Abstract: Alzheimer’s disease (AD) is the most common cause of dementia and the most common neurodegenerative disease. Apolipoprotein E (APOE) isoforms are known as a major risk factor of AD and dementia, while single nucleotide polymorphisms (SNPs) in the non-coding regulatory surrounding regions of the transcription reduce the levels of ApoE and the reduction is associated with the AD phenotypes. Despite crucial involvement of APOE in the AD/dementia pathogenesis has been well established, there is still no available treatments targeting APOE. The goal of the parent R01 award (R01AA026272) is to reveal mechanisms by which prenatal alcohol exposure (PAE) results in long-term impacts on the neurobehavior of offspring and find effective treatments for the symptoms caused by such impacts in Fetal Alcohol Spectrum Disorders (FASD). Through the research supported by this parent award, genome-wide chromatin accessibility was compared between control and PAE mice with the neurons dissociated from motor cortex. One of the major changes that we found was in the locus of ApoE. We also observed that the ApoE protein level is reduced in the motor cortex and plasma in postnatal PAE mice, and that daily administration of an ApoE mimetic during postnatal day 20-30 can mitigate the motor skill learning deficits in PAE mice. Interestingly, this treatment by the ApoE mimetic restored the level of endogenous ApoE while reduced the expression of a calcium-activated potassium channel, Kcnn2 (Potassium Calcium-Activated Channel Subfamily N Member 2), which is upregulated in the cerebral cortex of PAE mice and contributes to the motor skill learning deficits, as we have reported recently. In our collaboration with NIAAA- funded Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD), we also found that the SNP in the distal enhancer of APOE was a potential risk factor of cognitive deficits in human PAE subjects. Involvement of altered KCNN2 in AD and other neurodegenerative diseases has been also reported in many studies on human patients and animal models. A recent survey of 541 people with FASD in Canada and the United States also has reported that the frequency of early onset dementia is 209 times higher in FASD patients than in the general population, the underlying mechanisms of which remain unknown. Together, these lines of evidence suggest that PAE-mediated ApoE reduction (possibly by altered chromatin accessibility at the ApoE locus, and it might be exacerbated by the SNP in the APOE enhancer) contributes to learning disabilities and early onset dementia in FASD by involving the overproduction of KCNN2 in the cerebral cortex. In this supplementary project, we will first define whether the effect of ApoE replenishment in improving learning ability of PAE mice is mediated by suppression of Kcnn2 upregulation. Then we will define whether the suppression of Kcnn2 upregulation in PAE mice by ApoE replenishment is mediated by NMDAR. Successful compl...