluster lengths in N2a cells indicates changes in cluster structure after apoE treatment with and without a source of cholesterol (± chol). Data are expressed as mean ± SEM and n = 1,911 to 6,779 clusters from four to seven cells. (E) Quantitation of GM1 clusters in N2a cells shows that apoE decreased the number of clusters under low-cholesterol conditions, while apoE treatment with high, environmental cholesterol doesn’t affect cluster number. Data are expressed as mean ± SEM and one-way ANOVA. (F) Exposure of N2a cells to apoE removes cholesterol from cellular membranes, as measured by a fluorescent-based live cell cholesterol assay. Cholesterol loading by apoE increases cellular cholesterol level. Data are expressed as mean ± SEM, n = 4 to 7, one-way ANOVA, *P < 0.05, ***P < 0.001, and ****P < 0.0001.CC BY-NC-ND · PubMed Central
Fig. 2. APP is regulated by cholesterol, not its hydrolytic enzymes. (A) Workflow for dSTORM superresolution. Cultured cells (blue) are depicted in a dish. Cells were exposed to apoE with and without cholesterol supplementation and fixed. GM1 lipids and amyloid proteins were fluorescently labeled (CTxB and antibody, respectively) and imaged with superresolution (dSTORM). The proximity of the two labels (shown as red and green circles) was then determined by cluster analysis. Idealized pair correlations are shown for objects that strongly colocalize (Top) and weakly colocalize (Bottom) at a given radius. Pair correlations are unitless with 1 being little to no correlation and >5 a value typically significant in our experimental conditions. (B) α-secretase sits in the disordered region (low correlation with GM1 lipid clusters), while APP, β-, and γ-secretases are GM1 associated in N2a cells. (C and D) Pair correlation analysis showing that APP moving in (C) and out (D) of the GM1 clusters under high- and low-cholesterol conditions, respectively. (E) Under low-cholesterol conditions (−Chol), APP colocalization with GM1 clusters decreases markedly after apoE treatment. Under high-cholesterol conditions (+Chol), apoE-mediated APP colocalization with GM1 clusters increases (i.e., apoE induces APP to cluster with GM1 lipids). α-, β-, and γ-secretase localization do not respond to apoE-mediated GM1 clustering. (F) ELISA in N2a cells showing a shift from Aβ to sAPP-α production after apoE treatment under low-cholesterol condition and increased Aβ production under high-cholesterol condition. Data are expressed as mean ± SEM, n = 3 to 10. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, n.s. (not significant), and two-sided Student’s t test. (G and H) Because of cluster disruption mediated by apoE, APP is dissociated from GM1 clusters under low-cholesterol conditions, exposing it to α-secretase to be cleaved into nonamyloidogenic sAPP-α. With high, environmental cholesterol, apoE-induced cluster stabilization mediates more APP to be translocated into lipid clusters and cleaved by β- and γ-secretase, producing amyloidogenic Aβ peptides.
Fig. 2. APP is regulated by cholesterol, not its hydrolytic enzymes. (A) Workflow for dSTORM superresolution. Cultured cells (blue) are depicted in a dish. Cells were exposed to apoE with and without cholesterol supplementation and fixed. GM1 lipids and amyloid proteins were fluorescently labeled (CTxB and antibody, respectively) and imaged with superresolution (dSTORM). The proximity of the two labels (shown as red and green circles) was then determined by cluster analysis. Idealized pair correlations are shown for objects that strongly colocalize (Top) and weakly colocalize (Bottom) at a given radius. Pair correlations are unitless with 1 being little to no correlation and >5 a value typically significant in our experimental conditions. (B) α-secretase sits in the disordered region (low correlation with GM1 lipid clusters), while APP, β-, and γ-secretases are GM1 associated in N2a cells. (C and D) Pair correlation analysis showing that APP moving in (C) and out (D) of the GM1 clusters under high- and low-cholesterol conditions, respectively. (E) Under low-cholesterol conditions (−Chol), APP colocalization with GM1 clusters decreases markedly after apoE treatment. Under high-cholesterol conditions (+Chol), apoE-mediated APP colocalization with GM1 clusters increases (i.e., apoE induces APP to cluster with GM1 lipids). α-, β-, and γ-secretase localization do not respond to apoE-mediated GM1 clustering. (F) ELISA in N2a cells showing a shift from Aβ to sAPP-α production after apoE treatment under low-cholesterol condition and increased Aβ production under high-cholesterol condition. Data are expressed as mean ± SEM, n = 3 to 10. