Apolipoprotein E3 as a Risk Factor for Alzheimer's Disease Under Conditions of Nutritional Imbalance

Abstract

Abstract. The presence of one or more copies of the E4 allele of apolipoprotein E (ApoE) is strongly associated with of Alzheimer's disease (AD). The impact of E4 on neurodegeneration is potentiated by dietary oxidative challenge. Our prior studies in transgenic mice demonstrate that, in the face of dietary oxidative challenge, E3 does not provide any further protection than E4 or lack of murine ApoE for aggression, oxidative damage, presenilin-1 expression, and γ-secretase activity, and provides only partial reduction in phospho-tau levels. Extrapolation of these findings to the human condition leads us to hypothesize that the E3 allele may not provide sufficient neuroprotection under conditions of dietary compromise and/or oxidative challenge. Epidemiological evidence is consistent with this possibility. The E3 allele is approximately half as effective compared to E2 at buffering the impact of a single E4 allele. In addition, the risk of AD increases linearly for the genotypes E2/2, E2/3, and E3/3. It has been proposed that that clinical manifestation of AD may in some cases require the convergence of 2 or more risk factors. We hypothesize that the combined impact of dietary oxidative stress and either the ApoE3 or E4 genotype represents one such condition.Keywords: Alzheimer's disease, apolipoprotein E, diet, nutritional deficiency, oxidative stresss APOE, OXIDATIVE DAMAGE, AND ALZHEIMER'S DISEASEA major risk factor for Alzheimer's disease (AD) is the presence of the E4 allele of apolipoprotein E (ApoE), which accounts for up to 50% of the cases of AD [1][2][3][4][5]. Considerable effort has been devoted to determining the nature and extent of risk imparted by ApoE4 and what might be done to lessen this risk [6]. Oxidative damage represents an early and perhaps pivotal factor contributing to age-related decline in cogni- * Correspondence to: Thomas B. Shea, Center for Cellular Neurobiology and Neurodegeneration Research, UMassLowell, Lowell, Massachusetts 01854, USA. Tel.: +1 978 934 2881; Fax: +1 978 934 3044; E-mail: Thomas Shea@uml.edu. tive performance including that associated with AD [7][8][9][10][11][12]. Oxidative damage and ApoE4 are inter-related, as the extent of brain oxidative damage in AD is correlated with the presence of E4 [13][14][15][16]. ApoE mediates transport and clearance of lipids, including those subjected to oxidative damage. In doing so, ApoE prevents a cascade of neuronal oxidative damage by quenching downstream products of lipid oxidation, preventing secondary glutamate excitotoxicity and sequestering oxidative metals such as iron [4,17,18,20]. However, ApoE4 is thought to be less effective at this latter function [21].While over 20 other genes are suspected of being related to AD [22], deficiency in ApoE function has a particularly far-reaching impact in that it not only impairs overall brain metabolism and may impair compensato-

Neuroglialpharmacology: white matter pathophysiologies and psychiatric treatments

“…Given the increasing evidence of oxidative damage or deficient myelination in psychiatric disorders, it is not surprising that several clinical trials of an antioxidant intervention have shown efficacy in several disorders. Nacetyl cysteine (NAC) supplementation is well tolerated and helps replenish the rate-limiting supply of cysteine for glutathione (a tripeptide that is arguably the principal brain antioxidant) (reviewed in 383) (249,384) and is decreased in the brain of psychiatric subjects (141). NAC penetrates the blood-brain-barrier (385) and has been shown to protect oligodendrocytes from oxidative damage and a variety of toxins (134,(386)(387)(388)(389)(390)(391).…”