Research Models

APOE3 Targeted Replacement

Synonyms: APOE3 Humanized Knock-in

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Species: Mouse
Genes: APOE
Modification: APOE: Knock-In
Disease Relevance: Alzheimer's Disease, Multiple Conditions
Strain Name: B6.129P2-Apoetm2(APOE*3)Mae N8
Genetic Background: 129 x C57BL/6; back-crossed to C57BL/6
Availability: Taconic: Stock# 1548-F and 1548-M

Summary

The APOE3 Targeted Replacement model is one line in a set of three APOE knock-in lines created by Nobuyo Maeda, Patrick Sullivan, and colleagues. APOE2 and APOE4 Targeted Replacement mice are also available.

In this set of targeted replacement (knock-in) mice, the coding sequence of the endogenous murine Apoe gene was replaced by one of the three major human APOE alleles—E2, E3, or E4. Expression of the gene remains under the control of mouse regulatory elements.

These mice are the first APOE knock-in models, and they have been invaluable for comparing the effects of the major ApoE isoforms. However, these mice are probably not appropriate models for studying regulation of the human APOE gene or interactions between levels of expression and isoform. In the targeted replacement mice, expression of the APOE gene remains under the control of mouse regulatory elements, but there are differences in the promoter regions of the human and mouse genes, including potential transcription-factor binding sites, and the transcription-factor milieus also differ between the species (Maloney et al., 2007).

Commercially sourced mice are available as homozygotes and breeding restrictions apply. These restrictions led to two unfortunate consequences: 1) Relatively few studies have examined heterozygous pairings of the human alleles. 2) Within many studies, homozygous mice of different genotypes come from different litters, raising the possibility of confounding litter and genotype effects, especially when sample sizes are small (Barthelson et al., 2022). The Jackson Laboratory recently created a similar set of APOE knock-in mice that are not subject to breeding restrictions.

Initial characterization of these models focused on lipid metabolism and atherosclerosis. Mice homozygous for the common E3 allele were the first to be described (Sullivan et al., 1997). Levels of APOE3 mRNA in the targeted replacement mice are similar to those of endogenous murine mRNA in wild-type mice in most tissues, including liver and brain. The APOE3 mice have normal cholesterol and triglyceride levels on a standard diet but are more susceptible than wild-type animals to diet-induced atherosclerosis. APOE2 targeted replacement mice were the next published (Sullivan et al., 1998). Mice homozygous for the APOE2 allele exhibit characteristics of type III hyperlipoproteinemia: They have plasma cholesterol and triglyceride levels two to three times higher than levels in mice expressing human APOE3. The APOE2 mice also have deficits in clearing very-low-density lipoprotein (VLDL) particles and spontaneously develop atherosclerotic plaques. A high-fat diet exacerbates the atherosclerosis. Last described were APOE4 mice (Knouff et al., 1999). These mice are at increased risk of atherosclerosis compared with wild-type animals or mice expressing human APOE3. On a standard diet, the mice have normal plasma levels of cholesterol and triglycerides but altered relative levels of plasma lipoprotein particles. On a high-fat diet they have elevated cholesterol, ApoE, and ApoB-48 compared with mice expressing human APOE3. (It should be noted that the initial studies of these mice used early generations of the model on a mixed 129 x C57BL/6 background. In later studies, animals contained a larger fraction of C57BL/6 alleles, as mice were backcrossed to this strain in succeeding generations.)

Subsequently, many laboratories characterized the neurological and behavioral phenotypes of the APOE Targeted Replacement mice. A survey of these findings is presented here. Unless stated otherwise, mice are homozygous for the human APOE alleles.

ApoE levels | Aβ and other APP metabolites | Phospho-tau | Molecular and structural features of synapses | Dendritic morphology | Neural activity | Other neurological phenotypes | Behavior | Bioenergetics | Insulin signaling | Vesicle trafficking pathways | Transcriptomics | Proteomics | Metabolomics | APOE3 Targeted Replacement mice compared with wild-type mice | Modification details | Crosses with other AD-relevant models

ApoE levels

Levels of APOE mRNA in the cortex and hippocampus do not differ between genotypes (Bales et al., 2009; Riddell et al., 2008). Several laboratories have reported that levels of ApoE protein in the brain are genotype-dependent, generally finding that ApoE2 > ApoE3 > ApoE4 (Bales et al., 2009; DiBattista et al., 2016; Ramaswamy et al., 2005; Riddell et al., 2008; Shinohara et al., 2016). However, this result may depend on experimental conditions, with this order found when detergent-containing buffers are used to homogenize the tissue. In the absence of detergent, one study found levels of cortical ApoE4 > ApoE3 (DiBattista et al., 2016; APOE2 mice were not included in this study), while a second study found no differences in hippocampal ApoE levels between APOE2, APOE3, and APOE4 mice (Korweck et al., 2009).

Aβ and other APP metabolites

APOE Targeted Replacement mice do not make plaques, but several studies have measured soluble Aβ in the brains of these mice. A clear relationship between genotype and Aβ has not emerged. Increased levels of Aβ42 in E4 carriers relative to E3 carriers were measured by ELISA of hippocampal (Liraz et al., 2013) and cortical (Shang et al., 2020) homogenates from 4- and 16-month-old mice, respectively. However, two other studies found no differences in levels of Aβ40 or Aβ42 in 12- to 15-month-old mice in homogenates of whole brain (Venzi et al., 2017) or brains minus cerebella and olfactory bulbs (Novy et al., 2022). The latter study also found no differences in levels of APP or its metabolites sAPPα, sAPPβ, CTFα, or CTFβ between APOE genotypes.

Interestingly, peripheral clearance of Aβ42 was slower in APOE4 Targeted Replacement mice than in APOE2 or APOE3 mice (Sharman et al., 2010).

APOE Targeted Replacement mice have been crossed with mouse models of amyloidosis to study the influence of APOE genotype on amyloid accumulation. Some of these crosses are listed below.

Phospho-tau

Similar to Aβ, there is not a consensus regarding the effects of APOE genotype on tau hyperphosphorylation. Immunoreactivity to AT8, a monoclonal antibody that recognizes tau phosphorylated at serine-202 and threonine-205, is a common marker of tauopathy. Levels of AT8-immunoreactive tau were reported to be elevated in the hippocampi of APOE4 mice, compared with APOE3 mice, at 4 months of age but not at 1 month (Liraz et al., 2013; Salomon-Zimri et al., 2015). However, no differences in AT8 immunoreactivity were detected between the brains of APOE2, APOE3, or APOE4 mice at 23 months (Shinohara et al., 2016).

