Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms

ApoE promotes neurodegeneration and tau pathogenesis predominantly by driving microglial activation.

“ApoE had a strong immunomodulatory function and promoted neurodegeneration and tau pathogenesis predominantly by driving microglial activation (Shi et al., 2019).”

• cites Shi et al., 2019 sourceSupported

ApoE ablation in P301S tau transgenic mice markedly reduced brain atrophy and tau pathology compared to the presence of apoE.

“ApoE ablation in P301S tau transgenic (Tg) mice markedly reduced brain atrophy and tau pathology compared to the presence of apoE, whereas apoE4 significantly exacerbated neurodegeneration compared to apoE2 and apoE3 (Shi et al., 2017).”

• cites Shi et al., 2017 sourcePartly supported

  The paper reports that ApoE knockout largely attenuated brain atrophy in P301S mice expressing human ApoE. It also reports differences in tau pathology across ApoE genotypes, but not a marked overall reduction in tau pathology with knockout: at 9 months, overall p-tau staining differences had decreased, although staining patterns differed. The reported greater neurodegeneration with ApoE4 than with ApoE2 or ApoE3 is supported (main text, passages indexed under Abstract; page unavailable). (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Microglia-derived apoE cell-autonomously promotes microglial activation towards the neurodegenerative MGnD/DAM phenotype.

“microglia-derived apoE was shown to cell-autonomously promote microglial activation towards the neurodegenerative “MGnD/DAM” phenotype (Krasemann et al., 2017).”

• cites Krasemann et al., 2017 sourceSupported

ApoE4 significantly exacerbated neurodegeneration compared to apoE2 and apoE3 in P301S tau transgenic mice.

“ApoE ablation in P301S tau transgenic (Tg) mice markedly reduced brain atrophy and tau pathology compared to the presence of apoE, whereas apoE4 significantly exacerbated neurodegeneration compared to apoE2 and apoE3 (Shi et al., 2017).”

• cites Shi et al., 2017 sourceSupported

LDLR is one of the two primary metabolic receptors mediating the clearance of apoE lipoproteins.

“Low-density lipoprotein receptor (LDLR) is one of the two primary metabolic receptors (the other is low-density lipoprotein receptor-related protein 1, LRP1) mediating the clearance of apoE lipoproteins (Holtzman et al., 2012; Ishibashi et al., 1994).”

• cites Holtzman et al., 2012 sourceNot checked — no full text of the source
• cites Ishibashi et al., 1994 sourcePartly supported

  The Discussion supports LDLR as one of two receptors involved in apoE-mediated lipoprotein clearance. It cautions, however, that the identity of the second receptor is not known for certain, so the citing sentence’s definite identification of it as LRP1 goes beyond the paper’s conclusion. Page numbers are not given in the supplied passages. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Microglia are the principal driving force of neurodegeneration and tau pathogenesis in tauopathy mouse models.

“We and others subsequently identified microglia as the principal driving force of neurodegeneration and tau pathogenesis in tauopathy mouse models (Mancuso et al., 2019; Shi et al., 2019).”

• cites Mancuso et al., 2019 sourcePartly supported

  The Discussion reports that inhibiting microglial proliferation in P301S mice prevented neurodegeneration and potentially slowed tau aggregation. It describes activated microglia as deleterious, but does not establish them as the principal driving force of either process across tauopathy mouse models; it explicitly notes uncertainty about whether their effect on tau pathology is predominant. The indexed passages provide section labels but no page numbers. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Shi et al., 2019 sourceSupported

LDLR mice show a moderate increase in lysosomal enzyme activities compared to WT mice.

“LDLR mice also showed a moderate increase in enzyme activities compared to WT mice (Figure 5K)”

Similar differences in OPC density are observed in tau Tg mice.

“Similar differences were also observed in tau Tg mice (Figure 7B, C).”

ApoE levels in the CSF of LDLR and P301S/LDLR mice are markedly reduced by ~90% compared to WT and P301S mice respectively.

