APOE is Associated with Neurobehavioral Deficits in FASD
Open AccessThe premise of this dissertation is to investigate an association between Apolipoprotein E (APOE) and neurobehavioral deficits in fetal alcohol spectrum disorder (FASD). Prenatal alcohol exposure (PAE) damages the developing brain and causes FASD, characterized by broad neurodevelopmental disabilities and lifelong comorbidities. However, in light of the complexity and heterogeneity, there remain no treatments to mitigate the impact of PAE on the developing brain.Using the transcriptomics of periphery blood samples, we identified Apoe as a significantly downregulated gene that also correlates with motor learning deficits in PAE mice. In addition, immunohistochemistry of PAE brains showed a significant reduction of APOE level in layer V/VI of the motor cortex, and their level positively correlated with motor learning behavior, suggesting a low level of APOE is associated with poor learning. APOE is well studied in Alzheimer’s diseases (AD) as one of its isomers, APOE4, is associated with late-onset of AD. Moreover, both global and brain specific Apoe deficient mice demonstrate that lack of APOE results in synaptic disruption and cognitive issues, suggesting a proper function of APOE is crucial for brain function. Considering the important role of APOE in the brain, we evaluated if restoring APOE can mitigate neurobehavioral deficits in PAE mice. To test, we utilized APOE receptor agonist (APOE-RA), a short peptide that encodes the receptor binding domain of human APOE. Previous studies have demonstrated positive effects of APOE-RA treatment on the brain, such as reducing neuroinflammation, improving blood brain barrier (BBB) vii integrity, and restoring endogenous APOE levels in the rodent models of neurodegenerative disease. With PAE mice, we found that APOE-RA treatment fully rescues neurobehavioral deficits of PAE mice, suggesting restoring APOE function can be targeted as a therapeutic strategy for FASD. We further investigated the mechanism of APOE-RA that contributed to neurobehavioral improvements and found that the treatment restored the endogenous APOE level in layer V/VI of the motor cortex and altered NMDA receptor kinetic property. Furthermore, APOE-RA treatment reduced excessive expression of potassium intermediate/small calcium-activated channel, subfamily N, member 2 (KCNN2) in PAE mice. KCNN2 channels regulate the excitability of neurons, and our previous study demonstrated its association with motor learning deficits in PAE mice. To assess the clinical relevance, we extended our analysis to human samples. Using GWAS, we found a strong association between a single nucleotide polymorphism (SNP) in a distal regulatory region of APOE locus and delayed match to sample task scores in PAE children. Here, our findings demonstrate for the first time that APOE is closely associated with FASD in both preclinical and clinical settings.
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