, 2009). Apolipoprotein E (ApoE) was originally identified as a main component of lipoproteins in plasma and has important functions in cholesterol and lipid transport. Peripheral ApoE is synthesized in the liver, but expression is also high in the CNS, where ApoE is the dominant apolipoprotein, primarily synthesized by astrocytes, although neurons and microglia also may contribute to its production (Huang et al., 2004). Both animal

experiments and clinical studies in man have shown that after brain injury, large amounts of membrane lipids are released from the damaged axons, and in response astrocytes click here increase ApoE expression, with release of ApoE to the extracellular space to scavenge cholesterol and other lipids for reuse during axonal and synaptic regeneration (Poirier et al., 1991, 1993; Horsburgh et al., 2000b). Taken together, numerous studies suggest a central role for ApoE in lipid delivery for growth and regeneration of axons after neuronal injury. NVP-BKM120 molecular weight The APOE gene has three alleles

(APOE ε2, APOE ε3, and APOE ε4). APOE ε3 is the most common in the population. Solid scientific evidence shows that the APOE ε4 allele is a strong susceptibility gene for AD ( Roses, 1996). Similarly, Jordan et al. (1997) reported that high-exposure boxers with the APOE ε4 allele were at increased risk of CTE compared to high-exposure boxers without the APOE ε4 allele. All severely impaired boxers had at least one APOE ε4 allele. This finding suggests that risk of CTE after brain injury may be genetically determined. In agreement, a

meta-analysis of 14 cohort studies showed that the APOE ε4 allele is associated with poor long-term outcome after TBI, although it does not affect initial severity of the brain injury ( Zhou et al., 2008). The mechanism for the association between the APOE ε4 allele and poor outcome after TBI remains controversial. As reviewed above, ApoE is a key mediator of cholesterol and lipid transport in the brain and plays a crucial role in repair of damaged axons after trauma ( Poirier, 1994). A series of studies demonstrated that APOE knockout neurons show defective neurite sprouting, which can be restored by ApoE3 but not ApoE4 lipoproteins ( Teter et al., 1999) and that increased ApoE4 expression Terminal deoxynucleotidyl transferase reduces neuronal sprouting ( Teter et al., 2002). These findings suggest that the negative effect of ApoE4 on neuronal sprouting is a gain of negative activity. In the human brain, the APOE ε4 dose correlated inversely with dendritic spine density in the hippocampus in AD patients and cognitively normal older persons ( Ji et al., 2003). Experiments in the human APOE-targeted replacement mouse model show decreased spine density and a marked impairment in reactive neuronal sprouting and synaptogenesis in human APOE ε4 mice compared to APOE ε3 mice, despite similar increases in ApoE expression levels ( White et al., 2001; Blain et al., 2006; Dumanis et al., 2009).