“Corresponding to LDLR OX, apoE levels in the CSF of LDLR and P301S/LDLR mice were markedly reduced by ~90% compared to WT and P301S mice respectively (Figure 2A).”

In the absence of the tau transgene, apoE- and LDLR-associated gene expression changes are primarily enriched in neurons, particularly excitatory neurons.

“In the absence of the tau transgene, apoE- and LDLR-associated gene expression changes (WT vs. EKO or WT vs. LDLR) were primarily enriched in neurons, particularly in excitatory neurons.”

Cluster 0 and cluster 1 shrink drastically in P301S mice.

“Among the six astrocyte subclusters, cluster 0 and cluster 1 shrunk drastically in P301S mice (Figure 6A, B)”

Increased density of OPCs is confirmed in the molecular layer of dentate gyrus in the hippocampus of 9-month EKO and LDLR Tg mice compared to WT mice by CSPG4 staining.

“We confirmed increased density of OPCs in the molecular layer of dentate gyrus (DG) in the hippocampus of 9-month EKO and LDLR Tg mice compared to WT mice by immunofluorescent staining with the OPC marker CSPG4 (Figure 7B, C).”

ApoE level has a strong positive correlation with insoluble tau level in both P301S and P301S/LDLR mice.

“However, apoE level had a strong positive correlation with insoluble tau level, and trended toward a negative correlation with soluble tau levels in both P301S and P301S/LDLR mice (Figure 2C).”

Cluster 3 is strongly enriched in EKO and P301S/EKO mice (~20%), and to a less extent in LDLR and P301S/LDLR mice (10-13%) compared to WT and P301S mice (3-5%).

“cluster 3 was strongly enriched in EKO and P301S/EKO mice (~20%), and to a less extent in LDLR and P301S/LDLR mice (10-13%) compared to WT and P301S mice (3-5%) (Figure 6A, B).”

In 9-month P301S mice, activated microglia (CD68+) almost invariably show large punctate intracellular apoE staining.

“activated microglia (CD68+) in 9-month P301S mice almost invariably showed large punctate intracellular apoE staining”

This effect is not observed in 3-month old mice.

“This effect was not observed in 3-month old mice (Figure 5N).”

Acutely isolated LDLR Tg microglia show Ldlr overexpression compared to WT microglia.

“we consistently observed Ldlr overexpression in LDLR Tg microglia compared to WT microglia.”

In P301S/LDLR mice, activated microglia show minimal intracellular apoE or only tiny apoE puncta.

“whereas in P301S/LDLR mice, minimal intracellular apoE, or only tiny apoE puncta were observed in activated microglia (Figure 3L).”

Microglia isolated from aged (20-month) EKO mice show a similar reduction of p4EBP compared to microglia from WT mice even in the absence of tau transgene.

“microglia isolated from aged (20-month) EKO mice showed a similar reduction of p4EBP compared to microglia from WT mice (Figure 5M).”

LDLR microglia show a similarly increased level of LGMN compared to WT microglia.

“LDLR microglia showed a similarly increased level of LGMN compared to WT microglia”

LDLR OX in P301S mice significantly reduces p-tau levels in the RAB and RIPA fractions.

“In contrast to no change of total human tau levels, LDLR OX in P301S mice significantly reduced p-tau levels in the RAB and RIPA fractions (Figure 2B).”

Cultured LDLR-overexpressing microglia show increased Ldlr expression.

“corresponding to increased Ldlr expression (Figure 3C)”

At 3 months of age, LDLR OX does not affect early ptau histopathology present in the mossy fibers of the hippocampus (type1 ptau).

“At 3-months of age, an early time point before activation of DAM microglia (Figure S2A), LDLR OX did not affect early ptau histopathology that is present in the mossy fibers of the hippocampus (type1 ptau, not present in WT mice) (Figure S2B).”

P301S/LDLR mice show significantly reduced insoluble apoE compared to P301S mice.

