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

ApoE is not present in FBS.

“Importantly, apoE is not present in FBS (44).”

• cites [44] V. P. Varma., Ocular fluid as a replacement for serum in cell cryopreservation media. PLoS One 10, e0131291 (2015). 26135924 PMC4489643 sourceSupported

ApoE can both load and unload cholesterol from cells, including neurons.

“ApoE can both load and unload cholesterol from cells, including neurons (41–43) (see also SI Appendix).”

• cites [41] J. Luo, H. Yang, B.-L. Song, Mechanisms and regulation of cholesterol homeostasis. Nat. Rev. Mol. Cell Biol. 21, 225– 245 (2020). 31848472 sourceNot checked — no full text of the source
• cites [42] J. Chen, X. Zhang, H. Kusumo, L. G. Costa, M. Guizzetti, Cholesterol efflux is differentially regulated in neurons and astrocytes: Implications for brain cholesterol homeostasis. Biochim. Biophys. Acta 1831, 263– 275 (2013). 23010475 PMC3534809 sourcePartly supported

  The Results (§3.1; page unavailable) show that apoE3 increased cholesterol efflux from neurons, supporting the unloading part. The Introduction (§1; page unavailable) describes apoE-containing lipoproteins interacting with neuronal receptors but says whether their effects involve cholesterol uptake by neurons remains controversial; it does not establish the loading part as stated. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [43] H. Hayashi, R. B. Campenot, D. E. Vance, J. E. Vance, Apolipoprotein E-containing lipoproteins protect neurons from apoptosis via a signaling pathway involving low-density lipoprotein receptor-related protein-1. J. Neurosci. 27, 1933– 1941 (2007). 17314289 PMC6673537 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Both the nonamyloidogenic and amyloidogenic APP processing pathways are finely regulated by cholesterol.

“Strikingly, both pathways are finely regulated by cholesterol (6) (SI Appendix, Fig. S1B).”

• cites [6] M.-P. Marzolo, G. Bu, Lipoprotein receptors and cholesterol in APP trafficking and proteolytic processing, implications for Alzheimer’s disease. Semin. Cell Dev. Biol. 20, 191– 200 (2009). 19041409 PMC2691858 sourceSupported

Cholesterol is high in AD brains.

“Cholesterol is high in AD brains (1, 6).”

• cites [1] C. Haass, D. J. Selkoe, Cellular processing of β-amyloid precursor protein and the genesis of amyloid β-peptide. Cell 75, 1039– 1042 (1993). 8261505 sourceNot checked — no full text of the source
• cites [6] M.-P. Marzolo, G. Bu, Lipoprotein receptors and cholesterol in APP trafficking and proteolytic processing, implications for Alzheimer’s disease. Semin. Cell Dev. Biol. 20, 191– 200 (2009). 19041409 PMC2691858 sourcePartly supported

  Section 4 reports that one study suggested altered cholesterol homeostasis in AD brains, resulting in higher total cholesterol levels. The claim presents that qualified finding as an established general fact. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Neurons appear incapable of increasing cholesterol synthesis to compensate for astrocyte deficiency in any appreciable way.

“Neurons appear incapable of increasing cholesterol synthesis to compensate for astrocyte deficiency in any appreciable way (48).”

• cites [48] C.-C. Liu, C.-C. Liu, T. Kanekiyo, H. Xu, G. Bu, Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106– 118 (2013). 23296339 PMC3726719 sourcePartly supported

  The Introduction (page unavailable) says astrocytes supply cholesterol to neurons, and the Lipid metabolism section (page unavailable) suggests reduced delivery may impair neuronal health. Neither section says whether neurons can increase their own cholesterol synthesis when astrocyte supply is deficient, so the claim’s central assertion is unsupported. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

Microglia, which are able to produce apoE and are not impacted by the Cre, are unable to compensate for a lack of astrocyte cholesterol synthesis.

“In addition, microglia, which are also able to produce apoE (47) and are not impacted by the Cre, are unable to compensate for a lack of astrocyte cholesterol synthesis.”

• cites [47] H. A. Ferris., Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proc. Natl. Acad. Sci. U.S.A. 114, 1189– 1194 (2017). 28096339 PMC5293102 sourcePartly supported

  The Discussion (page unavailable) reports persistent brain and behavioral defects after astrocyte SREBP2 deletion, despite partial compensation by neurons. It does not establish that microglia were unaffected by Cre or test whether they could compensate; its compensation finding concerns neurons, not microglia. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

The APP protein has a cholesterol binding site.

