Development of a Human APOE Knock-in Mouse Model for Study of Cognitive Function After Cancer Chemotherapy

Speidell, Andrew; Demby, Tamar C.; Lee, Yi-Chien; Rodriguez, Olga; Albanese, Christopher; Mandelblatt, Jeanne S.; Rebeck, G. William

doi:10.1007/s12640-018-9954-7

Cited by 29 publications

(24 citation statements)

References 70 publications

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“…Potential effects of diet here may have been obscured by sex differences, which could be addressed in larger cohorts. Previous studies have shown APOE4 mice have cognitive deficits or decreased neuronal complexity from as early as three months and these deficits remain at later ages such as 21 months (Bour et al, 2008; Rodriguez et al, 2013; Speidell et al, 2019), consistent with APOE genotype dependent deficits seen in our study. Performance in cognitive tasks have differed between sexes also with females performing worse than males (Bour et al, 2008), further emphasizing the need for these behavioral assays to be replicated with a greater number of animals across sexes.…”

Section: Discussionsupporting

confidence: 92%

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Metabolic Disturbances of a High-Fat Diet Are Dependent on APOE Genotype and Sex

Jones

Watson

Rebeck

2019

eNeuro

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Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for Alzheimer’s disease (AD). APOE4 is also associated with an increased risk of metabolic syndrome. Obesity is a major environmental risk factor for AD. While APOE genotype and obesity independently affect metabolism and cognition, they may also have synergistic effects. Here, we examined the metabolic and behavioral alterations associated with a high-fat diet (HFD) in male and female APOE knock-in mice. Male and female mice were fed a 45% kcal HFD or a 10% kcal low-fat diet (LFD) for 12 weeks and adipose tissue accumulation, glucose levels, anxiety-like behavior, and spatial memory were examined. We found that with HFD, male APOE4 mice were more susceptible to metabolic disturbances, including visceral adipose tissue (VAT) accumulation and glucose intolerance when compared to APOE3 mice, while female APOE3 and APOE4 mice had similar metabolic responses. Behaviorally, there were no effects of HFD in mice of either genotype. Our results suggest that metabolic responses to HFD are dependent on both sex and APOE genotype.

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Section: Discussionsupporting

confidence: 92%

“…Mice were exposed to the BM for five consecutive days to test spatial learning and memory, as described (Speidell et al, 2019). The maze was present in a brightly lit room and 90-dB white noise.…”

Section: Methodsmentioning

confidence: 99%

Metabolic Disturbances of a High-Fat Diet Are Dependent on APOE Genotype and Sex

Jones

Watson

Rebeck

2019

eNeuro

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“…The role of APOE4 in neurological disease is certainly broader than the clearance or response to misfolded proteins, including Aβ and tau; for example, APOE receptors play diverse roles in brain physiology independent of Aβ (Holtzman et al, 2012) and APOE4 carriers may be susceptible to disorders that do not involve proteinopathy, such as chemotherapy-induced cognitive dysfunction (Mandelblatt et al, 2018; Speidell et al, 2019). In addition to the role of APOE4 derived from astrocytes and microglia, a growing body of literature also supports a role for APOE4 and pericytes at the blood brain barrier in neurovascular unit dysfunction and AD pathogenesis (Casey et al, 2015; Soto et al, 2015; Halliday et al, 2016; Ma et al, 2018).…”

Section: Overview Of Apoe Isoformsmentioning

confidence: 99%

The Role of APOE4 in Disrupting the Homeostatic Functions of Astrocytes and Microglia in Aging and Alzheimer’s Disease

Fernandez

Hamby

McReynolds

et al. 2019

Front. Aging Neurosci.

195

173

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APOE4 is the greatest genetic risk factor for late-onset Alzheimer’s disease (AD), increasing the risk of developing the disease by 3-fold in the 14% of the population that are carriers. Despite 25 years of research, the exact mechanisms underlying how APOE4 contributes to AD pathogenesis remain incompletely defined. APOE in the brain is primarily expressed by astrocytes and microglia, cell types that are now widely appreciated to play key roles in the pathogenesis of AD; thus, a picture is emerging wherein APOE4 disrupts normal glial cell biology, intersecting with changes that occur during normal aging to ultimately cause neurodegeneration and cognitive dysfunction. This review article will summarize how APOE4 alters specific pathways in astrocytes and microglia in the context of AD and the aging brain. APOE itself, as a secreted lipoprotein without enzymatic activity, may prove challenging to directly target therapeutically in the classical sense. Therefore, a deeper understanding of the underlying pathways responsible for APOE4 toxicity is needed so that more tractable pathways and drug targets can be identified to reduce APOE4-mediated disease risk.

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“…Cancer survivors have difficulties with memory, attention, learning, and processing of information months or even years after completing treatment, and the APOE4 allele is a prime suspect. An APOE mouse model of cancer-related cognitive problems showed that the mice developed chemotherapy-related changes in spatial learning and memory as well as physical changes in brain regions involved in those functions [8].…”

Section: Discussionmentioning

confidence: 99%

Breast Cancer, Alzheimer’s Disease, and APOE4 Allele in the UK Biobank Cohort

Lehrer

Rheinstein²

2021

ADR

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Background: Cognitive problems are common in breast cancer patients. The apolipoprotein E4 (APOE4) gene, a risk factor for Alzheimer’s disease (AD), may be associated with cancer-related cognitive decline. Objective: To further evaluate the effects of the APOE4 allele, we studied a cohort of patients from the UK Biobank (UKB) who had breast cancer; some also had AD. Methods: Our analysis included all subjects with invasive breast cancer. Single nucleotide polymorphism (SNP) data for rs 429358 and rs 7412 was used to determine APOE genotypes. Cognitive function as numeric memory was assessed with an online test (UKB data field 20240). Results: We analyzed data from 2,876 women with breast cancer. Of the breast cancer subjects, 585 (20%) carried the APOE4 allele. Numeric memory scores were significantly lower in APOE4 carriers and APOE4 homozygotes than non-carriers (p = 0.046). 34 breast cancer subjects (1.1%) had AD. There was no significant difference in survival among genotypes ɛ3/ɛ3, ɛ3/ɛ4, and ɛ4/ɛ4. Conclusion: UKB data suggest that cognitive problems in women with breast cancer are, for the most part, mild, compared with other sequelae of the disease. AD, the worst cognitive problem, is relatively rare (1.1%) and, when it occurs, APOE genotype has little impact on survival.

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Development of a Human APOE Knock-in Mouse Model for Study of Cognitive Function After Cancer Chemotherapy

Cited by 29 publications

References 70 publications

Metabolic Disturbances of a High-Fat Diet Are Dependent on APOE Genotype and Sex

Metabolic Disturbances of a High-Fat Diet Are Dependent on APOE Genotype and Sex

The Role of APOE4 in Disrupting the Homeostatic Functions of Astrocytes and Microglia in Aging and Alzheimer’s Disease

Breast Cancer, Alzheimer’s Disease, and APOE4 Allele in the UK Biobank Cohort

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