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, n.s. (not significant), and two-sided Student’s t test. (G and H) Because of cluster disruption mediated by apoE, APP is dissociated from GM1 clusters under low-cholesterol conditions, exposing it to α-secretase to be cleaved into nonamyloidogenic sAPP-α. With high, environmental cholesterol, apoE-induced cluster stabilization mediates more APP to be translocated into lipid clusters and cleaved by β- and γ-secretase, producing amyloidogenic Aβ peptides.CC BY-NC-ND · PubMed Central
Fig. 3. Astrocyte cholesterol regulates APP processing in neurons. (A) Strategy for conditional knockout of SREBP2 in astrocytes using Cre-Lox recombination system. SREBP2 flox mice were crossed to ALDH1L1-specific Cre transgenic mice, which express Cre recombinase specifically in astrocytes when presented 4-hydroxytamoxifen (4-HT). Cre promotes SREBP2 knockout and blocks cholesterol synthesis in astrocytes. (B–D) Cortical cells were isolated from embryonic day 17 mice and cultured for dSTORM imaging. (B) ApoE translocates APP from lipid clusters into disordered regions in a pure, neuronal population sorted with cell surface neuronal marker Thy1.2. (C) ApoE increases APP’s cluster localization in primary neurons cultured in mixed population with glia cells, including astrocytes. (D) Astrocyte-specific cholesterol depletion completely disrupts APP cluster localization in neurons in cultured cells. (E) Astrocyte cholesterol depletion disrupts APP cluster localization in vivo, as demonstrated in SREBP2fl/fl GFAP–Cre+/− mouse brain slices. Data are expressed as mean ± SEM, n = 3 to 10, *P < 0.05, **P < 0.01, one-way ANOVA (D), or two-sided Student’s t test (B, C, and E).
Fig. 3. Astrocyte cholesterol regulates APP processing in neurons. (A) Strategy for conditional knockout of SREBP2 in astrocytes using Cre-Lox recombination system. SREBP2 flox mice were crossed to ALDH1L1-specific Cre transgenic mice, which express Cre recombinase specifically in astrocytes when presented 4-hydroxytamoxifen (4-HT). Cre promotes SREBP2 knockout and blocks cholesterol synthesis in astrocytes. (B–D) Cortical cells were isolated from embryonic day 17 mice and cultured for dSTORM imaging. (B) ApoE translocates APP from lipid clusters into disordered regions in a pure, neuronal population sorted with cell surface neuronal marker Thy1.2. (C) ApoE increases APP’s cluster localization in primary neurons cultured in mixed population with glia cells, including astrocytes. (D) Astrocyte-specific cholesterol depletion completely disrupts APP cluster localization in neurons in cultured cells. (E) Astrocyte cholesterol depletion disrupts APP cluster localization in vivo, as demonstrated in SREBP2fl/fl GFAP–Cre+/− mouse brain slices. Data are expressed as mean ± SEM, n = 3 to 10, *P < 0.05, **P < 0.01, one-way ANOVA (D), or two-sided Student’s t test (B, C, and E).CC BY-NC-ND · PubMed Central
Fig. 4. Loss of cholesterol synthesis in astrocytes blocks Aβ plaque formation and Tau phosphorylation in vivo. 3xTg-AD mice (AD) were crossed to SREBP2fl/fl GFAP–Cre+/− mice (AD × SB2−/−) and aged to 60 wk. (A) Hippocampus were isolated and soluble (RIPA extracted) and insoluble (guanidine extracted) Aβ40 and Aβ42 species were measured by ELISA. (B) 60-wk-old brain slices stained for human Aβ (red) and DAPI (blue) in AD × SB2flox mice (Left) and AD × SB2−/− mice (Right). (C) pTau levels were measured in 60-wk-old hippocampus lysate by ELISA. (D) 60-wk-old brain slices were immune stained for pTau (green) and Aβ (red), and the subiculum region of the hippocampus was imaged. Data are expressed as mean ± SEM, n = 4 to 7, one-way ANOVA with Tukey’s post hoc analysis, *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.