“The conclusion is further supported by the existence of a cholesterol binding site in the APP protein (61).”

• cites [61] P. J. Barrett,. The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science 336, 1168– 1171 (2012). 22654059 PMC3528355 sourcePartly supported

  The paper identifies a cholesterol-binding site in C99, a fragment of APP, and reports cholesterol binding by that fragment. It says full-length APP is *likely* to bind cholesterol with similar avidity; the unqualified claim about the full-length protein goes beyond what was directly shown. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Amyloidogenic processing of APP in cultured cells occurs primarily in cholesterol-rich membrane domains.

“Our findings contribute to literature, demonstrating that amyloidogenic processing of APP in cultured cells occurs primarily in cholesterol-rich membrane domains (15, 62)”

• cites [15] R. Ehehalt, P. Keller, C. Haass, C. Thiele, K. Simons, Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts. J. Cell Biol. 160, 113– 123 (2003). 12515826 PMC2172747 sourcePartly supported

  The Results show that cholesterol depletion in cultured N2a cells inhibits β-cleavage and Aβ production. The Discussion supports a crucial role for lipid rafts but describes cleavage within rafts as a proposed model and says more work is needed to establish direct dependence on the raft environment. Thus, the paper does not demonstrate that processing occurs primarily within those domains. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [62] L. Puglielli, R. E. Tanzi, D. M. Kovacs, Alzheimer’s disease: The cholesterol connection. Nat. Neurosci. 6, 345– 351 (2003). 12658281 sourceNot checked — no full text of the source

APP/PS1/E4F brains have a slightly higher cholesterol level than APP/PS1/E3F brains.

“Similarly, the APP/PS1/E4F brains have a slightly higher cholesterol level than APP/PS1/E3F brains (Fig. 6D).”

Cultured neuroblastoma 2a (N2a) cells exhibited the smallest clusters, on average only 100 nm in apparent diameter.

“Cultured neuroblastoma 2a (N2a) cells exhibited the smallest clusters by far, on average only 100 nm in apparent diameter.”

APP in APOE4 brains (E4F) is more clustered with GM1 lipids compared with E3F.

“APP in APOE4 brains (E4F) are more clustered with GM1 lipids, compared with E3F.”

Aβ overexpression (APP/PS1) robustly increases APP's raft association.

“Aβ overexpression (APP/PS1) also robustly increases APP’s raft association.”

ApoE alone under low-cholesterol condition (−FBS) decreased APP clustering.

“Moreover, apoE alone (under low-cholesterol condition [−FBS]) decreased APP clustering (Fig. 2 B and C and SI Appendix, Fig. S2G), confirming that exogenously added apoE can unload cholesterol in neuronal membranes.”

When cholesterol was unloaded (apoE absent a cholesterol source), the apparent size and number of GM1 domains decreased.

“When cholesterol was unloaded, (ApoE absent a cholesterol source), the apparent size and number of GM1 domains decreased (Fig. 1 D and E and SI Appendix, Fig. S2B).”

In mixed cultures containing SREBP2 (−/−) astrocytes, there was a highly significant decrease in APP pair correlation with GM1 domains, similar to purified Thy1.2+ neuronal cultures.

“Fig. 3D shows a highly significant decrease in APP pair correlation with GM1 domains in mixed cultures containing SREBP2 (−/−) astrocytes, similar to purified Thy1.2+ neuronal cultures (Fig. 3B).”

Loading N2a cells with cholesterol (apoE and +FBS) caused an increase in the apparent cluster diameter from 100 to 130 nm.

“Loading cells with cholesterol (apoE and +FBS) caused an increase in the apparent cluster diameter from 100 to 130 nm in N2a cells (Fig. 1D).”

Insoluble Aβ40 and Aβ42 were almost entirely eliminated from the AD × SB2−/− hippocampus.

“More impressively, insoluble Aβ40 and Aβ42 were almost entirely eliminated from the AD × SB2−/− hippocampus (Fig. 4A).”

Knockout of SREBP2 in astrocytes of 3xTg-AD mice reduced soluble Aβ40 and Aβ42 levels in the hippocampus of 60-wk-old mice by twofold, to levels only slightly higher than WT controls.

“Knockout of SREBP2 in astrocytes of 3xTg-AD mice (AD × SB2−/−) reduced soluble Aβ40 and Aβ42 levels in the hippocampus of 60-wk-old mice by twofold, to levels only slightly higher than WT controls (Fig. 4A), suggesting a near complete loss of amyloidogenic processing of APP.”