Molecular and structural features of synapses

While several studies have examined features of synapses in APOE Targeted Replacement mice, and some genotype-dependent differences have been reported, these data do not support any general conclusions about allele-specific effects on synaptic integrity.

Levels of the presynaptic marker synaptophysin were reported to be lower in the brains of 12-month-old APOE4 mice than APOE3 mice (Yin et al., 2019).

Levels of the vesicular glutamate transporter, a presynaptic marker of excitatory synapses, were lower in hippocampal extracts of male APOE4 mice compared with APOE3 mice at 4 months of age (Liraz et al., 2013; Salomon-Zimri et al., 2015), while the opposite relationship was found in whole-brain homogenates (Dumanis et al., 2013). No differences were seen between groups of 23-month-old APOE2, APOE3, and APOE4 mice of mixed genders (Shinohara et al., 2016).

Levels of glutamic acid decarboxylase (GAD67) and the vesicular GABA transporter (VGAT), presynaptic markers of GABAergic synapses, were similar in the hippocampi of 4-month-old APOE3 and APOE4 Targeted Replacement mice (Liraz et al., 2013). At 23 months, no differences in the levels of hippocampal GAD67 were seen between APOE2, APOE3, and APOE4 mice (Shinohara et al., 2016).

One study reported that levels of the postsynaptic marker PSD95 in the hippocampus and cortex were similar in APOE2, APOE3, and APOE4 mice at 7 and 23 months of age (Shinohara et al., 2016). However, another study found lower levels of PSD95 in the CA1 region of 15-month-old APOE4 mice compared with APOE3 (Zalocusky et al., 2021) and a third group reported lower amounts of PSD95 in the brains of 12-month-old APOE4 mice compared with APOE3 (Yin et al., 2019).

Similar levels of the NR1 subunit of the NMDA receptor, another postsynaptic marker at glutamatergic synapses, were found in the hippocampi of APOE2, APOE3, and APOE4 mice at 23 months (Shinohara et al., 2016).

Interestingly, levels of C1q—a component of the complement cascade thought to label senescent synapses—were elevated in the hippocampi of 9- and 18-month-old APOE4 Targeted Replacement mice and reduced in APOE2 mice, compared with APOE3 animals (Chung et al., 2016).

Dendritic spine density in cortical pyramidal neurons was lower in APOE4 mice than APOE2 or APOE3 mice at 1, 3, and 12 months of age, but spine density did not differ between genotypes in the hippocampus (Dumanis et al., 2009). On average, dendritic spines were longer in cortical pyramidal neurons in APOE2 mice and shorter in APOE4 mice, while the opposite relationship was seen in the dentate gyri of year-old animals (Dumanis et al., 2009). In the medial entorhinal cortex, 3-month-old APOE4 mice exhibited lower spine densities than APOE3 mice (Rodriguez et al., 2013).

Dendritic morphology

Dendritic complexity in the amygdala was reported to be greater in E3 homozygotes than in carriers of the E4 allele at 7 months, but these differences were not apparent at 1 or 18 months (Klein et al., 2010; Klein et al., 2014).

In the medial entorhinal cortex, 3-month-old APOE4 mice exhibited shorter dendrites and lower spine densities than APOE3 mice (Rodriguez et al., 2013).

Apical dendrites of layer II/III pyramidal cells in the somatosensory cortex had fewer branches in APOE4 mice than APOE2 or APOE3 mice at 1, 3, and 12 months of age (Dumanis et al., 2009).

Neural activity

Electrophysiological and imaging studies suggest that aged APOE4 mice exhibit neural hyperactivity compared with APOE3 mice, at least in some brain regions.

Age- and genotype-dependent effects on synaptic function have been recorded in the amygdala of APOE Targeted Replacement mice. Young adult (1- and 7-month-old) homozygous APOE4 mice exhibited lower levels of spontaneous excitatory synaptic activity than APOE3 mice (Klein et al., 2010), but these differences were reversed by 18 months, when APOE4 mice showed higher levels of both excitatory and inhibitory synaptic activity than APOE3s (Klein et al., 2014). At the younger ages, the level of excitatory synaptic activity in E2/E4 heterozygotes was intermediate between E4/E4 and E3/E3 homozygotes, suggesting that the E2 allele may counteract some of the effects of E4 (Klein et al., 2010).

In the hippocampus, neither basal synaptic transmission nor paired-pulse facilitation at CA1 synapses differed between APOE2, APOE3, and APOE4 4-month-old mice, although NMDA receptor-dependent LTP was enhanced in slices from APOE4 mice compared with APOE2 animals (Korweck et al., 2009).

Excitability of the olfactory system was found to be elevated in APOE4 mice (East et al., 2018; Peng et al., 2017). At 6 months of age, the magnitude of odor-evoked local field potentials in the olfactory bulb and piriform cortex followed the order APOE4 > APOE3 > APOE2; by 12 months of age the difference between APOE4 and APOE3 was no longer statistically significant in the olfactory bulb but persisted in the piriform cortex.

Electrophysiological recordings in awake, freely moving mice revealed an elevated firing rate of excitatory neurons in the entorhinal cortices of 18-month APOE4 mice compared with APOE3 animals (Nuriel et al., 2017). Functional MRI measurements supported the finding of relative hyperactivity in aged APOE4 brains, with greater cerebral blood volume in the entorhinal cortex, subiculum, and CA1 subfield of the hippocampus in APOE4 than APOE3 mice (Nuriel et al., 2017).

FDG-PET findings are also consistent with elevated neural activity in aged APOE4 mice relative to APOE3 animals, with glucose uptake measured in the whole brain, cingulate cortex, cortex, and hippocampus greater in APOE4 than APOE3 mice at 15 months of age (Venzi et al., 2017). However, it should be noted that, by 6 months, APOE2 mice exhibited the highest levels of glucose uptake in the whole brain and in the regions mentioned.

Other neurological phenotypes

A few studies have compared hippocampal anatomy in Targeted Replacement mice of different APOE genotypes. While an MRI study found no differences in hippocampal volumes in 12-month-old APOE2, APOE3, and APOE4 animals (Badea et al., 2022), a second study—measuring hippocampal volume from histological sections—reported larger volumes in APOE3 mice compared with APOE4 mice at 15 months of age (Zalocusky et al., 2021). The latter study also found lower densities of neurons in the CA1 regions of APOE4 mice than APOE3 animals.