“Significantly reduced insoluble apoE was also observed in P301S/LDLR mice compared to P301S mice (Figure 2B).”

P301S mice show severe loss of postsynaptic densities in the stratum radiatum of hippocampal CA1.

“Electron microscopy also revealed severe loss of postsynaptic densities (PSDs) in the stratum radiatum of hippocampal CA1 region in P301S mice”

The proportion of inhibitory neurons is increased in P301S mice compared to other groups.

“The proportion of inhibitory neurons, in contrast, was increased in P301S mice compared to other groups (Figure 4C, D).”

Lgmn is upregulated in acutely isolated microglia from EKO mice compared to WT mice by qPCR.

“We verified upregulation of Lgmn in acutely isolated microglia from EKO mice compared to that from WT mice by qPCR (Figure 5H)”

Cultured LDLR-overexpressing microglia show significant reduction of Apoe gene expression.

“a significant reduction of Apoe gene expression (Figure 3C)”

Compared to cluster 2, top downregulated pathways in cluster 3 include myeloid leukocyte activation, antigen processing and presentation, and myeloid leukocyte differentiation, featuring genes involved in microglial activation.

“Compared to cluster 2, top downregulated pathways in cluster 3 include “myeloid leukocyte activation”, “antigen processing and presentation”, and “myeloid leukocyte differentiation”, all featuring genes involved in microglial activation”

At 3 months, no volume differences are observed between P301S and P301S/LDLR mice.

“no volume differences were observed between P301S and P301S/LDLR mice (Figure S2D).”

In 20-month mice, LDLR Tg microglia, like EKO microglia, show significantly reduced DAM and proinflammatory gene expression compared to WT microglia.

“in microglia isolated from 20-month mice, LDLR Tg microglia, like EKO microglia, showed significantly reduced “DAM” and proinflammatory gene expression compared to WT microglia”

The largest group of upregulated genes in cluster 4 encode lysosomal enzymes and proteins involved in cellular degradation.

“The largest group of upregulated genes in cluster 4 encode lysosomal enzymes and proteins involved in cellular degradation, including Lgmn, Ctss, Ctsl, Hexb, Man2b1, Lamp1, Lamp2, Abca2 and others (Figure 5F, G).”

Neurodegeneration-associated gene expression change (P301S vs WT) mainly occurs in microglia and astrocytes.

“neurodegeneration-associated gene expression change (P301S vs. WT) mainly occurred in microglia and astrocytes.”

Synaptic loss in P301S mice is significantly attenuated in P301S/LDLR mice.

“which was significantly attenuated in P301S/LDLR mice (Figure 1C, D).”

In tauopathy, the highest level of gene expression change shifts from neurons to microglia in both P301S vs P301S/EKO and P301S vs P301S/LDLR conditions.

“However, in the setting of tauopathy, the highest level of gene expression change shifted from neurons to microglia in both conditions (P301S vs. P301S/EKO, P301S vs. P301S/LDLR)”

P301S/LDLR mice show no alteration in total human tau levels in any fractions compared to P301S mice.

“P301S/LDLR mice showed no alteration in total human tau levels in any fractions compared to P301S mice (Figure 2B).”

ApoE levels positively correlate with p-tau levels in all fractions.

“In addition, apoE levels positively correlated with p-tau levels in all fractions (Figure 2D).”

Microglia from LDLR Tg mice overexpress LDLR, particularly a low molecular weight form of LDLR.

“microglia from LDLR Tg mice also overexpressed LDLR, particularly a low molecular weight form of LDLR (Figure 3A, B).”

Immunoblotting of acutely isolated microglia from 11-month P301S, P301S/LDLR and P301S/EKO female mice shows reduced phosphorylation of 4EBP in P301S/EKO microglia compared to P301S microglia.

“immunoblotting of acutely isolated microglia from 11-month P301S, P301S/LDLR and P301S/EKO female mice showed reduced phosphorylation of 4EBP (p4EBP) - an mTORC1 effector, in P301S/EKO microglia compared to P301S microglia (Figure 5L)”

ApoE level trends toward a negative correlation with soluble tau levels in both P301S and P301S/LDLR mice.