Aβ overexpression (APP/PS1) increases brain cholesterol level robustly.

“Aβ overexpression (APP/PS1) increases brain cholesterol level robustly.”

APP, β-secretase, and γ-secretase are associated with GM1 clusters, exhibiting strong pair correlation with CTxB-labeled GM1 lipids at short distances (5 nm).

“Fig. 2B shows that APP, β-secretase, and γ-secretase are associated with GM1 clusters (i.e., they exhibit strong pair correlation with CTxB-labeled GM1 lipids at short distances [5 nm]), consistent with experiments in DRMs.”

APP/PS1 overexpression robustly increases brain tissue cholesterol level.

“APP/PS1 overexpression robustly increases brain tissue cholesterol level (Fig. 6D).”

Neither cholesterol loading nor the unloading of N2a cells had a significant effect on α-, β-, or γ-secretase trafficking in or out of GM1 domains.

“Surprisingly, neither cholesterol loading nor the unloading of N2a cells had a significant effect on α-, β-, or γ-secretase trafficking in or out of GM1 domains (Fig. 2E and SI Appendix, Fig. S2 I–N).”

FBS alone (+Chol with no apoE added) did not increase APP trafficking to lipid clusters.

“In a control experiment, FBS alone (+Chol with no apoE added) did not increase APP trafficking to lipid clusters (Fig. 2 C and D and SI Appendix, Fig. S2 G and H), confirming that apoE is a specific and necessary mediator of cholesterol transport to the neuron.”

When astrocytes were mixed with neurons, the same apoE had the opposite effect: GM1 domains sequestered APP, evident by a 2.5-fold increase in APP association with GM1 lipids.

“However, when we mixed astrocytes with neurons, the same apoE had the exact opposite effect. GM1 domains sequestered APP, evident by a 2.5-fold increase in APP association with GM1 lipids (Fig. 3C).”

The main apoE component extracted from N2a cells is cholesterol, including free cholesterol and cholesterol ester.

“The main apoE component extracted from the cells is cholesterol, including free cholesterol and cholesterol ester (Fig. 1C).”

Overexpression of mutant APP and mutant PS1 with resulting amyloid deposition has a more dramatic effect on APP-GM1 association than APOE genotype.

“Interestingly, overexpression of mutant APP and mutant PS1 (APP/PS1) with resulting amyloid deposition has an even more dramatic effect than APOE genotype.”

In APOE knock-in mouse brain tissue, APP association with GM1 lipids is increased in E4F compared to E3F.

“We found that an increased association of APP with GM1 lipids in E4F compared to E3F (Fig. 6C).”

Astrocyte-secreted apoE loads cholesterol into neurons.

“The data from cultured neurons and astrocytes show that astrocyte-secreted apoE loads cholesterol into neurons.”

Under low-cholesterol conditions, both apoE3 and apoE4 traffic APP out of GM1 clusters into disordered regions, with no significant difference between the two isoforms.

“Under low-cholesterol condition, both apoE3 and apoE4 trafficked APP out of GM1 clusters into disordered regions, with no significant difference between the two isoforms (Fig. 6F).”

ApoE decreased the total cholesterol in N2a cells by ∼5%.

“ApoE decreased the total cholesterol by ∼5% (SI Appendix, Fig. S2E).”

When apoE loaded cholesterol into cells (apoE +FBS), APP association with GM1 domains was almost twofold higher than when apoE effluxed cholesterol (apoE and −FBS).

“We found that when ApoE loaded cholesterol into cells (apoE +FBS), APP association with GM1 domains was almost twofold higher than when apoE effluxed cholesterol (apoE and −FBS) (Fig. 2 C–E and SI Appendix, Fig. S2 G and H).”

SREBP2 deletion in astrocytes resulted in a robust and significant reduction of APP-GM1 pair correlation compared to littermate controls in vivo at 4 wk of age.

“SREBP2 deletion in astrocytes resulted in a robust and significant reduction of APP-GM1 pair correlation compared to littermate controls (Fig. 3E).”

When cholesterol was depleted from astrocytes by SREBP2 gene ablation, the cluster size of primary neurons was significantly reduced to 130 nm.

“We found that when cholesterol was depleted from astrocytes, the cluster size of primary neurons was significantly reduced (130 nm).”

There is no difference between apoE3 and apoE4 in cellular cholesterol level after cholesterol extraction.

