Apolipoprotein E–low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner

The risk of Alzheimer's disease is modified by various LDLR polymorphisms.

“In the context of AD, the risk of disease is modified by various LDLR polymorphisms (Gopalraj et al., 2005, Zou et al., 2008).”

• cites Gopalraj et al., 2005 sourceNot checked — no full text of the source
• cites Zou et al., 2008 sourcePartly supported

  The Results report increased Alzheimer’s disease risk for men with the LDLR rs688T/T genotype, but not for women. This paper establishes the association for one polymorphism under a sex-specific condition; it does not itself establish that various LDLR polymorphisms modify risk. No page number is available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Several genetic studies have implicated the LDLR and the apoE-LDLR interaction as a disease modifying mechanism in AD.

“Still, several important genetic studies have implicated the LDLR – and the apoE-LDLR interaction – as a disease modifying mechanism in AD.”

• cites Gopalraj et al. (2005) sourceNot checked — no full text of the source
• cites Zou et al. (2008) sourceSupported
• cites Retz et al. (2001) sourceNot checked — no full text of the source

In mice, the development of atherosclerosis is accelerated when human LDLR and E4 are combined in the background of diabetes.

“In addition, the development of atherosclerosis is accelerated in mice when human LDLR and E4 were combined in the background of diabetes (Johnson et al., 2013).”

• cites Johnson et al., 2013 sourceSupported

Polymorphisms in LDLR exon 8 and exon 13 present in conjunction with an ε4 allele increase AD risk.

“Furthermore, studies by Retz et al. (2001) and Cheng et al. (2005) demonstrated an increase in AD risk when polymorphisms in LDLR exon 8 and exon 13 were present in conjunction with an ε4 allele.”

• cites Retz et al. (2001) sourceNot checked — no full text of the source
• cites Cheng et al. (2005) sourceSupported

A functional interaction between apoE and LDLR is a potential mechanism to explain the apoE isoform-dependent disease risks associated with both CVD and AD.

“Together with epidemiological studies (Cheng et al., 2005, Gopalraj et al., 2005, Retz et al., 2001, Vermissen et al., 2011, Zou et al., 2008), these data point toward a functional interaction between apoE and LDLR as a potential mechanism to explain the apoE isoform-dependent disease risks associated with both CVD and AD.”

• cites Cheng et al., 2005 sourcePartly supported

  The Abstract concludes that the results imply a functional interaction between ApoE and LDL receptor proteins affecting Alzheimer’s disease (AD) risk, and the Discussion proposes that particular combinations may modify that risk. The paper discusses cholesterol metabolism but does not connect the interaction to cardiovascular disease (CVD) risk, so it supports the AD portion, not the claim about both diseases. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Gopalraj et al., 2005 sourceNot checked — no full text of the source
• cites Retz et al., 2001 sourceNot checked — no full text of the source

Increasing LDLR expression in the presence of apoE4 has harmful effects in a mouse model of CVD.

“Given the harmful effects of increasing LDLR expression in the presence of apoE4 in a mouse model of CVD (Altenburg et al., 2007, Johnson et al., 2013, Malloy et al., 2004)”

• cites Altenburg et al., 2007 sourceSupported
• cites Johnson et al., 2013 sourceSupported
• cites Malloy et al., 2004 sourceNot checked — no full text of the source

Astrocytes provide neurons with exogenous cholesterol in the form of apoE-containing high density lipoprotein (HDL)-like particles.

“astrocytes provide neurons with exogenous cholesterol in the form of apoE-containing high density lipoprotein (HDL)-like particles (Boyles et al., 1985, Boyles et al., 1989, Yu et al., 2010)”

• cites Boyles et al., 1985 sourcePartly supported

  The Discussion (page unavailable) identifies apoE as an astrocyte secretory product and speculates that apoE-containing lipoproteins could redistribute lipids among nervous-system cells. It does not establish that astrocytes provide cholesterol to neurons, or that the particles involved are HDL-like. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Boyles et al., 1989 sourcePartly supported

  The Discussion (page unavailable) proposes that apoE- and apoA-I-containing lipoproteins may transfer cholesterol within an injured rat sciatic nerve, potentially to growing axons. It does not show that astrocytes provide neurons with cholesterol; it identifies macrophages as the major apoE producers in the injured nerve. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Yu et al., 2010Not matched

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

There was a significant effect of APOE genotype on total time spent in the open areas of the elevated zero maze.