“However, apoE level had a strong positive correlation with insoluble tau level, and trended toward a negative correlation with soluble tau levels in both P301S and P301S/LDLR mice (Figure 2C).”

A similar pattern of p4EBP levels is observed in P301S/LDLR microglia compared to P301S and P301S/EKO microglia.

“a similar pattern of p4EBP levels was also observed in P301S/LDLR microglia compared to P301S and P301S/EKO microglia (Figure 5L-N)”

Two subpopulations of homeostatic microglia (cluster 0 and 1) are enriched in non-tau Tg mice, but drastically reduced in P301S mice.

“We identified two subpopulations of homeostatic microglia (cluster 0 and 1) that were enriched in non-tau Tg mice, but were drastically reduced in P301S mice (Figure 5A, B).”

LDLR microglia show an intermediate level of p4EBP compared to WT and EKO microglia.

“LDLR microglia showed an intermediate level of p4EBP compared to WT and EKO microglia”

Both LDLR and P301S/LDLR mice show an ~90% reduction of soluble apoE in cortical tissue.

“Both LDLR and P301S/LDLR mice showed an ~90% reduction of soluble apoE similar to that seen in the CSF (Figure 2B).”

Unsupervised clustering of microglia yielded six subclusters.

“Unsupervised clustering yielded six subclusters among all samples (Figure 5A).”

Cluster 4 is specifically associated with apoE deficiency, as it is enriched in apoE-deficient mice regardless of the presence or absence of tau transgene.

“Cluster 4 was specifically associated with apoE deficiency, as it was enriched in apoE-deficient mice, regardless of the presence or absence of tau transgene (Figure 5A, B).”

P301S mice show a marked increase of Apoe expression uniquely in microglia over other cell types compared to WT mice.

“Here we found that compared to WT mice, P301S mice showed a marked increase of Apoe expression that occurred uniquely in microglia over other cell types (Figure S4A).”

Downregulated genes in cluster 4 microglia primarily fall into anabolic pathways, including peptide chain elongation, glycolysis, and mTOR signaling.

“Downregulated genes in cluster 4 microglia primarily fell into anabolic pathways, such as “peptide chain elongation” characterized by ribosome protein genes; “glycolysis”, including genes encoding glycolytic enzymes such as Eno2, Gapdh, and Ldha; and “mTOR signaling””

The density of OPCs is increased in P301S mice compared to WT mice.

“The density of OPCs was increased in P301S mice compared to WT mice”

PSD loss in P301S mice is partially rescued in P301S/LDLR mice.

“which was partially rescued in P301S/LDLR mice (Figure 1E, F).”

P301S mice show marked synaptic loss compared to WT and LDLR mice, particularly in the stratum lucidum of hippocampal CA3.

“Synapsin staining revealed a marked synaptic loss in P301S mice compared to WT and LDLR mice, particularly in the stratum lucidum of hippocampal CA3 region”

LGMN protein level is increased in acutely isolated microglia from both young (3-month) and aged (20-month) EKO mice compared to WT mice by western blot.

“found increased LGMN protein level in acutely isolated microglia from both young (3-month) and aged (20-month) EKO mice compared to WT mice by western blot (Figure 5I, J).”

EKO mice show significantly increased activity of all three lysosomal enzymes (Hex, Gluc, Naglu) in mouse cortices compared to WT mice.

“We observed significantly increased activity of all three enzymes in EKO mice compared to WT mice (Figure 5K)”

P301S/LDLR mice have significantly less brain volume loss than P301S mice.

“whereas P301S/LDLR mice had significantly less brain volume loss than P301S mice (Figure 1A, B).”

The difference of intracellular apoE level between WT and LDLR Tg microglia is increased in aged mice (20-month) compared to young mice (3-month).