“We also measured cellular cholesterol level after cholesterol extraction by apoE3 and apoE4. Total cholesterol level decreased after apoE incubation. We didn’t observe any difference between the two isoforms (Fig. 6H).”

Brain tissue from APP/PS1 mice has significantly increased APP-GM1 association.

“Brain tissue from APP/PS1 mice has significantly increased APP-GM1 association (Fig. 6C).”

Incubation of purified cortical neurons (Thy1.2+ with no astrocytes) with cholesterol-free human apoE dramatically decreased APP association with GM1 domains (>twofold).

“We found that the incubation of purified cortical neurons (Thy1.2+ with no astrocytes) with cholesterol-free human apoE dramatically decreased APP association with GM1 domains (>twofold) (Fig. 3B) in primary neurons.”

Immunofluorescence staining demonstrated an absence of amyloid plaques in AD × SB2−/− mice.

“This was verified by immunofluorescence staining demonstrating an absence of amyloid plaques in AD × SB2−/− mice (Fig. 4B).”

Total cellular cholesterol level decreased after apoE incubation.

“Total cholesterol level decreased after apoE incubation.”

ApoE decreased the N2a total cellular cholesterol in the plasma membrane.

“We confirmed that apoE decreased the N2a total cellular cholesterol in the plasma membrane (Fig. 1F) using a live cell fluorescent cholesterol assay (see Materials and Methods).”

In WT mouse cortical tissue, GM1 domains averaged ∼141 nm in apparent diameter, slightly smaller than the apparent size in primary neurons (∼150-nm diameter).

“In WT mouse cortical tissue, GM1 domains averaged ∼141 nm in apparent diameter, slightly smaller than the apparent size in primary neurons (∼150-nm diameter) (Fig. 1B).”

In both control and APP/PS1 animals, E4F has a slightly higher cholesterol level in brain tissue compared with E3F.

“In both control and APP/PS1 animals, E4F has a slightly higher cholesterol level in brain tissue compared with E3F.”

Clusters appeared to be absent in cultured cells.

“Not surprisingly, clusters appeared to be absent in cultured cells (77).”

• cites [77] S. Moon., Spectrally resolved, functional super-resolution microscopy reveals nanoscale compositional heterogeneity in live-cell membranes. J. Am. Chem. Soc. 139, 10944– 10947 (2017). 28774176 sourceNot checked — no full text of the source

Not until cholesterol, supplied by astrocytes or cholesterol-containing apoE, was added were nanoscale clusters present (∼100 nm).

“Not until cholesterol, supplied by astrocytes or cholesterol-containing apoE, was added were nanoscale clusters present (∼100 nm).”

Cholesterol appears to be down-regulated in neurons as part of a mechanism to allow astrocytes to control APP presentation to proteolytic enzymes in the neuron.

“Cholesterol appears to be down-regulated in neurons as part of a mechanism to allow astrocytes to control APP presentation to proteolytic enzymes in the neuron.”

Astrocyte-derived cholesterol is a potent signal that controls APP association with α- or β-secretase in the neuron, based on GM1 domain affinity.

“Thus, astrocyte-derived cholesterol is a potent signal that controls APP association with α- or β-secretase in the neuron, based on GM1 domain affinity.”

SREBP2 is the master transcriptional regulator of the majority of enzymes involved in cholesterol synthesis.

“SREBP2 is the master transcriptional regulator of the majority of enzymes involved in cholesterol synthesis.”

• cites [39] X. Hua., SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. Proc. Natl. Acad. Sci. U.S.A. 90, 11603– 11607 (1993). 7903453 PMC48032 sourceNot checked yet

Aβ levels dictate insoluble plaques.

“and Aβ levels dictate insoluble plaques (Fig. 7).”

Astrocyte-derived cholesterol regulates APP translocation and association with secretases in the plasma membrane of neurons.

“These data further confirmed that astrocyte-derived cholesterol regulates APP translocation and association with secretases in the plasma membrane of neurons.”

The paper demonstrates a direct role for astrocytes in promoting the AD phenotype through the production and distribution of cholesterol to neurons.

“Here, we demonstrate a direct role for astrocytes in promoting the AD phenotype through the production and distribution of cholesterol to neurons.”

Increased brain cholesterol content promotes AD-associated amyloid pathology.

“This finding is in agreement with prior research, implicating increased brain cholesterol content as a factor which promotes AD-associated amyloid pathology.”

The data establish a molecular pathway that connects astrocyte cholesterol synthesis with apoE lipid trafficking and amyloidogenic processing of APP.