“There was a significant effect of APOE genotype on numbers of entries into open areas (p < 0.01, ANOVA) as well as total time spent in the open areas (p < 0.001 respectively by ANOVA) of elevated zero maze (Figure 2A-B).”

There was no difference in contextual freezing between any of the experimental groups.

“There was no difference in contextual freezing between any of the experimental groups (Figure 3E).”

No group showed a correlation between water maze performance and apoE levels in the cortex, amygdala, or cerebellum.

“Additionally, no group showed a correlation between water maze performance and apoE levels in the cortex, amygdale or cerebellum”

In mice with human LDLR, E2 and E3 demonstrated robust spatial memory retention at both 24 and 72 hours.

“When human LDLR was introduced, mice with E2 and E3 demonstrated robust spatial memory retention at both 24 and 72 hours.”

In the elevated zero-maze, mice with E4 displayed significantly more anxiety than those with E3 or E2.

“In the elevated zero-maze, a test of anxiety-like behavior, mice with E4 displayed significantly more anxiety than those with E3 or E2.”

In mice lacking LDLR, spatial memory retention was impaired at both 24 and 72 hours post-training, regardless of APOE genotype.

“Spatial memory retention was impaired in mice lacking LDLR when tested at both 24 and 72 hours post-training, regardless of APOE genotype.”

In mice with human LDLR, E4 performed similar to E2 and E3 in the 24-hour spatial memory test.

“While mice with human LDLR and E4 performed similar to their E2 and E3 counterparts in the 24 hour spatial memory test”

In mice with human LDLR, a clear pattern (E2 > E3 > E4) emerged in all brain regions measured (APOE*LDLR effect, all regions p < 0.01).

“In contrast, a clear pattern (E2 > E3 > E4) emerged in all brain regions measured in mice with human LDLR (APOE*LDLR effect, all regions p < 0.01).”

In TR mice with endogenous mouse LDLR, plasma apoE levels were significantly elevated in human E2 compared to E3 and E4 (p<0.01).

“Similar to previously published reports (Riddell et al., 2008, Sullivan et al., 2011), we observed significantly elevated plasma apoE levels in TR mice with human E2 compared to those with E3 and E4 (p<0.01)”

The majority of LDLR−/− mice displayed un-directed search patterns in the second probe trial.

“In the second probe trial (P2), LDLR deficient mice failed to show a preference for the target quadrant, regardless of APOE genotype (Figure 4C) and the majority of LDLR−/− mice displayed un-directed search patterns (Figure 4G, top row).”

When exposed to a novel object 24 hours later, all experimental groups regardless of APOE or LDLR genotype spent significantly more time examining the novel object, demonstrating robust object recognition memory.

“When exposed to a Novel object 24 hours later, all experimental groups – regardless of APOE or LDLR genotype – spent significantly more time examining the novel object, demonstrating robust object recognition memory (Figure 1B).”

In LDLR deficient mice, irrespective of APOE genotype, there was no positive correlation between hippocampal apoE levels and percent time spent in the target quadrant (all groups combined, r2 = 0.0065, p = 0.7502).

“This positive correlation was not present in LDLR deficient mice, irrespective of APOE genotype (all LDLR−/− groups combined, r2 = 0.0065, p = 0.7502, Pearson correlation) (Figure 7A).”

• AssumptionRests on an assumption: The hippocampus is a brain region critical for performance on the water maze spatial memory task.

There was a significant effect of APOE genotype on numbers of entries into open areas of the elevated zero maze.

“There was a significant effect of APOE genotype on numbers of entries into open areas (p < 0.01, ANOVA) as well as total time spent in the open areas (p < 0.001 respectively by ANOVA) of elevated zero maze (Figure 2A-B).”

In mice with human LDLR, better performance in the 72-hour probe trial of the water maze was associated with higher levels of hippocampal apoE.

“In mice with human LDLR, better performance in the 72 hour probe trial of the water maze was associated with higher levels of hippocampal apoE (Figure 7B).”