“the difference of intracellular apoE level between WT and LDLR Tg microglia was increased in aged mice (20-month) compared to young mice (3-month) (Figure 3H, I).”

P301S mice at 9 months show severe brain atrophy in the hippocampus and piriform/entorhinal cortex compared to WT and LDLR mice.

“Compared to WT and LDLR mice that had a normal brain volume, P301S mice showed severe brain atrophy in the hippocampus and piriform/entorhinal cortex”

These pathways highlight genes encoding ion channels and neurotransmitter receptors, such as Kcnc1, Kcnc3, Scn2a, Scn2b, Atp1a1, Grin2c, Gabra6, and Grm4.

“These pathways highlighted genes encoding ion channels and neurotransmitter receptors, such as voltage-gated K+ and Na+ channels (Kcnc1, Kcnc3, Scn2a, Scn2b), Na+/K+-ATPase (Atp1a1), NMDA receptor (Grin2c), GABA-A receptor (Gabra6), and metabotropic glutamate receptor (Grm4) (Figure S5A, B).”

The astrocyte population remains stable across groups.

“whereas the astrocyte population remained stable across groups (Figure 4C, D).”

P301S/LDLR mice show significantly attenuated microglial activation relative to P301S mice by CD68 staining.

“P301S/LDLR mice showed significantly attenuated microglial activation relative to P301S mice by CD68 staining (Figure 3M).”

Cluster 2 is highly enriched in P301S mice.

“Cluster 2 was highly enriched in P301S mice (Figure 6A, B)”

Cultured LDLR-overexpressing microglia show marked reduction of intracellular apoE protein level.

“as well as a marked reduction of intracellular apoE protein level (Figure 3A, B) was observed in cultured LDLR-overexpressing microglia.”

In the hippocampus, aged LDLR and EKO mice show a higher myelin density in the molecular layer compared to WT mice.

“In the hippocampus, aged LDLR and EKO mice also showed a higher myelin density in the molecular layer compared to WT mice (Figure S6D, E).”

A similar protective effect of apoE-deficiency and LDLR-OX on myelin integrity is observed in aged mice in the absence of tauopathy.

“Interestingly, a similar protective effect of apoE-deficiency and LDLR-OX on myelin integrity was also observed in aged mice in the absence of tauopathy.”

P301S mice show marked microglial activation in the corpus callosum.

“Corresponding to increased myelin damage, P301S mice showed marked microglial activation in the corpus callosum (Figure 7H, J)”

Even in the absence of tau pathology, LDLR and EKO mice show higher myelin coverage in the molecular layer compared to WT mice.

“Surprisingly, even in the absence of tau pathology, LDLR and EKO mice showed higher myelin coverage in the molecular layer compared to WT mice (Figure 7D, E)”

Significantly more preserved myelin structure is found in the molecular layer of DG in P301S/LDLR and P301S/EKO mice compared to P301S mice by MBP staining.

“we found significantly more preserved myelin structure in the molecular layer of DG in P301S/LDLR and P301S/EKO mice compared to P301S mice by myelin basic protein (MBP) staining (Figure 7D, E).”

LDLR OX drastically reduces extracellular murine apoE that is mainly derived from astrocytes.

“In our study, LDLR OX drastically reduces extracellular murine apoE that is mainly derived from astrocytes.”

LDLR OX upregulates Kv3.1 (Kcnc1) and Kv3.3 (Kcnc3).

“LDLR OX upregulates Kv3.1 (Kcnc1) and Kv3.3 (Kcnc3).”

OPCs in the corpus callosum trend at a higher density in apoE-deficient and LDLR-overexpressing mice with or without tau transgene.

“OPCs in the corpus callosum trended at a higher density in apoE-deficient and LDLR-overexpressing mice with or without tau transgene (Figure 7I, K)”

One key finding of our study is the role of apoE in regulating microglial metabolism.

“One key finding of our study is the role of apoE in regulating microglial metabolism.”

Cluster 2 represents a population of activated microglia in neurodegeneration.