Female APOE4 mice had fewer GABAergic interneurons in the hilus, the outermost layer of the dentate gyrus, than did female APOE3 mice, beginning at 6 months of age (Andrews-Zwilling et al., 2010; Leung et al., 2012; Li et al., 2009). This difference between the genotypes was not seen in males. Hilar interneurons make inhibitory synapses onto dentate granule cells, and immunohistochemical and electrophysiological evidence indicated that there were fewer GABA synapses on granule cells in APOE4 than APOE3 females (Andrews-Zwilling et al., 2010). GABA synapses from hilar interneurons promote the maturation of adult-born dentate granule neurons, and fewer mature neurons, but more immature neurons, were indeed found in the subgranular zone of the dentate gyrus—the site of granule cell neurogenesis in adults—in female APOE4 mice, compared with APOE3 animals (Li et al., 2009).

Markers of cell senescence—including levels of mRNA for P16, P19, and P53 and staining for senescence-associated β-galactosidase (SA-β-gal)—were elevated in the hippocampi of aged APOE4 versus APOE3 mice (Lv et al., 2023). Co-staining for SA-β-gal and neuronal (NeuN), astrocytic (GFAP), or microglial (Iba1) markers showed that the vast majority of SA-β-gal-positive cells were neurons. These genotype-dependent differences were apparent at 18 months but not 9 months.

Fractional anisotropy, a measure of white-matter integrity, was reported to be higher in the hippocampi of female APOE2 mice than APOE3 or APOE4 at one year; these genotype differences were not seen in males (Badea et al., 2022).

MRI has revealed other structural differences in the brains of Targeted Replacement mice of different APOE genotypes. The volume of the caudate putamen was found to vary between genotypes, with APOE4 > APOE2 > APOE3 in 12-month mice (Badea et al., 2022). This study also found that fractional anisotropy in this region was greater in APOE2 females than females of the other two genotypes. In another study, fractional anisotropy in several white-matter tracts, including the internal capsule, fimbria, anterior commissure, and corpus callosum was higher in 16-month-old APOE3 males than APOE4 animals, with females showing a similar, but not statistically significant, trend (Shang et al., 2020). The lateral ventricles of male APOE4 mice were larger than those of APOE2 or APOE3 animals, assessed at 9 months of age (Palavicini et al., 2022).

Behavior

A recent systematic review and meta-analysis provides a comprehensive comparison of the performance of homozygous APOE3 and APOE4 knock-in mice on a variety of cognitive tests (van Heuvelen et al., 2024). The studies contributing to the analyses primarily—but not exclusively—employed APOE Targeted Replacement mice. The meta-analyses revealed that APOE4 mice exhibited modest deficits in probe trials in the Morris water maze, in the novel object recognition task, and in contextual fear conditioning. The genotypes did not differ in their performance on novel object location tasks or cued fear conditioning. Meta-regression analyses did not reveal age- or sex-dependent effects in this sample of 1034 APOE3 mice and 1125 APOE4 mice aged 6 weeks to 25 months.

The behavioral findings in a sampling of studies of APOE Targeted Replacement mice are described below. Genotype-, age-, and sex-dependencies were reported in some, but not all, studies. Different protocols, outcome measures, and methods of analysis were employed in different laboratories, and readers are encouraged to refer to the original papers for details.

In a study comparing all three APOE genotypes, performance in the Morris water maze worsened with age in APOE3 and APOE4 mice, with the latter showing a more severe decline, while performance in APOE2 mice was preserved (Shinohara et al., 2016). Seven-month-old mice of all three genotypes learned the task and performed equally well in probe tests given 24 and 72 hours after the final training (hidden platform) trial, with all genotypes showing a preference for the target quadrant in the probe trials. At 23 months of age, APOE4 mice did not appear to learn the location of the hidden platform, while the other two genotypes did. During the memory portion of the task, both APOE2 and APOE3 mice showed a preference for the target quadrant during the 24-hour probe, but only APOE2 mice showed a preference during the 72-hour probe. Mice of both sexes were used in this study.

Another study also found age-related performance deficits in the Morris water maze in APOE4 mice compared with APOE3 animals (Andrews-Zwilling et al., 2010). Female mice were tested at 12, 16, and 21 months of age. APOE3 and APOE4 mice performed similarly at 12 months. At 16 and 21 months, APOE4 animals showed learning deficits. Nonetheless,the two genotypes obtained similar scores in probe trials at 24- and 72-hours post-training, with both genotypes showing a preference for the target quadrant. At 16 months, APOE3 mice continued to show a preference for the target quadrant in probe trials given 5 days after the last training day, but APOE4 mice did not (scores in the 5-day probe trial were not reported for 21-month-old mice). This study did not include APOE2 mice.

Yet another group subjected 4- to 5-month-old (Grootendorst et al., 2005) and 15- to 18-month-old (Bour et al., 2008) APOE3 and APOE4 mice to a battery of behavioral tests. In the younger group, only APOE3 females showed a preference for the target quadrant during a probe trial administered 24 hours after the final training trial. In the older group, APOE3 mice of both sexes and APOE4 males, but not APOE4 females, preferred the target quadrant. The finding that older, but not younger, male mice of both genotypes showed a preference for the target quadrant in the probe trial does not appear to be consistent with the decline in performance with age reported in some of the other studies cited in this section. However, as the age groups were reported in different studies, there was no direct comparison of performance as a function of age.

In a study that compared female Targeted Replacement mice of all three genotypes at young (6–8 months), middle (10–13 months), and old (14–22 months) ages, APOE4 mice appeared to perform better than the other genotypes during the training trials—collapsed across ages, APOE4 mice had lower latencies to reach the hidden platform. Memory retention was evaluated in probe trials administered one hour after the training trials of days three through five of the five-day training phase. Rather than more conventional measures of memory retention in the Morris water maze—target quadrant occupancy or platform crossings—this study used cumulative distance to the former platform location. Genotype differences were not seen in any of the probe trials (Siegel et al., 2012).

Additional studies, performed in separate laboratories, examined genotype-dependent differences in Morris water maze performance in single-aged cohorts of APOE Targeted Replacement mice.

In a study of 3-month-old APOE2, APOE3, and APOE4 mice, the three genotypes learned the task equally well and did not differ in target quadrant occupancy or platform-location crossings in a probe trial administered 72 hours after the last training trial, although it should be noted that only APOE3 mice actually showed a preference for the target quadrant over the other quadrants in this study (Rodriguez et al., 2013).

