. Astroglial regulation of apolipoprotein E expression in neuronal cells. Implications for Alzheimer's disease. J Biol Chem. 2004 Jan 30;279(5):3862-8. PubMed.


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  1. This study furthers our understanding of the contribution of neuronal ApoE expression and its potential relevance to Alzheimer’s disease. This study shows that the expression of both human and mouse ApoE genes are regulated in neurons by a glia-secreted factor or factors. Human ApoE gene was examined in N2A cells transfected with human ApoE genomic DNA with 17kb upstream and downstream regulatory elements, and in human neuronal precursor NT2, while mouse ApoE was examined in primary cortical neurons (cultures which are unlikely to contain detectable astrocyte-derived ApoE). The first important result is that the glial factor(s) act through the ERK pathway, based on inhibition of the response by treatment with the MEK1/2-specific inhibitor, U0126 (Calbiochem). Secondly, although one candidate for the glial factor could be ApoE itself, since ApoE4 can activate the ERK pathway Ohkubo, 2001), this study showed that the activation occurs equally well with media conditioned from ApoE-null astrocytes. Although the possibility still exists that mouse ApoE can independently activate ERK and thereby be autoregulatory, this study shows that in glial-conditioned media, mouse ApoE is not the main activator, raising the question whether mouse ApoE is capable of activating the ERK pathway, since ApoE4 can but ApoE3 cannot Ohkubo, 2001). This may become relevant in conditions where glia are not activated (unlike most cell culture conditions) and potentially are not secreting the factor(s). Several obvious candidate factors of activated astrocytes (cytokines, etc.) were described as being inactive in inducing neuronal ApoE expression (data not shown). Lastly, an interesting observation was reported that most neuronal ApoE is not secreted, in contrast to astrocyte ApoE, and accumulated as punctate staining along the neurites (the latter observation was made on neurons treated with C6 glioma-conditioned media, but the source of ApoE was concluded to be neuronal, since C6 glioma cells apparently do not secrete detectable ApoE). That neurons seem to be transporting ApoE along neurites (see also Nathan et al., 1995; DeKroon and Armati, 2002) may contribute to the differential effects of human ApoE isotypes in supporting neurite outgrowth, since the isotypes are differentially trafficked in neurons (Nathan et al., 1995; Ji et al., 1998; DeKroon and Armati, 2001; Nathan et al., 1994; Mahley and Rall, 2000).


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