Cumulative effects of the ApoE genotype and gender on the synaptic proteome and oxidative stress in the mouse brain

Abstract

Elderly females, particularly those carrying the apolipoprotein E (ApoE)-ε4 allele, have a higher risk of developing Alzheimer's disease (AD). However, the underlying mechanism for this increased susceptibility remains unclear. In this study, we investigated the effects of the ApoE genotype and gender on the proteome of synaptosomes. We isolated synaptosomes and used label-free quantitative proteomics, to report, for the first time, that the synaptosomal proteomic profiles in the cortex of female human-ApoE4 mice exhibited significantly reduced expression of proteins related to energy metabolism, which was accompanied by increased levels of oxidative stress. In addition, we also first demonstrated that the proteomic response in synaptic termini was more susceptible than that in the soma to the adverse effects induced by genders and genotypes. This suggests that synaptic mitochondria might be 'older' than mitochondria in the soma of neurons; therefore, they might contain increased cumulative damage from oxidative stress. Furthermore, female human-ApoE4 mice had much lower oestrogen levels in the cortex and treatment with oestrogen protected ApoE3 stable transfected C6 neurons from oxidative stress. Overall, this study reveals complex ApoE- and gender-dependent effects on synaptic function and also provides a basis for future studies of candidates based on specific pathways involved in the pathogenesis of AD. The lack of oestrogen-mediated protection regulated by the ApoE genotype led to synaptic mitochondrial dysfunction and increased oxidative stress, which might make older females more susceptible to AD.

Human ApoE ɛ2 Promotes Regulatory Mechanisms of Bioenergetic and Synaptic Function in Female Brain: A Focus on V-type H+-ATPase

“…Gpd1l is a regulatory enzyme implicated in the modulation of cardiac sodium channels. While Gpd1l has not been previously implicated in the progression of any neurodegenerative disorders, it has been demonstrated that Uqcrc1 expression is significantly reduced in synaptosomal fractions of ApoE4 mice when compared to ApoE3 mice [45] - a finding that corresponds with our data. Contrary to these data, aldehyde dehydrogenase 2 (Aldh2) and B-type creatine kinase (Ckb) were both significantly down-regulated in ApoE2 brain when compared to ApoE3 or ApoE4 brains.…”

Evidence in support of chromosomal sex influencing plasma based metabolome vs APOE genotype influencing brain metabolome profile in humanized APOE male and female mice

“…Further, given the high energy demand of the brain, glucose hypometabolism and mitochondrial bioenergetic dysregulation have a profound impact on the balance of brain metabolome. Brain proteomic analysis in humanized APOE4 knock-in mice revealed down-regulation of enzymes involved in metabolic processes from glycolysis, TCA cycle, amino acid metabolism, and to lipid metabolism [47]. Metabolomic analysis in AD patients also confirmed alternations in brain lipid profiles [51][52][53].…”

“…Mechanistic analyses indicate that brain glucose hypometabolism in AD models is associated with impairment in mitochondrial oxidative phosphorylation (OXPHOS) [36][37][38][39][40][41][42][43] which is also evident in perimenopausal females [44,45] and in APOE4 carriers [31,46,47]. While previous studies using humanized APOE4 knock-in mice and isolated neurons confirmed down regulation of OXPHOS and energy metabolism genes compared to APOE3 counterparts [48][49][50], the impact of sex, and potentially sex-APOE interplay, is not fully understood.…”

Toward more predictive genetic mouse models of Alzheimer's disease

“…In human brains, APOE is normally synthesized and secreted by astrocytes and microglia and binds to high-density lipoproteins to facilitate cholesterol and phospholipid transport to LDL receptors. Low plasma APOE and APOE4 genotype are associated with morphological changes to the hippocampus, specifically reductions in size [16, 17]. Mouse models for studying both Apoe function and the human APOE variants have been created and have highlighted a complex role for APOE in the aging and diseased brain.…”