• AssumptionRests on an assumption: The hippocampus is a brain region critical for performance on the water maze spatial memory task.

We observed a strong effect of APOE genotype on cued memory.

“Conversely, we observed a strong effect of APOE genotype on cued memory.”

When human LDLR was present, plasma apoE concentrations were significantly higher in mice with E2 than in mice with E3 or E4.

“However, when human LDLR was present, plasma apoE concentrations were significantly higher in mice with E2 (20.3 ± 1.5 μg/ml) than E3 or E4 (7.0 ± 0.9 and 5.9 ± 0.5 μg/ml, respectively) (Figure 6B-C).”

The interaction between E4 and LDLR resulted in deficiencies that were not present in E2 and E3, specifically in the context of long term memory retention (72 hours).

“Furthermore, the interaction between E4 and LDLR resulted in deficiencies that were not present in E2 and E3, specifically in the context of long term memory retention (72 hours).”

Novel object recognition is unaffected by APOE and LDLR genotype.

“Novel object recognition is unaffected by APOE and LDLR genotype”

In TR mice with endogenous mouse LDLR, there was a significant genotype effect on apoE levels in the cortex (p < 0.05, ANOVA).

“as well as in the cortex (p < 0.05, ANOVA) (Supplemental Figure 1).”

In mice with human LDLR, hippocampal apoE levels correlated with long-term spatial memory retention.

“Furthermore, in mice with human LDLR, hippocampal apoE levels correlated with long-term spatial memory retention.”

• AssumptionRests on an assumption: The hippocampus is a brain region critical for performance on the water maze spatial memory task.

There was a significant effect of APOE on freezing in response to the tone in the cued fear conditioning task.

“there was a significant effect of APOE (p < 0.01, repeated measures) on freezing in response to the tone.”

ApoE levels in cortex, amygdala, or cerebellum did not correlate with other behavioral tests (object recognition, anxiety, fear conditioning, or spatial memory retention in water maze probe trials).

“nor did apoE levels in any of these brain regions correlate with other behavioral tests (object recognition, anxiety, fear conditioning, or spatial memory retention in the water maze probe trials).”

All groups demonstrated an increase in freezing across the training session, indicating a learned fear response.

“All groups demonstrated an increase in freezing across the training session (p < 0.01, repeated measures), indicating a learned fear response (Figure 3-C-D).”

Anxiety-like behavior was unaffected by LDLR in this study.

“Unlike spatial memory, anxiety-like behavior was unaffected by LDLR in this study.”

Plasma cholesterol was higher in mice with E2 compared to mice with E3, whether or not human LDLR was expressed.

“Plasma cholesterol was higher in mice with E2 compared to mice with E3, whether or not human LDLR was expressed.”

In human LDLR mice with E4, the correlation between hippocampal apoE levels and percent time spent in the target quadrant did not reach significance (r2 = 0.468, p = 0.089).

“While the overall trend was similar, the correlation did not reach significance in human LDLR mice with E4 (r2 = 0.468, p = 0.089, Pearson correlation).”

• AssumptionRests on an assumption: The hippocampus is a brain region critical for performance on the water maze spatial memory task.

In human LDLR mice, apoE levels in cortex and cerebellum were higher in E2 than in either E3 or E4.

“apoE levels in cortex and cerebellum were higher in E2 than in either E3 or E4 (Figure 6E-H, right side).”

Introducing human LDLR in the presence of E2 or E3 completely ameliorated the spatial memory deficits observed in LDLR−/− mice.

“Importantly, introducing human LDLR in the presence of E2 or E3 completely ameliorated the spatial memory deficits observed in LDLR−/− mice.”

Both anxiety-like behavior and cued associative memory are strongly influenced by APOE genotype in both the absence and presence of human LDLR.

“We show that both anxiety-like behavior and cued associative memory are strongly influenced by APOE genotype in both the absence and presence of human LDLR”

In mice with human LDLR, expression of LDLR in the brain was within a physiological range comparable to that of wild type mice, ranging between 30.3 to 145.8% of wild type mice.

“In mice with human LDLR, expression of LDLR in the brain was within a physiological range comparable to that of WT mice, ranging between 30.3 to 145.8% of wild type mice (WT).”

In most brain regions examined, APOE genotype had no effect on levels of apoE in the absence of LDLR.