Fig. 4. Loss of cholesterol synthesis in astrocytes blocks Aβ plaque formation and Tau phosphorylation in vivo. 3xTg-AD mice (AD) were crossed to SREBP2fl/fl GFAP–Cre+/− mice (AD × SB2−/−) and aged to 60 wk. (A) Hippocampus were isolated and soluble (RIPA extracted) and insoluble (guanidine extracted) Aβ40 and Aβ42 species were measured by ELISA. (B) 60-wk-old brain slices stained for human Aβ (red) and DAPI (blue) in AD × SB2flox mice (Left) and AD × SB2−/− mice (Right). (C) pTau levels were measured in 60-wk-old hippocampus lysate by ELISA. (D) 60-wk-old brain slices were immune stained for pTau (green) and Aβ (red), and the subiculum region of the hippocampus was imaged. Data are expressed as mean ± SEM, n = 4 to 7, one-way ANOVA with Tukey’s post hoc analysis, *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.CC BY-NC-ND · PubMed Central
Fig. 5. Astrocyte cholesterol regulates APP and Tau processing, not protein expression. Primary embryonic cultures of mixed neurons and astrocytes were grown by crossing 3xTg SREBP2fl/fl mice with 3xTg SREBP2fl/fl GFAP–Cre mice. Each culture was grown independently from a single embryo, and Cre genotype was confirmed by PCR. (A) Human sAPP-α levels (from transgenic APP) were measured in conditioned media from mixed cultures. (B) Protein in conditioned media was precipitated, and sAPP-β, an APP fragment produced by β-secretase cleavage, was measured by Western blot. (C) Mixed cultures were lysed, and protein content was examined by Western blot. Data are expressed as mean ± SEM and n = 4 per genotype. *P < 0.05 and ***P < 0.001.
Fig. 5. Astrocyte cholesterol regulates APP and Tau processing, not protein expression. Primary embryonic cultures of mixed neurons and astrocytes were grown by crossing 3xTg SREBP2fl/fl mice with 3xTg SREBP2fl/fl GFAP–Cre mice. Each culture was grown independently from a single embryo, and Cre genotype was confirmed by PCR. (A) Human sAPP-α levels (from transgenic APP) were measured in conditioned media from mixed cultures. (B) Protein in conditioned media was precipitated, and sAPP-β, an APP fragment produced by β-secretase cleavage, was measured by Western blot. (C) Mixed cultures were lysed, and protein content was examined by Western blot. Data are expressed as mean ± SEM and n = 4 per genotype. *P < 0.05 and ***P < 0.001.CC BY-NC-ND · PubMed Central
Fig. 6. Astrocytic apoE is required for cholesterol transportation from astrocytes to neurons. (A) Cartoon diagram showing the experimental setup for neuron culture with ACM. Neurons from SREBP2 GFAP–Cre mice were used to eliminate transport of cholesterol from contaminating astrocytes in the culture. Neurons were cultured with ACM from either WT or APOE−/− astrocytes. (B) dSTORM superresolution imaging shows that astrocytic apoE is required for regulating APP’s GM1 clustering in neurons. Neurons cultured with ACM-containing apoE increased APP’s clustering with GM1 lipids, while ACM from APOE−/− animals fail to increase APP’s cluster association. (C) APP in APOE4 brains (E4F) are more clustered with GM1 lipids, compared with E3F. Aβ overexpression (APP/PS1) also robustly increases APP’s raft association. APP/PS1/E4F has slightly higher APP-GM1 pair correlation than APP/PS1/E3F. (D) Aβ overexpression (APP/PS1) increases brain cholesterol level robustly. In both control and APP/PS1 animals, E4F has a slightly higher cholesterol level in brain tissue compared with E3F. Data are expressed as mean ± SEM, n = 3 to 10, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, and one-way ANOVA. (E) N2a cells were treated with purified apoE3 or apoE4 proteins to compare their abilities to load and unload cholesterol (± Chol) from the plasma membrane. (F) Under low-cholesterol condition, apoE extracts cholesterol from the cells, decreasing APP’s GM1 clustering. There is no significant difference between apoE3 and apoE4. (G) Under high-cholesterol condition, apoE loads cholesterol into the cells, increasing APP’s GM1 clustering. There is no significant difference between apoE3 and apoE4. (H) Exposure of N2a cells to apoE removes cholesterol from cellular membranes, as measured by a fluorescent-based live cell cholesterol assay. There is no significant difference between apoE3 and apoE4.