“Combined, our data establish a molecular pathway that connects astrocyte cholesterol synthesis with apoE lipid trafficking and amyloidogenic processing of APP (Fig. 7).”

A mobile substrate (APP) moves between relatively static enzymes (secretases) in the plasma membrane.

“This suggests that a mobile substrate (APP) moves between relatively static enzymes (secretases) in the plasma membrane.”

The difference in in vivo regulation is not a functional difference in the efficiency of an apoE isoform to transport cholesterol.

“The results indicate that the difference in the in vivo regulation is not a functional difference in the efficiency of an isoform to transport cholesterol.”

Administration of statins to guinea pigs significantly reduces Aβ levels in the cerebrospinal fluid.

“Administration of statins to guinea pigs significantly reduces Aβ levels in the cerebrospinal fluid (58)”

• cites [58] K. Fassbender., Simvastatin strongly reduces levels of Alzheimer’s disease β -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A. 98, 5856– 5861 (2001). 11296263 PMC33303 sourceNot checked — no full text of the source

Cholesterol is a critical lipid that controls the signaling state of a neuron.

“The pathway establishes cholesterol as a critical lipid that controls the signaling state of a neuron.”

The data support the proposed molecular mechanism in which amyloidogenic processing of APP is promoted by cholesterol increasing APP interactions with β- and γ-secretases through substrate presentation.

“the data presented here support the proposed molecular mechanism in which amyloidogenic processing of APP is promoted by cholesterol increasing APP interactions with β- and γ-secretases through substrate presentation (SI Appendix, Fig. S1).”

Astrocytic apoE is required for cholesterol transportation from astrocytes to neurons.

“This result again confirms that astrocytic apoE is required for cholesterol transportation from astrocytes to neurons.”

By keeping cholesterol low, the astrocyte can move the neuron through a concentration gradient that profoundly affects APP processing and eventual plaque formation.

“By keeping cholesterol low, the astrocyte can move the neuron through a concentration gradient that profoundly affects APP processing and eventual plaque formation.”

With low cholesterol, apoE moves APP to α-secretase, generating more sAPP-α.

“With low cholesterol, apoE moves APP to α-secretase, generating more sAPP-α (Fig. 2 H, Top).”

Astrocyte cholesterol is a key regulator of neuronal Aβ accumulation.

“Together, our data support astrocyte cholesterol as a key regulator of neuronal Aβ accumulation.”

In the adult brain, the ability of neurons to produce cholesterol is impaired.

“In the adult brain, the ability of neurons to produce cholesterol is impaired (24).”

• cites [24] G. Quan, C. Xie, J. M. Dietschy, S. D. Turley, Ontogenesis and regulation of cholesterol metabolism in the central nervous system of the mouse. Brain Res. Dev. Brain Res. 146, 87– 98 (2003). 14643015 sourceNot checked — no full text of the source

Increased cholesterol in neurons drives APP to associate with β- and γ-secretases in lipid clusters.

“Increased cholesterol in neurons drives APP to associate with β- and γ-secretases in lipid clusters.”

Mice with SREBP2 knocked out of astrocytes have reduced production of cholesterol in the astrocytes.

“Mice with SREBP2 knocked out of astrocytes have reduced the production of cholesterol in the astrocytes (47) (SI Appendix, Fig. S4A).”

• cites [47] H. A. Ferris., Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proc. Natl. Acad. Sci. U.S.A. 114, 1189– 1194 (2017). 28096339 PMC5293102 sourceNot checked yet

The observed effect of astrocyte SREBP2 ablation on neurons suggests decreased cholesterol transport to neurons, presumably through apoE.

“The observed effect of astrocyte SREBP2 ablation on neurons suggests the decreased cholesterol transport to neurons—presumably through apoE.”

Astrocyte cholesterol synthesis plays an essential role in maintaining cholesterol content in neuronal lipid clusters.

“This suggests that astrocyte cholesterol synthesis plays an essential role in maintaining cholesterol content in neuronal lipid clusters.”

Cholesterol loading of neuronal membranes regulates Aβ production by increasing APP interactions with β- and γ-secretase.

“Cholesterol loading of the neuronal membranes regulates Aβ production by increasing APP interactions with β- and γ-secretase.”

Statins reduced β secretase processing in induced pluripotent stem cell-derived neurons.

“statins reduced β secretase processing in induced pluripotent stem cell (iPSC) –derived neurons (59).”