“In most brain regions examined, APOE genotype had no effect on levels of apoE in the absence of LDLR.”

There was a trend towards lower cholesterol in human LDLR mice with E4 compared to human LDLR mice with E3 or E2.

“However, there was a trend towards lower cholesterol in human LDLR mice with E4 compared to human LDLR mice with E3 or E2 .”

Lack of LDLR was associated with impairments in the retention of long-term spatial memory.

“Particularly, both the lack of LDLR and the specific interaction between apoE4 and the LDLR were associated with impairments in the retention of long-term spatial memory.”

In the water maze, the absence of LDLR resulted in major deficits in spatial memory.

“In the water maze, the absence of LDLR resulted in major deficits in spatial memory.”

Mice with E4 displayed more anxiety-like behavior than those with E3 or E2.

“Mice with E4 displayed more anxiety-like behavior than those with E3 or E2.”

In human LDLR mice with all three apoE isoforms analyzed together, there was a strong positive correlation between hippocampal apoE levels and percent time spent in the target quadrant (r2 = 0.722, p < 0.001).

“When the data of human LDLR mice with all three apoE isoforms were analyzed together, there was a strong positive correlation between hippocampal apoE levels and the percent time spent in the target quadrant (r2 = 0.722, p < 0.001, Pearson correlation).”

• AssumptionRests on an assumption: The hippocampus is a brain region critical for performance on the water maze spatial memory task.

In human LDLR mice, apoE levels in the hippocampus and amygdala were higher in E2 than E4 mice.

“In human LDLR mice, apoE levels in the hippocampus and amygdala were higher in E2 than E4 mice”

In the cerebellum of LDLR−/− mice, levels of apoE were significantly greater in E2 than E3 or E4 mice.

“However, in the cerebellum of LDLR−/− mice, levels of apoE were significantly greater in E2 than E3 or E4 mice (Figure 6D-H, left side).”

Fasting plasma cholesterol concentrations were drastically altered by both APOE and LDLR genotype.

“Fasting plasma cholesterol concentrations were drastically altered by both APOE and LDLR genotype (APOE effect p < 0.001, LDLR effect p < 0.001, APOE × LDLR interaction, p < 0.001, ANOVA).”

In human LDLR mice with E2, hippocampal apoE levels were positively correlated with percent time spent in the target quadrant in the probe trial (r2 = 0.695, p < 0.05).

“Hippocampal apoE levels were positively correlated with the percent time spent in the target quadrant in the probe trial in human LDLR mice with E2 (r2 = 0.695, p < 0.05, Pearson correlation)”

• AssumptionRests on an assumption: The hippocampus is a brain region critical for performance on the water maze spatial memory task.

There were no group differences in ability to reach the platform during the visible platform sessions.

“There were no group differences in ability to reach the platform during the visible platform sessions (Figure 4A-B, “Visible”).”

In mice with human LDLR, E4 showed impaired long-term memory retention during the 72-hour test.

“they showed impaired long term memory retention during the 72 hour test.”

In human LDLR mice with E3, hippocampal apoE levels were positively correlated with percent time spent in the target quadrant in the probe trial (r2 = 0.695, p < 0.05 and r2 = 0.884, p < 0.01).

“and E3 (r2 = 0.695, p < 0.05 and r2 = 0.884, p < 0.01, Pearson correlation).”

• AssumptionRests on an assumption: The hippocampus is a brain region critical for performance on the water maze spatial memory task.

In TR mice with endogenous mouse LDLR, there was a significant genotype effect on apoE levels when all brain regions were analyzed together (p<0.01, repeated measures).

“as well as a significant genotype effect on apoE levels when all regions were analyzed together (p<0.01, Repeated Measures)”

In the absence of LDLR, plasma apoE concentrations did not differ by APOE genotype.

“In the absence of LDLR, plasma apoE concentrations did not differ by APOE genotype (Figure 6B, left).”

Cholesterol levels in the cortex did not significantly differ by APOE genotype.

“Cholesterol levels in the cortex did not significantly differ by APOE genotype.”

In both the absence and presence of human LDLR, mice with E4 spent less time in the open area of the zero maze compared to mice with E3 or E2.