Another study compared the three APOE genotypes in 4- to 5-month-old mice of both sexes and concluded that APOE3 mice performed best during the learning phase of the Morris water maze test and that APOE2 mice showed the worst retention (Reverte et al., 2012). This study employed a relatively long acquisition period (10 days of hidden platform trials) and multiple probe trials—with probe trials before the training sessions on days 3, 5, 8 and 10 and a long-term probe three days after the last training day. Compared with the other two genotypes, APOE3 mice showed the shortest distances and latencies to reach the target platform during the training sessions. A two-way ANOVA (genotype x sex) did not show an effect of genotype or sex on time spent in the target quadrant in the 72-hour probe trial, but APOE2 mice did not show a preference for the target quadrant, while APOE3 mice of both sexes and APOE4 males did.

In a study comparing 12-month-old APOE3 and APOE4 mice, the former mice performed better during the training phase—showing shorter latencies to reach the target platform on days 2,3, and 4 of the 4-day training phase—and spent more time in the target quadrant during a probe trial conducted 24 hours after the last training trial (Yin et al., 2019). The sex of the mice used in this study was not specified.

In a study comparing 16-month-old APOE3 and APOE4 mice, genotype effects were seen only in females. APOE4 females took longer to find the hidden platform during training trials. While both genotypes showed a preference for the target quadrant in a 24-hour probe trial, only APOE3 mice showed a preference during a 72-hour probe trial. APOE3 and APOE4 males learned the maze equally well and performed similarly in both probes, with both genotypes spending more time in the target quadrant than the other quadrants (Leung et al., 2012).

Learning and memory deficits have been reported in APOE4 mice in other spatial navigation tasks. Compared with APOE3 mice, young (3-4 month) APOE4 mice showed impairments in the Barnes maze (Rodriguez et al., 2013) and the dry maze modification of the hole-board test, which challenges water-deprived mice to find a small water-filled well in a circular arena (Liraz et al., 2013). In the radial arm water maze, 10- to 12-month-old APOE4 mice made more errors and took longer to find the escape platform than did APOE3 mice (Nichol et al., 2009).

The object location task (also referred to as the “novel objection location” task) is another test of spatial memory. In the meta-analysis of behavior in APOE knock-in mice cited above (van Heuvelen et al., 2024), there was no clear effect of genotype on performance in this task. In Alzforum’s small survey of three studies, APOE4 Targeted Replacement mice showed impairments in this task under some conditions: One group reported that 4- to 5-month-old APOE4 female mice performed more poorly than APOE3 females on this test, while males of the two genotypes performed similarly (Grootendorst et al., 2005), but that there were no clear effects of genotype in mice 15 to 18 months of age (Bour et al., 2008). A second group that used both sexes found that APOE4 mice showed performance deficits, compared with APOE3 animals, at 10 to 12 months of age (Nichol et al., 2009).

Spontaneous alternation in the Y-maze, a measure of working memory, was not affected by genotype in 6-month-old mice of either sex or 18-month-old males, but APOE4 females performed better than APOE3 females at 18 months (Holden et al., 2022).

Fear conditioning is a commonly studied form of associative learning and memory. APOE4 mice showed deficits in contextual fear conditioning (where the animal learns to associate a shock with an otherwise neutral context) but not cued fear conditioning (where the animal associates the shock with an auditory cue) in the meta-analysis of behavior in APOE knock-in mice cited above (van Heuvelen et al., 2024). In a study of 4-month-old male APOE Targeted Replacement mice, E4 carriers showed impairments in contextual—but not cued—fear conditioning, compared with E3 carriers (Salomon-Zimri et al., 2015). In another study of fear conditioning using 6- and 18-month-old mice, genotype- and sex-dependent differences in baseline activity and responses to shocks made the results of the contextual and cued tests difficult to interpret (Holden et al., 2022).

Learning and memory in a passive avoidance task was age- and genotype-dependent in a study that included young (6–8 months), middle-aged (10–13 months), and old (14–22 months) female APOE Targeted Replacement mice of all three genotypes (Siegel et al., 2012). This task takes advantage of rodents’ natural tendency to prefer dark spaces. Mice were placed in the illuminated side of a box with two chambers, one illuminated and one dark, and received a shock when they entered the dark chamber. Learning—assessed as the number of trials to reach a criterion of three consecutive trials where the mouse refused to enter the dark chamber—occurred more quickly in young APOE2 and APOE4 mice than APOE3 animals, while middle-aged APOE3 and APOE4 mice learned more quickly than APOE2 mice, and old APOE4 mice learned more quickly than the other two genotypes. Retention—latency to enter the dark compartment 24 hours after the last training session—did not vary with genotype in the young and middle-aged cohorts but was worse in old APOE2 mice compared with the other two genotypes. Another group compared APOE3 and APOE4 mice of both sexes at 4-5 months of age (Grootendorst et al., 2005) and 15-18 months (Bour et al., 2008). This group used only a single acquisition trial before testing for retention 24 hours later. With this protocol, APOE3 and APOE4 mice performed similarly at the younger age, but the older E4 carriers did not avoid the dark chamber during the retention test.

Motor learning might be impaired in aged APOE4 mice, compared with APOE2 or APOE3 animals: In one study, latency to fall off the rotarod increased with session number in all genotypes, but by the final session, the latency to fall was significantly shorter for APOE4 animals than APOE2 or APOE3 mice (Shinohara et al., 2020).

APOE genotype has been reported to influence levels of activity and measures of anxiety in Targeted Replacement mice, but it is difficult to draw general conclusions from studies that examined different ages, sexes, and contexts. That said, among the small number of studies surveyed here, there was a tendency for APOE2 mice to be more active and APOE4 mice to be more anxious (Holden et al., 2022; Reverte et al., 2012; Shinohara et al., 2020; Siegel et al., 2012).

Bioenergetics

Functional analysis—using the Seahorse platform—showed decreased respiration in mitochondria isolated from the hippocampi and cortices of APOE4 mice, compared with APOE3 mice, with differences becoming more pronounced with age between 6 and 20 months (Area-Gomez et al., 2020). Decreased mitochondrial respiration, accompanied by increased aerobic glycolysis, was also seen in primary microglia cultured from APOE4 mice, compared with APOE3 mice (Lee et al., 2023).

Using stable isotope resolved metabolomics (SIRM) to measure glucose utilization, increased conversion of glucose to lactate was observed in the brains of APOE4 mice compared with APOE3 animals (12- to 13-month-old females), as well as in astrocytes cultured from neonatal mice of those genotypes (Farmer et al., 2021). Conversely, lower levels of tricarboxylic acid (TCA) cycle intermediates were found in astrocytes from APOE4 mice compared with APOE3. These findings support increased aerobic glycolysis and decreased mitochondrial respiration in E4 homozygotes compared with E3 homozygotes.

