ApoE4 confers better spatial memory than apoE3 in young adult hAPP-Yac/apoE-TR mice

Moreau, Pierre-Henri; Bott, Jean-Bastien; Zerbinatti, Celina; Renger, John J.; Kelche, Christian; Cassel, Jean‐Christophe; Mathis, Chantal

doi:10.1016/j.bbr.2012.12.043

Cited by 10 publications

(5 citation statements)

References 29 publications

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“…In our study, targeted transgenic mice expressing human apoE4 protein have an advantage in eliminating C. parvum oocysts after being exposed to a high load of parasitic inoculum supporting the concept of antagonistic pleiotropy for the APOE4 gene [45].…”

Section: Discussionsupporting

confidence: 72%

Apolipoprotein E Plays a Key Role against Cryptosporidial Infection in Transgenic Undernourished Mice

et al. 2014

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Apolipoliprotein E (apoE), a critical targeting protein in lipid homeostasis, has been found to have immunoinflammatory effects on murine models of infection and malnutrition. The effects of apoE in undernourished and Cryptosporidium parvum-infected mice have not been investigated. In order to study the role of apoE in a model of C. parvum infection, we used the following C57BL6J mouse genetic strains: APOE-deficient, wild-type controls, and APOE targeted replacement (TR) mice expressing human APOE genes (E3/3; E4/4). Experimental mice were orally infected with 107-unexcysted-C. parvum oocysts between post-natal days 34–35 followed by malnutrition induced with a low-protein diet. Mice were euthanized seven days after C. parvum-challenge to investigate ileal morphology, cytokines, and cationic arginine transporter (CAT-1), arginase 1, Toll-like receptor 9 (TLR9), and inducible nitric oxide synthase (iNOS) expression. In addition, we analyzed stool oocyst shedding by qRT-PCR and serum lipids. APOE4/4-TR mice had better weight gains after infection plus malnutrition compared with APOE3/3-TR and wild-type mice. APOE4/4-TR and APOE knockout mice had lower oocyst shedding, however the latter exhibited with villus blunting and higher ileal pro-inflammatory cytokines and iNOS transcripts. APOE4/4-TR mice had increased ileal CAT-1, arginase-1, and TLR9 transcripts relative to APOE knockout. Although with anti-parasitic effects, APOE deficiency exacerbates intestinal inflammatory responses and mucosal damage in undernourished and C. parvum-infected mice. In addition, the human APOE4 gene was found to be protective against the compounded insult of Cryptosporidium infection plus malnutrition, thus extending our previous findings of the protection against diarrhea in APOE4 children. Altogether our findings suggest that apoE plays a key role in the intestinal restitution and immunoinflammatory responses with Cryptosporidium infection and malnutrition.

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Section: Discussionsupporting

confidence: 72%

Apolipoprotein E Plays a Key Role against Cryptosporidial Infection in Transgenic Undernourished Mice

et al. 2014

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“…On most measures the CRND8/E4 mice performed slightly, but not significantly, better than CRND8 mice. This is consistent with other recent behavioral data in younger Tg mice modeling late-onset AD (Moreau et al, 2013 ). Similar observations of intermediacy were reported in circadian rhythm and nest building behavior, as well as in markers for inflammatory cytokines (Graybeal et al, 2014 ).…”

Section: Discussionsupporting

confidence: 94%

Spatial memory deficits in a mouse model of late-onset Alzheimerâ€™s disease are caused by zinc supplementation and correlate with amyloid-beta levels

Flinn

Bozzelli

Adlard

et al. 2014

Front. Aging Neurosci.