“In both the absence and presence of human LDLR, mice with E4 spent less time in the open area of the zero maze (13.0 ± 3.6, 14.3 ± 4.2%) compared to mice with E3 (18.6 ± 6.0, 19.4 ± 6.1 %) or E2 (24.5 ± 4.5, 26.3 ± 8.9 %) (Figure 2B).”

Performance improved during the visible and hidden platform sessions.

“Performance improved during the visible and hidden platform sessions (Session effect in each, p < 0.01).”

In LDLR deficient mice, apoE levels in the cortex, hippocampus and amygdala were similar among E2, E3, and E4.

“LDLR deficient mice with E2, E3 or E4 had similar levels of apoE in the cortex, hippocampus and amygdala (Figure 6E-G, left side).”

Anxiety was strongly determined by APOE genotype in both the presence and absence of LDLR.

“Instead, anxiety was strongly determined by APOE genotype in both the presence and absence of LDLR.”

Human LDLR expression considerably lowered total plasma cholesterol regardless of apoE isoforms.

“Human LDLR expression considerably lowered total plasma cholesterol regardless of apoE isoforms (Table 1).”

The effect of LDLR absence on spatial memory is independent of APOE genotype.

“Here we extend these findings to show that this effect is independent of APOE genotype.”

In LDLR−/− mice, the freezing response to the tone was apoE isoform-dependent (E4 > E3 > E2).

“In LDLR−/− mice, the freezing response to the tone was apoE isoform-dependent (E4 > E3 > E2).”

In the 72-hour probe trial, mice lacking the LDLR failed to show a preference for the target quadrant, regardless of APOE genotype.

“As in the first two probe trials, mice lacking the LDLR failed to show a preference for the target quadrant, regardless of APOE genotype (Figure 4E, G bottom row).”

All groups spent a comparable amount of time exploring each of the two identical objects on the first day of the novel object recognition paradigm.

“All groups spent a comparable amount of time exploring each of the two identical objects (Figure 1A).”

None of the groups showed spatial memory retention in the first probe trial.

“None of the groups showed spatial memory retention in the first probe trial (not shown).”

Following additional training, some groups did show spatial memory retention.

“However, following additional training, some groups did show spatial memory retention.”

Hippocampal cholesterol was not affected by APOE genotype.

“Hippocampal cholesterol was not affected by APOE genotype (Figure 5, shaded bars).”

In the second probe trial (P2), LDLR deficient mice failed to show a preference for the target quadrant, regardless of APOE genotype.

“In the second probe trial (P2), LDLR deficient mice failed to show a preference for the target quadrant, regardless of APOE genotype (Figure 4C) and the majority of LDLR−/− mice displayed un-directed search patterns (Figure 4G, top row).”

Levels of hippocampal apoE correlate with long term spatial memory retention in mice with human LDLR.

“Finally, levels of hippocampal apoE correlate with long term spatial memory retention in mice with human LDLR.”

There was no significant difference in human LDLR expression between E2, E3 and E4 mice.

“There was no significant difference in human LDLR expression between E2, E3 and E4 mice (88.5 ± 17.2, 92.1 ± 10.7, and 87.3 ± 19.6 % of WT, respectively) (Figure 6A).”

Neither cortical nor hippocampal cholesterol levels were significantly affected by APOE genotype in human apoE mice with human LDLR.

“Neither cortical nor hippocampal cholesterol levels o were significantly affected by APOE genotype, although there was a trend towards lower cortical cholesterol in human LDLR mice with E4.”

There was a trend towards lower cortical cholesterol in human LDLR mice with E4.

“although there was a trend towards lower cortical cholesterol in human LDLR mice with E4”

Brain cholesterol concentrations did not correlate with any of the behavioral outcomes measured in this study.

“However, brain cholesterol concentrations did not correlate with any of the behavioral outcomes measured in this study.”

ApoE levels in E2 mice with human LDLR did not differ in any brain region from apoE levels in any of the LDLR−/− mice.

“Interestingly, apoE levels in E2 mice with human LDLR did not differ in any brain region from apoE levels in any of the LDLR−/− mice.”

• AssumptionRests on an assumption: The insoluble (detergent-soluble) fraction more accurately reflects the levels of lipidated apoE.