Citrate synthase activity was lower in mitochondria isolated from the hippocampi of 18-month-old APOE4 mice, compared with mitochondria from APOE3 animals; these genotype-dependent differences were not apparent in mitochondria from 9-month mice. This change was accompanied by lower levels of ATP and acetyl-CoA, but a higher NAD+/NADH ratio, in hippocampal homogenates from E4 carriers (Lv et al., 2023).

Consistent with the physiological findings, single-cell RNA sequencing showed decreased expression of genes involved in oxidative phosphorylation in the brains of 11- to 12-month-old female APOE4 mice, compared with age- and sex-matched APOE3 animals; this difference was especially pronounced in astrocytes (Farmer et al., 2021). Additionally, expression of the lactate dehydrogenase A gene (Ldha) and levels of lactate dehydrogenase protein were greater in astrocytes cultured from APOE4 mice than APOE3 mice (Farmer et al., 2021). Bulk RNA-sequencing of the hippocampi of 18-month-old females also showed downregulation of genes related to oxidative phosphorylation in APOE4 mice, compared with APOE3 (Lv et al., 2023). Differences in expression of genes related to oxidative phosphorylation between APOE4 and APOE3 mice were already apparent by 3 months (Barthelson et al., 2022; re-analysis of the 3-month dataset from Zhao et al., 2020). However, the authors of this study noted that litter effects, as well as different proportions of cell types in the samples from the two groups, might have created the false impression of genotype-dependent changes in gene expression.

The effect of APOE genotype on bioenergetics has been reported to depend on sex. For example, complex I-mediated respiration, assessed using Seahorse, was decreased in mitochondria from aged (20 month) female APOE4 mice, compared with APOE3, but this genotype-dependent difference was more pronounced in mitochondria isolated from male mice (Area-Gomez et al., 2020). Additionally, an analysis of the hippocampal transcriptomes of 16-month-old mice found lower expression of oxidative phosphorylation genes in female APOE4 mice compared with APOE3 animals, while APOE4 males had higher expression of genes involved in glycolysis and the TCA cycle (Shang et al., 2020).

The effects of APOE genotype have also been reported to depend on brain region (Area-Gomez et al., 2020). Contrary to the findings in the hippocampus and other cortical regions, where mitochondrial respiration is impaired in E4 homozygotes compared with E3, mitochondrial respiration is increased in the entorhinal cortex of aged E4 mice. Transcriptomic data support these physiological findings: Upregulation of genes encoding mitochondrial transporters, subunits of complexes I through V of the electron transport chain, and enzymes involved in the malate-aspartate shuttle was observed in the entorhinal cortex of mice carrying the E4 allele—although this analysis compared APOE3/4 heterozygotes with APOE3/3 homozygotes.

Insulin signaling

Decreased basal insulin signaling, accompanied by cerebral insulin resistance, was observed in the brains of aged APOE4 mice, compared with APOE3 mice (Zhao et al., 2017).

A targeted transcriptomic study focusing on pathways involved in glucose utilization found higher expression of Igf1 (insulin-like growth factor 1), Irs (insulin receptor substrates), and Glut4 (insulin-regulated glucose transporter) genes in the hippocampi of 6-month-old female APOE2 mice compared with APOE3 and APOE4 animals; levels of Pparγ (peroxisome proliferator activated receptor gamma), and Ide (insulin degrading enzyme) were also higher in APOE2 mice than APOE4 mice (Keeney et al., 2015). Western blot analyses of protein expression supported the transcriptomic findings.

Vesicle trafficking pathways

APOE genotype was shown to influence vesicle trafficking pathways in aged APOE Targeted Replacement mice, with APOE2 and APOE4 appearing to have opposite effects when compared with APOE3.

Increased numbers of Rab5-immunoreactive early endosomes or increased levels of Rab5 immunoreactivity were found in the brains of APOE4 mice (Nuriel et al., 2017; Zhao et al., 2017), while Rab5 levels were decreased in APOE2 brains (Peng et al., 2024).

Lower levels of the exosomal markers TSG101 and ALIX were seen in APOE4 brains, compared with APOE3; these differences emerged between 6 and 12 months (Peng et al., 2019). The exosomes derived from the two genotypes differed with regard to lipid composition, with higher levels of cholesterol, ceramide, and ganglioside GD1a found in exosomes from APOE4 mice (Peng et al., 2019). Conversely, there was an age-dependent increase in the number of exosomes and in the levels of exosomal markers in APOE2 brains, compared with APOE3, with differences becoming apparent between 12 and 18 months of age (Peng et al., 2024).

More Cathepsin D-positive structures—likely lysosomes—were found in the entorhinal cortices of APOE4 mice, compared with APOE3; APOE2 mice were not examined in this study (Nuriel et al., 2017).

A transcriptomic analysis of the brains of 12-month-old APOE Targeted Replacement mice noted differential expression of vesicle-related genes in APOE2 compared with APOE3 mice, with downregulation of genes related to endosomal trafficking, fusion, and localization and upregulation of genes related to endosomal recycling to the plasma membrane and the formation and release of exosomes (Peng et al., 2024). The directions of these effects are consistent with the histological and biochemical findings mentioned above.

Transcriptomic analyses comparing E4 and E3 carriers, however, do not paint a clear picture. In one study, endosome- and lysosome-related genes were found to be upregulated in the entorhinal cortices of heterozygous carriers of the E4 allele (APOE3/4 mice) compared with APOE3/3 mice, although differential expression of these genes was not seen in the primary visual cortex (Nuriel et al., 2017). This finding is consistent with elevated markers of these vesicles in the entorhinal cortices of homozygous carriers of the E4 allele. However, a second transcriptomic study noted downregulation of lysosomal genes in the brains of E4 homozygotes compared with E3 homozygotes (Zhao et al., 2020). In yet a third study, which selectively quantified levels of mRNA for endolysosomal and autophagy markers in the hippocampi, mRNAs related to endosomes, lysosomes, and autophagy were elevated in aged E4 homozygotes compared with E3 homozygotes (Lv et al., 2023).

