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Riddell DR, Zhou H, Atchison K, Warwick HK, Atkinson PJ, Jefferson J, Xu L, Aschmies S, Kirksey Y, Hu Y, Wagner E, Parratt A, Xu J, Li Z, Zaleska MM, Jacobsen JS, Pangalos MN, Reinhart PH. Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels. J Neurosci. 2008 Nov 5;28(45):11445-53. PubMed.
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Duke University Medical Center and Cognosci
Compelling and widely accepted genetic evidence shows that the presence of one or more APOE4 genes is associated with more severe disease in Alzheimer’s, stroke, traumatic brain injury, multiple sclerosis, and many others. The question is, How does APOE4/ApoE4 protein contribute to disease or conversely, how does the absence of APOE3/ApoE3 protein contribute to disease? The likely explanations are quantity and quality of ApoE differs between APOE4 carriers and non-APOE4 carriers (i.e., APOE3 carriers). Riddell and colleagues confirm, as we had previously reported (Vitek et al., 2007), that the amount of ApoE protein in APOE4/4 targeted replacement (TR) mice appears to be significantly less than in their APOE3/3 counterparts. Thus, like many diseases where some critical factor is reduced in the disease, a critical therapeutic path becomes supplementation of that missing critical factor with either the authentic protein or a mimetic of that protein.
But in the case of ApoE, amount is not the whole story. We (Colton et al., 2002; Vitek et al., 2007) have shown that the presence of the APOE4 gene is associated with a significantly greater pro-inflammatory innate immune response. This is observed despite the lower ApoE4 mRNA and ApoE4 protein levels in brain. We asked the question if the increased pro-inflammatory immune response observed in macrophages from the APOE4/4 TR compared to APOE3/3 TR mice was due to the lower level of ApoE protein. Thus, we generated a targeted replacement mouse that expressed levels of total ApoE protein equivalent to those found in APOE4/4 TR mice by crossing APOE knockout mice (APOE0/0) to APOE3/3 TR mice to generate heterozygous APOE3/0 TR mice. The response of macrophages in the APOE3/0 mice showed increased levels of pro-inflammatory cytokines compared to macrophages from APOE3/3 TR mice, cytokine levels that were significantly lower than those seen in APOE4/4 TR cells. This genetic experiment clearly shows that the effect of the APOE4 gene allele is complex and depends on both the absolute levels of ApoE protein and on an independent effect of the ApoE4 protein. Although understanding the mechanisms underlying how the unique APOE4 gene affects inflammation is clearly important, replacement of lost ApoE protein using ApoE mimetics may help to reduce the pathophysiological outcomes associated with APOE4 gene expression in many neurological disease states.
M. P. Vitek is also a Prinicipal in Cognosci, Inc.
References:
Colton CA, Brown CM, Cook D, Needham LK, Xu Q, Czapiga M, Saunders AM, Schmechel DE, Rasheed K, Vitek MP. APOE and the regulation of microglial nitric oxide production: a link between genetic risk and oxidative stress. Neurobiol Aging. 2002 Sep-Oct;23(5):777-85. PubMed.
Vitek MP, Brown CM, Colton CA. APOE genotype-specific differences in the innate immune response. Neurobiol Aging. 2009 Sep;30(9):1350-60. PubMed.
Beffert U, Cohn JS, Petit-Turcotte C, Tremblay M, Aumont N, Ramassamy C, Davignon J, Poirier J. Apolipoprotein E and beta-amyloid levels in the hippocampus and frontal cortex of Alzheimer's disease subjects are disease-related and apolipoprotein E genotype dependent. Brain Res. 1999 Oct 2;843(1-2):87-94. PubMed.
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