ABSTRACT
Identified in 1993, APOE4 is the greatest genetic risk factor for Alzheimer's disease (AD), increasing risk up to 15-fold compared to the common variant APOE3. Since the mid 1990's, transgenic (Tg) mice have been developed to model AD pathology and progression, primarily via expression of the familial AD (FAD) mutations in the presence of mouse-APOE (m-APOE). APOE4, associated with enhanced amyloid-ß (Aß) accumulation, has rarely been the focus in designing FAD-Tg mouse models. Initially, FAD-Tg mice were crossed with human (h)-APOE driven by heterologous promoters to identify an APOE genotype-specific AD phenotype. These models were later supplemented with FAD-Tg mice crossed with APOE-knockouts (APOE-/- or APOE-KO) and h-APOE-targeted replacement (h-APOE-TR) mice, originally generated to study the role of APOE genotype in peripheral lipid metabolism and atherosclerotic lesion development. Herein, we compare the m- and h-APOE multi-gene clusters, and then critically review the relevant history and approaches to developing a Tg mouse model to characterize APOE-dependent AD pathology, in combination with genetic (sex, age) and modifiable (e.g., inflammation, obesity) risk factors. Finally, we present recent data from the EFAD mice, which express 5xFAD mutations with the expression of the human apoE isoforms (E2FAD, E3FAD and E4FAD). This includes a study of 6- and 18-month-old male and female E3FAD and E4FAD, a comparison that enables examination of the interaction among the main AD risk factors: age, APOE genotype and sex. While no single transgenic mouse can capture the effects of all modifiable and genetic risk factors, going forward, a conscious effort needs to be made to include the factors that most significantly modulate AD pathology.
Subject(s)
Alzheimer Disease/metabolism , Apolipoproteins E/metabolism , Disease Models, Animal , Age Factors , Alzheimer Disease/genetics , Animals , Apolipoproteins E/genetics , Female , Male , Mice, Transgenic , Mutation , Phenotype , Sex Factors , tau Proteins/geneticsABSTRACT
Identified in 1993, APOE4 is the greatest genetic risk factor for sporadic Alzheimer's disease (AD), increasing risk up to 15-fold compared with APOE3, with APOE2 decreasing AD risk. However, the functional effects of APOE4 on AD pathology remain unclear and, in some cases, controversial. In vivo progress to understand how the human (h)-APOE genotypes affect AD pathology has been limited by the lack of a tractable familial AD-transgenic (FAD-Tg) mouse model expressing h-APOE rather than mouse (m)-APOE. The disparity between m- and h-apoE is relevant for virtually every AD-relevant pathway, including amyloid-ß (Aß) deposition and clearance, neuroinflammation, tau pathology, neural plasticity and cerebrovascular deficits. EFAD mice were designed as a temporally useful preclinical FAD-Tg-mouse model expressing the h-APOE genotypes for identifying mechanisms underlying APOE-modulated symptoms of AD pathology. From their first description in 2012, EFAD mice have enabled critical basic and therapeutic research. Here we review insights gleaned from the EFAD mice and summarize future directions.
Subject(s)
Alzheimer Disease , Apolipoprotein E4/genetics , Disease Models, Animal , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/therapy , Animals , Apolipoprotein E4/blood , Humans , Mice , Mice, Transgenic , PhenotypeABSTRACT
Increasing evidence suggests that brain cytochrome P450 (CYP) can contribute to the in situ metabolism of xenobiotics. In the liver, some xenobiotics can be metabolized by CYPs into more reactive products that can damage hepatocytes and induce cell death. In addition, normal CYP activity may produce reactive oxygen species (ROS) that contribute to cell damage through oxidative mechanisms. CYP2E1 is a CYP isoform that can generate ROS leading to cytotoxicity in multiple tissue types. The aim of this study was to determine whether CYP2E1 induction may lead to significant brain cell impairment. Immunological analysis revealed that exposure of primary cerebellar granule neuronal cultures to the CYP inducer isoniazid, increased CYP2E1 expression. In the presence of buthionine sulfoximine, an agent that reduces glutathione levels, isoniazid treatment also resulted in reactive oxygen species (ROS) production, DNA oxidation and cell death. These effects were attenuated by simultaneous exposure to diallyl sulfide, a CYP2E1 inhibitor, or to a mimetic of superoxide dismutase/catalase, (Euka). These results suggest that in cases of reduced antioxidant levels, the induction of brain CYP2E1 could represent a risk of in situ neuronal damage.