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Much of the research in Alzheimer’s disease (AD) that uses mouse models focuses on the early-onset form of the disease, which accounts for less than 5% of cases. In contrast, this study used a late-onset AD model to examine the interaction between increased dietary zinc (Zn) and the apolipoprotein E (ApoE) gene. ApoE ε4 is overrepresented in late-onset AD and enhances Zn binding to amyloid-β (Aβ). This study sought to determine if elevated dietary Zn would impair spatial memory in CRND8 mice (CRND8), as well as mice who carry both the mutated human amyloid precursor protein (APP) and ApoE ε4 genes (CRND8/E4). Mice were provided with either lab tap water or water enhanced with 10 ppm Zn (ZnCO3) for 4 months. At 6 months of age, spatial memory was measured by the Barnes maze. CRND8 mice exhibited significant memory deficits compared to WT mice, as shown by an increased latency to reach the escape box. For the CRND8/E4, but not the CRND8 mice, those given Zn water made significantly more errors than those on lab water. During the probe trial for the WT group, those on Zn water spent significantly less time in the target quadrant than those on lab water. These data suggest that increased dietary Zn can significantly impair spatial memory in CRND8/E4. WT mice given Zn water were also impaired on the 24-h probe trial when compared to lab water WTs. Within the CRND8/E4 group only, levels of soluble Aβ were significantly correlated with average primary latencies. Within the Zn-treated CRND8/E4 group, there was a significant correlation between insoluble Aβ and average primary errors. Levels of the zinc transporter 3, ZnT3, were negatively correlated with soluble Aβ (p < 0.01). These findings are particularly relevant because increased intake of dietary supplements, such as Zn, are common in the elderly—a population already at risk for AD. Given the effects observed in the CRND8/E4 mice, ApoE status should be taken into consideration when evaluating the efficacy of therapies targeting metals.

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“…Few cross-sectional or short longitudinal studies have been able to show better cognitive performance in young ε4 carriers [17,34,40]. An experimental study on mice found that ε4 allele was initially associated with better spatial memory in young animals and then deleterious effect at later ages [41]. Interestingly, we found that the early cognitive benefit associated with the ε4 allele is mainly in executive function (reasoning, phonemic fluency), while no difference was observed for memory or semantic tasks which involve temporal and temporal intern area.…”

Section: Discussionmentioning

confidence: 99%

The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study

et al. 2021

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Background Approximately 25% of the general population carries at least one ε4 allele of the Apolipoprotein E (APOE ε4), the strongest genetic risk factor for late onset Alzheimer’s disease. Beyond its association with late-onset dementia, the association between APOE ε4 and change in cognition over the adult life course remains uncertain. This study aims to examine whether the association between Apolipoprotein E (APOE) ε4 zygosity and cognition function is modified between midlife and old age. Methods A cohort study of 5561 participants (mean age 55.5 (SD = 5.9) years, 27.1% women) with APOE genotyping and repeated cognitive tests for reasoning, memory, and semantic and phonemic fluency, during a mean (SD) follow-up of 20.2 (2.8) years (the Whitehall II study). We used joint models to examine the association of APOE genotype with cognitive function trajectories between 45 and 85 years taking drop-out, dementia, and death into account and Fine and Gray models to examine associations with dementia. Results Compared to non-carriers, heterozygote (prevalence 25%) and homozygote (prevalence 2%) APOE ε4 carriers had increased risk of dementia, sub-distribution hazard ratios 2.19 (95% CI 1.73, 2.77) and 5.97 (95% CI 3.85, 9.28) respectively. Using data spanning 45–85 years with non-ε4 carriers as the reference, ε4 homozygotes had poorer global cognitive score starting from 65 years; ε4 heterozygotes had better scores between 45 and 55 years, then no difference until poorer cognitive scores from 75 years onwards. In analysis of individual cognitive tests, better cognitive performance in the younger ε4 heterozygotes was primarily attributable to executive function. Conclusions Both heterozygous and homozygous ε4 carriers had poorer cognition and greater risk of dementia at older ages. Our findings show some support for a complex antagonist pleiotropic effect of APOE ε4 heterozygosity over the adult life course, characterized by cognitive advantage in midlife.

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ApoE4 confers better spatial memory than apoE3 in young adult hAPP-Yac/apoE-TR mice

Cited by 10 publications

References 29 publications

Apolipoprotein E Plays a Key Role against Cryptosporidial Infection in Transgenic Undernourished Mice

Apolipoprotein E Plays a Key Role against Cryptosporidial Infection in Transgenic Undernourished Mice

Spatial memory deficits in a mouse model of late-onset Alzheimerâ€™s disease are caused by zinc supplementation and correlate with amyloid-beta levels

The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study

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