Association Of APOE Genotype With Academic And Physical Education Performance;The Role Of TREM2/DAP12 Complex In Microglial Signaling Pathway

Apolipoprotein E(apoE)is a major apolipoprotein and a cholesterol carrier in the brain.Human APOE gene is polymorphic and it exists in three major isoforms:?2,?3,s4.The ?4 allele is the strongest risk factor for late-onset Alzheimer's disease.Although it has been widely recognized that APOE polymorphic alleles are associated with cognitive impairment in the elderly people,there have been relatively few studies examining the association of APOE polymorphic alleles with cognitive function in young adults and children.Moreover,the reports on the association between APOE genotype and cognitive function in early adulthood have been controversial in different ethnic population.To further investigate the influence of APOE polymorphism on cognitive function in children,we analysed the association between APOE genotypes and cademic and physical education performance scores in a cohort of 571 Chinese primary students aged 10 to 12.After statistical analysis,we found there were no statistically significant associations with academic performance scores of Chinese,Math,English subjects for either the ?4 or ?2 alleles.Similarly,APOE ?4 and ?2 were not significantly associated with physical education performance scores after adjusting for multiple testing.There was a nominally significant(P<0.05)association between APOE ?4 and 50-meter dash time,which was slightly lower(Mean:0.23 seconds,P=0.026)for students with a copy of ?4.The lack of a significant association of s4 and ?2 with academic and physical education performance scores was consistent when examining scores at each separate time point.The results of this study indicate that APOE polymorphism does not play a majoy role in learning ability and normal cognitive function in Chinese primary school students.DNAX-activating protein of 12 kDa(DAP 12)is a signaling adapter protein expressed in cells that participate in innate immune responses.By pairing with different receptors,DAP12 has both positive and negative modulation of cellular responses.Triggering receptor expressed on myeloid cells 2(TREM2),as one of DAP12-coupled receptors,is highly expressed in microglia within the central nervous system.The TREM2/DAP12 complex inhibits the pro-inflammatory responses,stimulates the phagocytosis of apoptotic neurons in microglia.Notably,loss-of-function mutations of either DAP12 or TREM2 result in disorders known as Nasu-Hakola disease and Alzheimer's disease,suggesting that TREM2 and DAP12 may regulate common signaling pathways in the disease pathogenesis.In this study,we demonstrated an anti-inflammatory role of DAP12 in murine microglia that relies on the presence of intact TREM2.We uncovered the functional mechanism by showing that the TREM2/DAP12 complex suppressed the hyperactivation of JNK signaling pathway upon LPS stimulation.Interestingly,LPS down-regulates the expression of Trem2 via the activation of JNK and NF-?B signaling pathways,resulting in a vicious cycle that synergistically promotes the inflammatory responses.Our study provides insights into mechanism-based therapies for neuroinflammatory disorders.