Transcriptomics

The differential expression of genes related to bioenergetics and immune function is a consistent finding in studies comparing brain transcriptomes of APOE Targeted Replacement mice (see, for example, Lee et al., 2023; Williams et al., 2023). However, the direction of change is not always constant between studies, with age, sex, region, and cell type potentially interacting with APOE genotype to influence expression levels. In a study comparing the brain transcriptomes of APOE3 and APOE4 mice across the lifespan (sampled at 3, 12, and 24 months of age), single-cell RNA sequencing showed that glial cells—including microglia, astrocytes, oligodendrocytes, and ependymal cells—were the cell types most influenced by APOE genotype (Lee et al., 2023).

Some transcriptomic findings related to bioenergetics are mentioned above.

Several genes related to immune signaling or gliosis were found to be up-regulated in APOE4 brains, including major histocompatibility complex-related genes (Shang et al., 2020), interferon-response-related genes (Shang et al., 2020; Williams et al., 2023), and members of the Serpina3 gene family (Lee et al., 2023; Lv et al., 2023; Williams et al., 2023; Zhao et al., 2020).

Genes related to RNA splicing and ribosomes were slightly upregulated in the cortices of APOE4 mice compared with APOE3 (Barthelson et al., 2022; Zhao et al., 2020). Upregulation of genes related to protein processing in the endoplasmic reticulum was seen in the hippocampi of aged female APOE4 mice, compared with APOE3, while genes related to oxidative phosphorylation, steroid biosynthesis, and aldosterone synthesis and secretion were downregulated (Lv et al., 2023).

Differential expression of genes involved in the endosomal-lysosomal pathway has also been noted, as mentioned above.

Proteomics

A study comparing the cortical proteomes of 6-month-old female APOE2, APOE3, and APOE4 mice found differences in proteins involved in cellular bioenergetics and synaptic transmission (Woody et al., 2016). The authors of this study highlighted differences in expression of Atp6v1B2, a component of vacuolar ATPase—an enzyme complex responsible for the acidification of organelles including synaptic vesicles—with highest levels found in APOE2 mice and lowest levels in APOE4.

Metabolomics

Genotype-dependent differences in the brain metabolomes of APOE Targeted Replacement mice have also been described. A targeted metabolomic analysis of 14- to 15-month-old male mice found downregulation of some fatty acids and upregulation of certain vitamins and oligosaccharides in the entorhinal and primary visual cortices of APOE4 animals compared with APOE3 (Nuriel et al., 2017). Additionally, upregulation of energy-related metabolites—including TCA-cycle metabolites, fructose-6-phosphate, carnitine, and ATP itself—was seen in the entorhinal cortex of APOE4 mice. A pathway analysis of an untargeted metabolomic dataset from these same mice showed genotype-dependent differences in fatty acid, inosine 5'-monophosphate, steroid, and vitamin metabolism and in ketone catabolism (Area-Gomez et al., 2020).

A study of the cortical metabolome of 16-month-old mice of both sexes showed higher levels of amino acids, carnitine, and lysophosphatidylcholines in APOE4 mice, compared with APOE3 (Shang et al., 2020). Higher levels of sphingomyelins and phosphatidylcholines were seen in APOE3 versus APOE4 males, but not females.

An untargeted metabolomic study of the hippocampi of female mice noted genotype-dependent differences in glucose metabolism at 9 months and lipid metabolism at 18-months (Lv et al., 2023). However, unlike the study cited above, levels of sphingomyelins were elevated in aged APOE3 versus APOE4 females.

In a study examining levels of L-carnitine and associated metabolites, levels of acylcarnitines in the cerebrovasculature and brain parenchyma were seen to increase between 10 and 50 weeks of age in APOE2 and APOE3 mice (Huguenard et al., 2023). There was a transient increase in acylcarnitine levels in the cerebrovasculature of APOE4 mice, seen at 25 weeks but not 50 weeks.

APOE3 Targeted Replacement mice compared with wild-type mice

APOE3 was considered the neutral allele against which the other human APOE genotypes were compared in most studies of neurological and behavioral phenotypes in Targeted Replacement mice. Data comparing Targeted Replacement mice to wild-type mice expressing mouse Apoe are sparse.

APOE3 mice were found to be similar to wild-type mice with respect to several aspects of hippocampal anatomy and physiology, including basal synaptic transmission and long-term potentiation at Schaffer collateral-CA1 synapses (Korweck et al., 2009), dendritic spine density in dentate granule cells of year-old mice (Dumanis et al., 2009), dendritic complexity of adult-born neurons (Li et al., 2009), number of GABA interneurons int he hilus of the dentate gyrus (Li et al., 2009), and hippocampal neurogenesis (Li et al., 2009).

Spine densities of layer II/III cortical pyramidal neurons were also similar in year-old APOE3 and wild-type mice (Dumanis et al., 2009).

Morphological properties of neurons in the lateral amygdala were similar in APOE3 mice and wild-type mice, but the frequency of spontaneous excitatory post-synaptic currents (sEPSCs) in these neurons was lower in wild-type mice than APOE3 mice (Klein et al., 2010).

Four- to 5-month-old APOE3 mice and wild-type mice performed similarly in a novel object location task, but wild-type mice performed better than APOE3 mice in avoidance tasks (Grootendorst et al., 2005).

Modification details

A region of the endogenous murine Apoe gene, spanning exons 2-4, was replaced with the corresponding region of the human APOE gene. This modification resulted in substitution of the mouse coding sequence with the human coding sequence, and retention of the mouse regulatory sequence and the noncoding exon one (Sullivan et al., 1997).

Crosses with other AD-relevant models

5xFAD. The 5xFAD line is a model of aggressive amyloidosis. These mice carry human APP and PSEN1 transgenes with a total of five AD-linked mutations. APOE Targeted Replacement mice were bred to 5xFAD mice and the progeny intercrossed. Animals homozygous for the human APOE alleles and hemizygous for the 5xFAD transgenes have been studied extensively and are referred to as EFAD mice (Youmans et al., 2012).

APPPS1. In order to investigate the effects of APOE haploinsufficiency on amyloidosis, APPPS1 mice—which carry APP and PSEN1 transgenes with the AD-linked Swedish and L166P mutations, respectively— were intercrossed with APOE Targeted Replacement mice and Apoe knockout mice (Kim et al., 2011). While this study focused on the effects of gene dosage, it was noted that carriers of the E4 allele had greater plaque burdens than E3 carriers.