“representing a population of activated microglia in neurodegeneration.”

LDLR OX and associated Apoe downregulation in microglia suppressed microglial activation.

“This could suggest that LDLR OX and associated Apoe downregulation in microglia suppressed microglial activation.”

ApoE deficiency-associated activation of cell catabolism and suppression of cell anabolism likely constitute a crucial mechanism preventing microglial activation.

“ApoE deficiency-associated activation of cell catabolism and suppression of cell anabolism likely constitute a crucial mechanism preventing microglial activation.”

ApoE-deficient microglia in the setting of tauopathy show reduced mTOR activation and mTOR-mediated anabolism.

“indicating reduced mTOR activation and mTOR-mediated anabolism in apoE-deficient microglia in the setting of tauopathy.”

Cluster 2 represents a population of reactive astrocytes.

“representing a population of reactive astrocytes.”

The moderate increase in lysosomal enzyme activities in LDLR mice may be related to apoE reduction.

“which may be related to apoE reduction.”

Apoe downregulation is inherently associated with LDLR OX in microglia.

“These results suggest that Apoe downregulation was inherently associated with LDLR OX in microglia.”

LDLR microglia share potentially shared mechanisms with apoE-deficient microglia in elevating cell catabolism, likely due to apoE reduction.

“indicating its potentially shared mechanisms with apoE-deficient microglia in elevating cell catabolism that was likely due to apoE reduction.”

LDLR OX shares certain common mechanisms with apoE deficiency in controlling microglial metabolism, likely via apoE reduction.

“suggesting that LDLR OX shares certain common mechanisms with apoE deficiency in controlling microglial metabolism, likely via apoE reduction.”

Microglial Apoe plays a key role in mediating LDLR's protective effect.

“further supporting a key role of microglial Apoe in mediating LDLR’s protective effect.”

Microglia-derived apoE has a potential role in neurodegeneration.

“The distinctive upregulation of apoE in microglia in P301S mice highlights the potential role of microglia-derived apoE in neurodegeneration.”

Cluster 0 and cluster 1 represent homeostatic astrocyte states.

“thus representing homeostatic states.”

ApoE-deficiency inherently suppresses mTOR activation upon microglial activation, likely by enhancing microglial catabolism.

“these results indicate that apoE-deficiency inherently suppresses mTOR activation upon microglial activation, likely by enhancing microglial catabolism.”

Proliferating OPCs may play a potential role in repairing damaged myelin in neurodegeneration.

“suggesting a potential role of proliferating OPCs in repairing damaged myelin in neurodegeneration.”

Cluster 3 represents oligodendrocyte progenitor cells (OPCs), indicated by uniquely high expression of Cspg4 and Pdgfra.

“The uniquely high expression of Cspg4 and Pdgfra (Figure 7A) - markers of oligodendrocyte progenitor cells (OPCs, also known as NG2 glia) (Nishiyama et al., 2009), indicated that this cluster represented OPCs.”

• cites Nishiyama et al., 2009 sourceNot checked — no full text of the source

The enlarged OPC pools in EKO and LDLR Tg mice may be essential in promoting oligodendrocyte genesis and maintaining myelin integrity under neurodegenerative conditions.

“The enlarged OPC pools in EKO and LDLR Tg mice may be essential in promoting oligodendrocyte genesis and maintaining myelin integrity under neurodegenerative conditions.”

ApoE deficiency results in enhanced lysosomal functions under physiological conditions.

“indicating that apoE deficiency resulted in enhanced lysosomal functions under physiological conditions.”

Cluster 3 indicates a specific population of microglia associated with disease but whose property is regulated by LDLR OX.

“indicating a specific population of microglia associated with disease but whose property was regulated by LDLR OX.”

Overexpressing LDLR is an effective approach to reduce extracellular brain apoE level via increased uptake and degradation.

“suggesting that overexpressing LDLR is an effective approach to reduce extracellular brain apoE level via increased uptake and degradation.”

