EFAD transgenic mice as a human APOE relevant preclinical model of Alzheimerŉs disease

Tai, Leon M.; Balu, Deebika; Ávila-Muñoz, Evangelina; Abdullah, Laila; Thomas, Riya; Collins, Nicole; Valencia-Olvera, Ana; LaDu, Mary Jo

doi:10.1194/jlr.r076315

Cited by 58 publications

(68 citation statements)

References 359 publications

(372 reference statements)

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“…Our findings are consistent with previous studies where APOE-TR mice were crossed to various models of amyloidosis [58] and recapitulate (at least in part) the allele-dependent effect of APOE on amyloid deposition found in humans.…”

Section: Qualitative Assessment Of Microglia and Astrocyte-derived Apsupporting

confidence: 92%

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

Huynh

Wang

Tran

et al. 2019

Mol Neurodegeneration

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Background The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD). ApoE is produced by both astrocytes and microglia in the brain, whereas hepatocytes produce the majority of apoE found in the periphery. Studies using APOE knock-in and transgenic mice have demonstrated a strong isoform-dependent effect of apoE on the accumulation of amyloid-β (Aβ) deposition in the brain in the form of both Aβ-containing amyloid plaques and cerebral amyloid angiopathy. However, the specific contributions of different apoE pools to AD pathogenesis remain unknown. Methods We have begun to address these questions by generating new lines of APOE knock-in (APOE-KI) mice (ε2/ε2, ε3/ε3, and ε4/ε4) where the exons in the coding region of APOE are flanked by loxP sites, allowing for cell type-specific manipulation of gene expression. We assessed these mice both alone and after crossing them with mice with amyloid deposition in the brain. Using biochemical and histological methods. We also investigated how removal of APOE expression from hepatocytes affected cerebral amyloid deposition. Results As in other APOE knock-in mice, apoE protein was present predominantly in astrocytes in the brain under basal conditions and was also detected in reactive microglia surrounding amyloid plaques. Primary cultured astrocytes and microglia from the APOE-KI mice secreted apoE in lipoprotein particles of distinct size distribution upon native gel analysis with microglial particles being substantially smaller than the HDL-like particles secreted by astrocytes. Crossing of APP/PS1 transgenic mice to the different APOE-KI mice recapitulated the previously described isoform-specific effect (ε4 > ε3) on amyloid plaque and Aβ accumulation. Deletion of APOE in hepatocytes did not alter brain apoE levels but did lead to a marked decrease in plasma apoE levels and changes in plasma lipid profile. Despite these changes in peripheral apoE and on plasma lipids, cerebral accumulation of amyloid plaques in APP/PS1 mice was not affected. Conclusions Altogether, these new knock-in strains offer a novel and dynamic tool to study the role of APOE in AD pathogenesis in a spatially and temporally controlled manner.

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Section: Qualitative Assessment Of Microglia and Astrocyte-derived Apsupporting

confidence: 92%

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

Huynh

Wang

Tran

et al. 2019

Mol Neurodegeneration

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“…It can be argued that the diminished potential for additional increases in both pathology and behavioral dysfunction reduces the likelihood of observing negative consequences of WD in the E4FAD mice. However, EFAD mice show age-related increases in pathology and reductions in cognition through $8 mo of age (reviewed in (67). Further, the EFAD model was generated from the 5xFAD mouse, which exhibits progressive worsening of pathology and behavior through $16 mo of age (67).…”

Section: Discussionmentioning

confidence: 99%

“…However, EFAD mice show age-related increases in pathology and reductions in cognition through $8 mo of age (reviewed in (67). Further, the EFAD model was generated from the 5xFAD mouse, which exhibits progressive worsening of pathology and behavior through $16 mo of age (67). Thus, although extensive, the ADrelated outcomes at the age of 5.5 mo are not maximal.…”

Section: Discussionmentioning

confidence: 99%

APOEgenotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice

Christensen

Pike

2018

FASEB j.

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Development of Alzheimer's disease (AD) is regulated by interactive effects of genetic and environmental risk factors. The most significant genetic risk factor for AD is the ε4 allele of apolipoprotein E (APOE4), which has been shown to exert greater AD risk in women. An important modifiable AD risk factor is obesity and its associated metabolic dysfunctions. Whether APOE genotype might interact with obesity in females to regulate AD pathogenesis is unclear. To investigate this issue, we studied the effects of Western diet (WD) on female EFAD mice, a transgenic mouse model of AD that includes human APOE alleles ε3 (E3FAD) and ε4 (E4FAD). EFAD mice were fed either control (10% fat, 7% sugar) or WD (45% fat, 17% sugar), and both metabolic and neuropathologic outcomes were determined. Although E4FAD mice generally exhibited poorer metabolic status at baseline, E3FAD mice showed greater diet‐induced metabolic impairments. Similarly, E4FAD mice exhibited higher levels of AD‐related pathology overall, but only E3FAD showed significant increases on select measures of β‐amyloid pathology after exposure to WD. These data demonstrate a gene–environment interaction between APOE and obesogenic diets in females. Understanding how AD‐promoting effects of obesity are modulated by genetic factors will foster the identification of at‐risk populations and development of preventive interventions.—Christensen, A., Pike, C. J. APOE genotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice. FASEB J. 33, 4054–4066 (2019). http://www.fasebj.org

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“…Conversely, the ApoE2 variant appears to have a protective role in LOAD. The human ApoE-targeted knock-in mice have been used extensively to investigate the role of ApoE isoforms in the onset and progression of LOAD [reviewed in (112) and (159)]. ApoE affects A aggregation and clearance in the brain in an isoform-specific manner (128,129).…”

Section: Ad and The Involvement Of Cholesterol And Apoe4mentioning

confidence: 99%

“…Fifth, studies in vivo have shown that human ApoE4 causes age-dependent learning and memory impairment in mice without amyloidopathy (156,157) [reviewed in (112)]. It also exacerbates neuroinflammation [reviewed in (112,158,159)].…”

Section: Ad and The Involvement Of Cholesterol And Apoe4mentioning

confidence: 99%

Cellular cholesterol homeostasis and Alzheimer's disease

Chang

Yamauchi

Hasan

et al. 2017

Journal of Lipid Research

112

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Alzheimer's disease (AD) is the most common form of dementia in older adults. Currently, there is no cure for AD. The hallmark of AD is the accumulation of extracellular amyloid plaques composed of amyloid-β (Aβ) peptides (especially Aβ1-42) and neurofibrillary tangles, composed of hyperphosphorylated tau and accompanied by chronic neuroinflammation. Aβ peptides are derived from the amyloid precursor protein (APP). The oligomeric form of Aβ peptides is probably the most neurotoxic species; its accumulation eventually forms the insoluble and aggregated amyloid plaques. ApoE is the major apolipoprotein of the lipoprotein(s) present in the CNS. ApoE has three alleles, of which the allele constitutes the major risk factor for late-onset AD. Here we describe the complex relationship between ApoE4, oligomeric Aβ peptides, and cholesterol homeostasis. The review consists of four parts:) key elements involved in cellular cholesterol metabolism and regulation; ) key elements involved in intracellular cholesterol trafficking;) links between ApoE4, Aβ peptides, and disturbance of cholesterol homeostasis in the CNS; ) potential lipid-based therapeutic targets to treat AD. At the end, we recommend several research topics that we believe would help in better understanding the connection between cholesterol and AD for further investigations.

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EFAD transgenic mice as a human APOE relevant preclinical model of Alzheimerŉs disease

Cited by 58 publications

References 359 publications

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

APOEgenotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice

Cellular cholesterol homeostasis and Alzheimer's disease

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