ApoE levels in E4 mice with human LDLR were significantly lower than those of all LDLR−/− mice in the four brain regions analyzed.

“Conversely, apoE levels in E4 mice with human LDLR were significantly lower than those of all LDLR−/− mice in the four brain regions analyzed.”

• AssumptionRests on an assumption: The insoluble (detergent-soluble) fraction more accurately reflects the levels of lipidated apoE.

A functional interaction between apoE and LDLR determines Alzheimer's disease risk.

“Furthermore, the risk associated with a certain LDLR polymorphism differs dramatically depending on the patients’ APOE genotype, implying that a functional interaction between apoE and LDLR determines AD risk (Cheng et al., 2004, Retz et al., 2001).”

• cites Cheng et al., 2004Not matched

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

• cites Retz et al., 2001 sourceNot checked — no full text of the source

In patients who lack functioning LDLR, the disparities in cardiovascular disease risk usually associated with APOE genotype disappear.

“For example, the disparities in CVD risk usually associated with APOE genotype disappear in patients who lack functioning LDLR, suggesting that the diseases-modifying effects of the apoE isoforms depend on the presence of a fully functioning LDLR protein (Vermissen et al., 2011).”

• cites Vermissen et al., 2011Not matched

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

There were no apparent differences in health or physical appearance among the experimental groups.

“There were also no apparent differences in health or physical appearance, and all groups performed similarly with regard to activity levels in an open field, sensorimotor function on a Rotarod, and swim speeds in the water maze (Table 2).”

The risk associated with a certain LDLR polymorphism differs dramatically depending on the patients' APOE genotype.

“Furthermore, the risk associated with a certain LDLR polymorphism differs dramatically depending on the patients’ APOE genotype, implying that a functional interaction between apoE and LDLR determines AD risk (Cheng et al., 2004, Retz et al., 2001).”

• cites Cheng et al., 2004Not matched

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

• cites Retz et al., 2001 sourceNot checked — no full text of the source

The disease-modifying effects of the apoE isoforms depend on the presence of a fully functioning LDLR protein.

“For example, the disparities in CVD risk usually associated with APOE genotype disappear in patients who lack functioning LDLR, suggesting that the diseases-modifying effects of the apoE isoforms depend on the presence of a fully functioning LDLR protein (Vermissen et al., 2011).”

• cites Vermissen et al., 2011Not matched

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

The interaction between LDLR and E4 appears to be an important disease modifying mechanism in the setting of CVD.

“but regardless of the mechanism, the interaction between LDLR and E4 appears to be an important disease modifying mechanism in the setting of CVD.”

There were no group differences in swim speeds in the water maze.

“There were no group differences in swim speeds (Table 2).”

There were no group differences in the response to the shock during fear conditioning training.

“There were no group differences in the response to the shock (Figure 3B).”

In mice, the introduction of human LDLR results in apoE isoform-dependent differences in diet-induced atherosclerotic plaque development.

“In mice, the introduction of human LDLR results in apoE isoform-dependent differences in diet-induced atherosclerotic plaque development (Malloy et al., 2004).”

• cites Malloy et al., 2004 sourceNot checked — no full text of the source

The apoE isoforms differentially affect anxiety-like behavior (E4 > E3 ≥ E2) through an LDLR-independent process.

“This data suggests that the apoE isoforms differentially affect anxiety-like behavior (E4 > E3 ≥ E2) through an LDLR-independent process.”

The increased CVD risk normally associated with APOE4 genotype disappears in Familial Hypercholesterolemia patients who lack functioning LDLR.

“Interestingly, the increased CVD risk normally associated with APOE4 genotype disappears in Familial Hypercholesterolemia (FH) patients, who lack functioning LDLR (Vermissen et al., 2011).”

• cites Vermissen et al., 2011Not matched

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

The LDLR is the only receptor in its class to show varying binding affinities for the three apoE isoforms (E4 > E3 >> E2).

“While numerous lipoprotein receptors have been shown to interact with apoE in the brain, the LDLR is the only receptor in its class of receptors to show varying binding affinities for the three apoE isoforms (E4 > E3 >> E2) (Innerarity et al., 1983, Yamamoto et al., 2008).”