Fig. 6. Astrocytic apoE is required for cholesterol transportation from astrocytes to neurons. (A) Cartoon diagram showing the experimental setup for neuron culture with ACM. Neurons from SREBP2 GFAP–Cre mice were used to eliminate transport of cholesterol from contaminating astrocytes in the culture. Neurons were cultured with ACM from either WT or APOE−/− astrocytes. (B) dSTORM superresolution imaging shows that astrocytic apoE is required for regulating APP’s GM1 clustering in neurons. Neurons cultured with ACM-containing apoE increased APP’s clustering with GM1 lipids, while ACM from APOE−/− animals fail to increase APP’s cluster association. (C) APP in APOE4 brains (E4F) are more clustered with GM1 lipids, compared with E3F. Aβ overexpression (APP/PS1) also robustly increases APP’s raft association. APP/PS1/E4F has slightly higher APP-GM1 pair correlation than APP/PS1/E3F. (D) Aβ overexpression (APP/PS1) increases brain cholesterol level robustly. In both control and APP/PS1 animals, E4F has a slightly higher cholesterol level in brain tissue compared with E3F. Data are expressed as mean ± SEM, n = 3 to 10, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, and one-way ANOVA. (E) N2a cells were treated with purified apoE3 or apoE4 proteins to compare their abilities to load and unload cholesterol (± Chol) from the plasma membrane. (F) Under low-cholesterol condition, apoE extracts cholesterol from the cells, decreasing APP’s GM1 clustering. There is no significant difference between apoE3 and apoE4. (G) Under high-cholesterol condition, apoE loads cholesterol into the cells, increasing APP’s GM1 clustering. There is no significant difference between apoE3 and apoE4. (H) Exposure of N2a cells to apoE removes cholesterol from cellular membranes, as measured by a fluorescent-based live cell cholesterol assay. There is no significant difference between apoE3 and apoE4.CC BY-NC-ND · PubMed Central
Fig. 7. Astrocyte cholesterol-dependent regulation of amyloid processing in neurons through apoE. A model for amyloid production in the Alzheimer’s brain. Cholesterol is synthesized in astrocytes and shuttled to neurons in apoE lipoprotein particles. Adding recombinant, cholesterol-containing apoE enriches neuronal membrane cholesterol levels, while delipidated apoE reduces membrane cholesterol. Cholesterol loading of the neuronal membranes regulates Aβ production by increasing APP interactions with β- and γ-secretase. In low-cholesterol membranes, APP interacts with α-secretase, generating sAPPα. When neuronal membranes are loaded with cholesterol, APP increasingly interacts with β- and γ-secretases generating Aβ peptides, resulting in brain plaque formation over time.
Fig. 7. Astrocyte cholesterol-dependent regulation of amyloid processing in neurons through apoE. A model for amyloid production in the Alzheimer’s brain. Cholesterol is synthesized in astrocytes and shuttled to neurons in apoE lipoprotein particles. Adding recombinant, cholesterol-containing apoE enriches neuronal membrane cholesterol levels, while delipidated apoE reduces membrane cholesterol. Cholesterol loading of the neuronal membranes regulates Aβ production by increasing APP interactions with β- and γ-secretase. In low-cholesterol membranes, APP interacts with α-secretase, generating sAPPα. When neuronal membranes are loaded with cholesterol, APP increasingly interacts with β- and γ-secretases generating Aβ peptides, resulting in brain plaque formation over time.CC BY-NC-ND · PubMed Central