APPswe/PSEN1dE9 (line 85). APPSwe/PSEN1dE9 mice carry human APP and PSEN1 transgenes with the AD-linked Swedish and ΔE9 mutations, respectively. Mice develop abundant amyloid plaques in the hippocampus and cortex, beginning by 6 months of age. APPSwe/PSEN1dE9 mice on an Apoe-null background were intercrossed with APOE2, APOE3 or APOE4 Targeted Replacement mice to generate mice hemizygous for the APP and PSEN1 transgenes and homozygous for the human APOE alleles (Kuszczyk et al., 2013). Cortical amyloid plaque burdens in 11-month-old female E4 carriers were nearly twice those of E2 or E3 carriers. A later study comparing E4 and E3 carriers of both sexes confirmed elevated plaque burdens in E4 brains, accompanied by increased gliosis (Grenon et al., 2024).

J20. APOE3 and APOE4 Targeted Replacement mice have been crossed with J20 mice, which carry a human APP transgene with the Swedish and Indiana mutations linked to Alzheimer’s disease (Chan et al., 2016). In this study, mice carried one copy each of the human APOE allele and the endogenous mouse Apoe allele and were hemizygous for the APP transgene. Differences in amyloid plaque burden between E4 and E3 carriers emerged with age, with E4 carriers having an approximately one-third greater plaque load at one year. Compared with E3 carriers, carriers of the E4 allele exhibited performance deficits in the eight-arm radial maze as early as 26 weeks—a time when insulin responses were impaired in hippocampal slices derived from E4 carriers—and the cognitive deficits became more pronounced with age.

PDAPP. To examine the influence of APOE genotype on amyloid deposition, APOE Targeted Replacement mice were crossed with PDAPP mice lacking mouse Apoe (Bales et al., 2009). The PDAPP line carries a human APP transgene with the AD-linked Indiana mutation, and mice hemizygous for the transgene begin depositing amyloid plaques at 6 months of age. Through intercrosses, mice were generated that were homozygous for both the APP transgene and the humanized APOE alleles. Levels of soluble and insoluble Aβ were elevated in the hippocampi and cortices of mice homozygous for the E4 allele, compared with E3/E3 and E2/E2 mice at ages ranging from 3 to 18 months. Higher plaque densities were also seen in E4/E4 mice.

Tau P301S (Line PS19). PS19 mice express a human tau transgene with the P301S mutation linked to frontotemporal dementia. To study the influence of the major human APOE isoforms on tauopathy in the absence of amyloidosis, APOE Targeted Replacement mice were intercrossed with PS19 mice, generating mice homozygous for the human APOE alleles and hemizygous for the tau transgene. One study reported that mice carrying the E4 allele displayed more brain atrophy, ventricular enlargement, and neuroinflammation than mice carrying the E2 or E3 alleles (Shi et al., 2017). However, a second study failed to observe differences among the APOE genotypes in ventricular size, gliosis, or expression of immune-related genes (Williams et al., 2023).

α-synuclein A53T Mouse (Tg). α-synuclein A53T transgenic mice carry a human α-synuclein transgene with the A53T mutation linked to Parkinson’s disease. Alpha-synuclein A53T mice were intercrossed with APOE Targeted Replacement mice to generate animals homozygous for the human APOE alleles and hemizygous for the α-synuclein transgene (Davis et al., 2020). E4 carriers exhibited more α-synuclein pathology than E3 or E2 carriers, while E2 carriers showed better motor performance and increased survival.

Complementary Models

Human induced pluripotent cell lines (iPSCs) are complementary models for the study of ApoE biology at the cellular level. This survey focuses on reports of the generation and use of isogenic lines—lines in which gene editing was used to change the parental APOE allele to a different APOE allele—to compare the effects of the major human ApoE isoforms on essentially identical genetic backgrounds. Isogenic human iPSC lines expressing the three major APOE alleles, as well as corresponding APOE-null lines, have been generated.

Starting with an existing iPSC line derived from an 80-year-old male Alzheimer’s patient homozygous for the E4 allele (Peitz et al., 2018), Schmid, Cabrera-Socorro and colleagues used CRISPR/Cas9 gene editing to generate APOE-knockout, E3/E4, and E3/E3 lines, and then edited the latter line to generate the isogenic E2/E2 line (Schmid et al., 2021). These lines are available through the European Bank for induced pluripotent Stem Cells (EBiSC) [UKBi011-A, parental line APOE4/4; UKBi011-A-1, APOE knockout; UKBi011-A-2, APOE2/2; UKBi011-A-3, APOE3/3; UKBi011-A-4, APOE3/4]. These cells have been used to study the responses of human microglia-like cells to amyloid pathology (Mancuso et al., 2024). IPSCs were differentiated into microglial precursors and transplanted into the brains of mice genetically engineered to lack an adaptive immune system and that have the AD-linked Swedish, Iberian, and Arctic mutations knocked into the mouse App gene. Transcriptomic analysis of microglia isolated from these brains 6 to 7 months after transplantation showed that APOE4/4 microglia resembled APOE knockout microglia, suggesting that the E4 allele has a loss-of-function effect with regards to the response of microglia to amyloid pathology. The effect of microglial APOE genotype on amyloid pathology was not reported. Microglia-like cells derived from the APOE3/3, APOE4/4 and APOE knockout lines have also been used to test the activity of anti-sense oligonucleotides directed against APOE (Vandermeulen et al., 2024).

This same group had previously attempted to create a set of isogenic lines homozygous for the three major APOE alleles starting with iPSCs derived from skin fibroblasts from a healthy 18-year-old with the E3/E4 APOE genotype (Schmid et al., 2019). However, it was found that the resulting E2, E3, and E4 lines were actually hemizygous for the APOE alleles, while the knockout line was as expected (Schmid et al., 2020). These lines are also available through the EBiSC (BIONi010-C, parental line APOE3/4; BIONi010-C-2, hemizygous for the APOE3 allele; BIONi010-C-4, hemizygous for the APOE4 allele; BIONi010-C-6, hemizygous for the APOE2 allele; BIONi010-C-3, APOE knockout). IPSCs from these lines were differentiated into astrocytes and subjected to proteomic and functional analyses (de Leeuw et al., 2022). Proteomic analysis suggested a reduction in components of cholesterol and lipid metabolic and biosynthetic pathways in E4 carriers and an enhancement in E2 carriers compared with E3. Biochemical studies confirmed decreased biosynthesis and efflux of cholesterol from APOE4 astrocytes. Conversely, proteomics showed genotype-dependent effects on immunoregulatory pathways that followed the pattern APOE4 > APOE3 > APOE2. Biochemical studies confirmed increased inflammatory signaling in E4 carriers, and decreased signaling in E2 carriers, compared with E3: When stimulated with IL-1β or TNF, astrocytes of all genotypes increased their release of cytokines, with the responses of APOE4 > APOE3 > APOE2. Uptake of glutamate and of aggregated Aβ42 were lowest in APOE4 astrocytes and highest in APOE2 and APOE knockout cells. The iPSCs have also been differentiated into neurons. In a study that measured energy metabolism in vitro, APOE4 was found to increase mitochondrial and glycolytic ATP production compared with the other genotypes, while cells expressing APOE2 or APOE3 resembled the APOE knock-out neurons (Budny et al., 2024). These results suggest that the E4 allele confers a gain-of-function with regards to neuronal energy metabolism. In another study, the E4 allele led to endolysosomal dysfunction in the iPSC-derived neurons (Somogyi et al., 2023).