• cites Innerarity et al., 1983 sourceNot checked — no full text of the source
• cites Yamamoto et al., 2008 sourceNot checked — no full text of the source

The pathways that underlie spatial memory require functional interaction between apoE and the LDLR.

“These data suggest that the pathways that underlie spatial memory - at least in regards to specific cognitive processes tested by the water maze – require functional interaction between apoE and the LDLR.”

A functional interaction between apoE and LDLR may modify AD risk in an apoE isoform-dependent manner.

“These studies imply that a functional interaction between apoE and LDLR may modify AD risk in an apoE isoform-dependent manner.”

The strong APOE genotype effect on anxiety (E4 > E3 > E2) occurs through an LDLR-independent mechanism.

“These data suggest that this strong APOE genotype effect on anxiety (E4 > E3 > E2) occurs through an LDLR-independent mechanism.”

The partial rescue of long-term spatial memory deficits by human LDLR in E4 mice may be due to an inability of the LDLR to rescue these impairments by interacting with E4 as it does with E2 and E3.

“This may be due to an inability of the LDLR to rescue the impairments in long-term spatial memory by interacting with E4 as it is able to do with E2 and E3.”

Upregulation of LDLR in the brain is a potential therapeutic strategy for AD.

“These studies, in which LDLR over-expression increases Aβ clearance, point to upregulation of LDLR in the brain as a potential therapeutic strategy for AD.”

Regional variations in apoE level may exist.

“Together, these data suggest that the LDLR regulates brain apoE levels in an isoform-dependent manner, and that regional variations in apoE level may also exist.”

The specific interaction between apoE4 and the LDLR was associated with impairments in the retention of long-term spatial memory.

“Particularly, both the lack of LDLR and the specific interaction between apoE4 and the LDLR were associated with impairments in the retention of long-term spatial memory.”

The apoE isoforms may exert unique effects in the amygdala through an LDLR-independent mechanism.

“these data imply that the apoE isoforms may exert unique effects in this particular brain region through an LDLR-independent mechanism.”

• AssumptionRests on an assumption: Both contextual fear conditioning and cued fear conditioning strongly rely on the amygdala.

A SNP in LDLR exon 12 was associated with increased AD risk in men.

“Zou et al. (2008) demonstrated that a SNP in LDLR exon 12 was associated with increased AD risk in men.”

• cites Zou et al. (2008) sourceNot checked yet

The apoE isoform present is more important than actual apoE levels in the amygdala.

“more likely that – at least in regard to the amygdale – the apoE isoform present is more important than actual apoE levels.”

Type III Hyperlipoproteinemia and grossly elevated plasma apoE concentrations in TR mice (and knock-in mice) with E2 are significant confounders.

“the type III Hyperlipoproteinemia (HLP) and grossly elevated plasma apoE concentrations in TR mice (and knock-in mice) with E2 are significant confounders (Mahley et al., 1999)”

• cites Mahley et al., 1999 sourceNot checked — no full text of the source

The LDLR regulates brain apoE levels in an isoform-dependent manner.

“Together, these data suggest that the LDLR regulates brain apoE levels in an isoform-dependent manner, and that regional variations in apoE level may also exist.”

LDLR regulates hippocampus apoE levels in an isoform dependent manner.

“Taken together, these data suggest that: 1) LDLR regulates hippocampus apoE levels in an isoform dependent manner”

• AssumptionRests on an assumption: Trafficking of apoE-containing HDL-like particles in the brain is likely affected by interaction of apoE with the LDLR, as it is in the periphery.

This is the first study to demonstrate an association between hippocampus human apoE levels and cognitive performance in a test of long term spatial memory.

“To our knowledge, this is the first study to demonstrate an association between hippocampus human apoE levels and cognitive performance in a test of long term spatial memory.”

In regards to the retention of long term spatial memory, total apoE levels may be more important than the specific isoform present.

“2) in regards to the retention of long term spatial memory, total apoE levels may be more important than the specific isoform present.”

Expression of human LDLR in hemizygous human LDLR (h/−) mice is limited to a range of 16-205%, with a mean of 99%, compared to murine LDLR in wild-type mice.

“Expression of human LDLR in these mice is limited to a range of 16-205%, with a mean of 99%, compared to murine LDLR in wild-type mice.”