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48 Own result · 35 Own interpretation · 18 Partly supported · 9 Supported · 6 No full text of the sources · 5 Not checked yet · 2 Sources not found · 2 Own method · 1 Supported so far · accuracy not yet measured

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  • It may state two separate claims as one. 35
  • Probably not a substantial claim. 16
45 of 45

  • The paper relies on this without support.

    ApoE is the major cholesterol transport protein in the brain.

    “Although apoE is the major cholesterol transport protein in the brain, there are other proteins that may also contribute significantly to cholesterol transportation in the central nervous system.”

  • The paper relies on this without support.

    The APOE knock-in mouse model, in which human APOE ε3 and ε4 replace the endogenous murine Apoe locus, faithfully models human apoE3/apoE4 isoform-specific effects in vivo.

    “we analyzed the brain tissue from APOE knock in (KI) mice, in which the human APOE variants (ε3 and ε4) replace the endogenous murine Apoe locus (termed E3F and E4F mice individually).”

  • The paper relies on this without support.

    Brain tissue cholesterol level is a valid proxy for neuronal membrane cholesterol relevant to APP-GM1 clustering.

    “We also measured the tissue cholesterol level of the brains and observed a similar trend, as we found in APP-GM1 pair correlation.”

  • The paper relies on this without support.

    Purified apoE3 and apoE4 proteins added to N2a cells model astrocyte-secreted apoE cholesterol trafficking to neurons.

    “We incubated N2a cells with purified apoE proteins with or without cholesterol exposure (Fig. 6E).”
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Metadata

Authors
Wang, H., Kulas, J. A., Wang, C., Holtzman, D. M., Ferris, H. A., & Hansen, S. B.
Affiliations
  • Scripps Research Institute (US)
  • University of Virginia (US)
  • Washington University in St. Louis (US)
Corresponding author
  • Ferris, Heather A.
  • Hansen, Scott B.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2021-08-12
Volume
118
Issue
33
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2102191118
PMC
PMC8379952
OpenAlex
W3103328760
Semantic Scholar
5a42b23f7b9e9c76ec8aa6f32bf87f6bb51613ce
Cited by
301
References
79
Citations by year
2026: 32 · 2025: 55 · 2024: 61 · 2023: 76 · 2022: 68 · 2021: 8
FWCI
19.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
Funders
  • HHS | NIH | NIH Office of the Director (DP2NS087943)
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (R01NS112534)
  • HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (K08DK097293, T32DK764627)
  • HHS | NIH | National Institute on Aging (NS090934, AG047644)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Keywords
Alzheimer's disease, amyloid-beta, apolipoprotein E, amyloid precursor protein, lipid clusters, cholesterol biosynthesis, secretases, alpha-secretase, soluble APP alpha, astrocyte-neuron interaction, amyloid plaques, tau protein
MeSH terms
Animals, Apolipoproteins E, Astrocytes, Brain, Cell Membrane, Cholesterol, Gene Expression Regulation, Humans, Neurons, Amyloid beta-Peptides, Mice, Knockout, Protein Isoforms, Mice, Sterol Regulatory Element Binding Protein 2, Amyloid Precursor Protein Secretases, HEK293 Cells

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