• cites [59] V. F. Langness,. Cholesterol-lowering drugs reduce APP processing to Aβ by inducing APP dimerization. Mol. Biol. Cell 32, 247– 259 (2021). 33296223 PMC8098827 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

The association of APP with lipid clusters regulates the amount of Aβ accumulation.

“The association of APP with lipid clusters appears to regulate the amount of Aβ accumulation”

In low-cholesterol membranes, APP interacts with α-secretase, generating sAPPα.

“In low-cholesterol membranes, APP interacts with α-secretase, generating sAPPα.”

APP/PS1 AD mice overexpressing a truncated active form of SREBP2 display an accelerated Aβ burden with aging.

“APP/PS1 AD mice overexpressing a truncated active form of SREBP2 display an accelerated Aβ burden with aging (60).”

• cites [60] E. Barbero-Camps, A. Fernández, L. Martínez, J. C. Fernández-Checa, A. Colell, APP/PS1 mice overexpressing SREBP-2 exhibit combined Aβ accumulation and tau pathology underlying Alzheimer’s disease. Hum. Mol. Genet. 22, 3460– 3476 (2013). 23648430 PMC3736868 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Cholesterol in APP regulation suggests a correlative link between inflammation in AD and Aβ production.

“hence, cholesterol in APP regulation suggests a correlative link between inflammation in AD and Aβ production.”

Cholesterol and its trafficking by lipoprotein particles influences hyperphosphorylation of tau in neurons.

“Several lines of evidence suggest that cholesterol and its trafficking by lipoprotein particles also influences hyperphosphorylation of tau in neurons.”

The availability of astrocyte cholesterol regulates Aβ production by substrate presentation.

“We conclude that the availability of astrocyte cholesterol regulates Aβ production by substrate presentation.”

The conditions with cholesterol are the more physiologically relevant conditions for cultured cells.

“We conclude from our data that the conditions with cholesterol are the more physiologically relevant conditions for cultured cells.”

The dramatic decrease in Aβ and pTau observed in AD × SB2(−/−) mice cannot readily be explained by the minority of knocked out neurons.

“Thus, the dramatic decrease in Aβ and pTau that we observe in our AD × SB2(−/−) mice cannot readily be explained by the minority of knocked out neurons.”

This provides a potential explanation for the role of cholesterol-associated genes as risk factors for AD.

“This contributes to the understanding of AD and provides a potential explanation for the role of cholesterol-associated genes as risk factors for AD.”

Cultured cells lacking apoE supplementation likely underestimate physiological GM1 domain size, especially those derived from the brain where cholesterol is high.

“Our data suggest cultured cells lacking apoE supplementation likely underestimate physiological GM1 domain size, especially those derived from the brain where cholesterol is high (76).”

• cites [76] A. B. Reiss., Cholesterol in neurologic disorders of the elderly: Stroke and Alzheimer’s disease. Neurobiol. Aging 25, 977– 989 (2004). 15212822 sourceNot checked — no full text of the source

The small changes in Aβ production seen in cell culture models may have a meaningful impact in vivo, such that the cumulative impact of altering cholesterol delivery to neurons can be observed.

“Our data emphasize that the small changes in Aβ production we see in our cell culture models may have a meaningful impact in vivo, such that the cumulative impact of altering cholesterol delivery to neurons can be observed.”

Overall cholesterol synthesis by neurons increases to compensate for the loss of astrocyte cholesterol.

“we have previously demonstrated that overall cholesterol synthesis by neurons increases to compensate for the loss of astrocyte cholesterol (47).”

• cites [47] H. A. Ferris., Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proc. Natl. Acad. Sci. U.S.A. 114, 1189– 1194 (2017). 28096339 PMC5293102 sourceNot checked yet

Cellular regulation of apoE, or protein abundance, is likely responsible for apoE's isoform-specific effects in vivo.

“we conclude that cellular regulation of apoE, or protein abundance, is likely responsible apoE’s isoform-specific effects in vivo.”

Disrupting cholesterol production using statins or enhancing cholesterol clearance reduced both pTau and total tau levels in cultured iPSC neurons.

“van der Kant et al. found that, by disrupting cholesterol production using statins or enhancing cholesterol clearance, both pTau and total tau levels were reduced in cultured iPSC neurons (51).”

• cites [51] R. van der Kant., Cholesterol metabolism is a druggable axis that independently regulates tau and amyloid-β in iPSC-derived Alzheimer’s disease neurons. Cell Stem Cell 24, 363– 375.e9 (2019). 30686764 PMC6414424Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.