The company Alstem distributes two sets of isogenic human iPSCs—E2/E2, E3/E3, E4/E4, and APOE-knockout lines. One of these sets also carries a doxycycline-inducible Ngn2 gene to facilitate differentiation into neurons. Neurons and astrocytes induced from these lines were used to study APOE genotype effects on the expression of PPP2CB—a variant in this gene having been shown to associate with AD in E2 carriers (Jun et al., 2022).

Other groups created isogenic pairs of iPSCs to compare the effects of the E2 or E4 alleles with E3. Beginning with iPSC lines carrying AD-linked mutations in APP (APP V717I or an APP duplication) or PSEN1 (PSEN1 A246E) on an E3/3 background, Brafman and colleagues generated isogenic partner lines homozygous for E2 (Brookhouser et al., 2021). Converting the E3 allele to E2 lowered the levels of Aβ42 produced in neuron-astrocyte co-cultures derived from these iPSCs, but the E3 to E2 switch decreased the Aβ42/Aβ40 ratio only in cultures carrying PSEN1 A246E. The ratio of tau phosphorylated at threonine-231 to total tau was also decreased in cells carrying the PSEN1 mutation when the APOE genotype was switched from E3 to E2.

Li-Huei Tsai and her team made two sets of isogenic pairs of iPSCs to compare the effects of the E3 and E4 alleles (Lin et al., 2018; Jun 2018 news). Beginning with cells homozygous for E3 from an individual cognitively intact at age 75, they created a matching E4/E4 line, then differentiated the iPSCs into neurons, astrocytes, and microglia. APOE-dependent differences in gene expression were seen in all three cell types: Comparing cells expressing E4 with those expressing E3, prominent differences included downregulation of genes involved in cell proliferation and upregulation of genes involved in differentiation in neurons, and upregulation of genes related to lipid metabolism and immune responses in astrocytes and microglia, respectively. Functional differences between the genotypes were also observed: E4 neurons had higher frequencies of excitatory post-synaptic currents (ePSCs), elevated levels of pre- and post-synaptic markers, generated more Aβ42 and had more early endosomes than E3 neurons. Astrocytes generated less ApoE4 than ApoE3 and took up less Aβ42 added to the culture medium. ApoE4-expressing microglia were similarly less efficient than ApoE3-expressing microglia at taking up Aβ42. In a complementary series of experiments, this group created an isogenic E3/E3 iPSC line from an E4/E4 line generated from a person with sporadic AD. Here, too, astrocytes made less ApoE4 than ApoE3, E4-expressing glia took up less Aβ than E3-expressing cells, and E4 neurons showed elevated excitatory synaptic activity and made more synapses than E3 cells. However, the two genotypes did not differ in the amount of Aβ generated by neurons or numbers of early endosomes in neurons.

Yadong Huang’s group first generated iPSCs from a 64-year-old woman with AD, homozygous for the E4 allele, then converted these cells to E3/E3 (Wang et al., 2018; Jun 2018 news). When differentiated into neurons, cells carrying the E3 allele released less Aβ and contained less hyperphosphorylated tau, compared with neurons with the E4 allele, and more E3 GABAergic neurons survived.

In another study, genotype-dependent inflammatory profiles were compared in astrocytes derived from sets of isogenic APOE knockout and E4/E4 lines generated from E3/E3 lines; elevated levels of cytokines were consistently found in astrocytes carrying the E4 allele (Arnaud et al., 2022).

An E4/E4 iPSC line was also generated from an E3/E3 parental line derived from an apparently healthy 36-year-old Caucasian woman (Watanabe et al., 2023,). When differentiated into astrocytes, cells carrying the E4 allele had larger soma sizes than E3 carriers. Dendritic spine densities were lower in mouse primary neurons co-cultured with E4/E4 IPSC-derived astrocytes, compared with E3/E3, congruent with findings of lower spine densities in the brains of APOE4 Targeted Replacement mice compared with APOE3 mice. APOE genotype did not affect dendritic complexity in co-cultures of mouse neurons with human iPSC-derived astrocytes, in contrast to findings in Targeted Replacement mice, where dendritic complexity was lower in E4 carriers—an effect that may be age- or region-dependent.

Cerebral organoids have been generated from isogenic iPSC lines homozygous for either E3 or E4 (Lin et al., 2018; Zhao et al., 2020). In both studies, lower levels of Aβ and less hyperphosphorylated tau were found in the organoids when cells carried the E3 allele.

Last Updated: 30 Aug 2024

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References

Research Models Citations

  1. APOE2 Targeted Replacement
  2. APOE4 Targeted Replacement
  3. 5xFAD (B6SJL)
  4. APPPS1
  5. APPswe/PSEN1dE9 (line 85)
  6. J20 (PDGF-APPSw,Ind)
  7. PDAPP(line109)
  8. Tau P301S (Line PS19)
  9. α-synuclein A53T Mouse (Tg)

Mutations Citations

  1. APP K670_M671delinsNL (Swedish)
  2. PSEN1 L166P
  3. APP V717F (Indiana)
  4. MAPT P301S
  5. APP K670_M671delinsNL (Swedish)
  6. APP I716F (Iberian)
  7. APP E693G (Arctic)
  8. APP V717I (London)
  9. PSEN1 A246E

Mutation Position Table Citations

  1. PSEN1 S290 Mutations
  2. APP Duplication - Mutations

News Citations

  1. In Human Neurons, ApoE4 Promotes Aβ Production and Tau Phosphorylation

Paper Citations

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External Citations

  1. Taconic: Stock# 1548-F and 1548-M
  2. UKBi011-A
  3. UKBi011-A-1
  4. UKBi011-A-2
  5. UKBi011-A-3
  6. UKBi011-A-4
  7. BIONi010-C
  8. BIONi010-C-2
  9. BIONi010-C-4
  10. BIONi010-C-6
  11. BIONi010-C-3
  12. isogenic human iPSCs

Further Reading

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