The unique alteration in gene expression of these ion channels and receptors likely constitutes an important aspect of LDLR's function in regulating microglial activation.

“The unique alteration in gene expression of these ion channels and receptors likely constitutes an important aspect of LDLR’s function in regulating microglial activation.”

Reduced tau pathology and neurodegeneration upon LDLR OX may mainly result from attenuated microglial activation due to apoE reduction.

“Thus, the reduced tau pathology and neurodegeneration upon LDLR OX may mainly result from attenuated microglial activation due to apoE reduction.”

Cluster 4 appears to be a type of activated microglia in the setting of apoE deficiency, as it clusters together with cluster 2 DAM microglia at lower resolution.

“this subset of microglia also appeared to be a type of activated microglia in the setting of apoE deficiency, as it clustered together with cluster 2 DAM microglia when using a lower resolution for cell clustering.”

Microglia play a key role in mediating the effect of apoE and LDLR on neurodegeneration.

“suggesting a key role of microglia in mediating the effect of apoE and LDLR on neurodegeneration.”

The increased difference in apoE level between WT and LDLR Tg microglia with age is likely due to aging-induced microglial activation that is stronger in WT microglia than in LDLR microglia.

“the increased difference in apoE level is likely due to aging-induced microglial activation that is stronger in WT microglia (with a higher degree of Apoe upregulation) than in LDLR microglia.”

ApoE plays a key role in p-tau pathogenesis.

“supporting a key role of apoE in p-tau pathogenesis.”

Increased Kv3 channel expression in microglia may reduce proinflammatory microglial activation.

“Hence, increased Kv3 channel expression in microglia may reduce proinflammatory microglial activation.”

The protective effect of LDLR OX may be partially due to reduction in the astrocyte-derived apoE pool.

“Therefore, the protective effect may be partially due to reduction in this pool of apoE.”

There is intrinsic regulation of myelination by apoE/LDLR, likely in part through regulating OPCs.

“suggesting intrinsic regulation of myelination by apoE/LDLR, likely in part through regulating OPCs.”

The expression of oligodendrocyte genes in microglia was likely due to formation of doublets between a portion of microglia and oligodendrocyte nuclei instead of being real biological effects.

“which was likely due to formation of doublets between a portion of microglia and oligodendrocyte nuclei instead of being real biological effects.”

These oligodendrocyte genes did not drive apoE-deficiency or LDLR-associated effects in microglia.

“These oligodendrocyte genes did not drive apoE-deficiency or LDLR-associated effects in microglia”

Regulation of the OPC pool and myelin homeostasis by apoE/LDLR may constitute a new mechanism underlying their effects on neurodegeneration.

“Regulation of the OPC pool and myelin homeostasis by apoE/LDLR may constitute a new mechanism underlying their effects on neurodegeneration.”

The inability to turn on the anabolic machinery in apoE-deficient microglia is likely a key mechanism preventing their activation.

“The similar metabolic changes in apoE-deficient and TREM2-deficient microglia suggests that the inability to turn on the anabolic machinery in apoE-deficient microglia is likely a key mechanism preventing their activation.”

LDLR itself may not significantly impact pathological tau spreading.

“suggesting that LDLR itself may not significantly impact pathological tau spreading.”

The effect of LDLR on suppressing microglial activation via apoE regulation may overwhelm any potential direct effects of LDLR on tau spreading.

“the effect of LDLR on suppressing microglial activation via apoE regulation may overwhelm any potential direct effects of LDLR on tau spreading.”

OPCs have potential roles in maintaining myelin integrity.

“supporting their potential roles in maintaining myelin integrity.”

The marked microglial activation in the corpus callosum of P301S mice is likely to clear damaged myelin.

“likely to clear damaged myelin.”

Lower extracellular apoE level may also contribute to suppressed microglial activation through reduced microglial signaling.

“Lower extracellular apoE level may also contribute to suppressed microglial activation through reduced microglial signaling.”