Article

Roles of apolipoprotein E4 (ApoE4) in the pathogenesis of Alzheimer's disease: lessons from ApoE mouse models

Gladstone Institute of Neurological Disease, Department of Pathology, University of California, San Francisco, CA 94158, USA.
Biochemical Society Transactions (Impact Factor: 3.24). 08/2011; 39(4):924-32. DOI: 10.1042/BST0390924
Source: PubMed

ABSTRACT ApoE4 (apolipoprotein E4) is the major known genetic risk factor for AD (Alzheimer's disease). In most clinical studies, apoE4 carriers account for 65-80% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis. Emerging data suggest that apoE4, with its multiple cellular origins and multiple structural and biophysical properties, contributes to AD in multiple ways either independently or in combination with other factors, such as Aβ (amyloid β-peptide) and tau. Many apoE mouse models have been established to study the mechanisms underlying the pathogenic actions of apoE4. These include transgenic mice expressing different apoE isoforms in neurons or astrocytes, those expressing neurotoxic apoE4 fragments in neurons and human apoE isoform knock-in mice. Since apoE is expressed in different types of cells, including astrocytes and neurons, and in brains under diverse physiological and/or pathophysiological conditions, these apoE mouse models provide unique tools to study the cellular source-dependent roles of apoE isoforms in neurobiology and in the pathogenesis of AD. They also provide useful tools for discovery and development of drugs targeting apoE4's detrimental effects.

0 Followers
 · 
97 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The presence of the E4 allele of apolipoprotein E (apoE) is the strongest known genetic risk factor for sporadic Alzheimer's disease (AD). Other risk factors for developing AD have been identified, including lifestyle such as dietary habits. The present study was designed to explore the impact of the interaction between variant human apoE isoforms and a high carbohydrate diet (HCD) on mechanisms behind learning and memory retention. As an investigative model, we compared young apoE3 and apoE4 target replacement mice fed on a HCD for 6 months. Our results indicate that HCD compromises memory processes in apoE4 mice. ApoE4 mice on HCD showed decreased activity-regulated cytoskeletal-associated protein (Arc) and brain derived neurotrophic factor (BDNF) levels, as well as decreased BDNF signaling in the hippocampus. In contrast, apoE3 mice were resistant to the deleterious effects of HCD on both behavior and memory-related proteins. Our results support the hypothesis that already in mid-life, genetic, and environmental risk factors act together on the mechanisms behind cognitive impairment.
    Journal of Alzheimer's disease: JAD 07/2012; 32(2):341-55. DOI:10.3233/JAD-2012-120697 · 3.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Desmosterol is a C27 sterol intermediate in cholesterol synthesis generated during the metabolic pathway that transforms lanosterol into cholesterol. It has become of particular interest in the pathogenesis of Alzheimer's disease (AD) because of the report that the activity of the gene coding for the enzyme DHCR24, which metabolizes desmosterol to cholesterol, is selectively reduced in the affected areas of the brain. Any change in the pattern of C27 sterol intermediates in cholesterol synthesis merits investigation with respect to the pathogenesis of AD, since neurosteroids such as progesterone can modulate the tissue levels. We therefore analyzed the C27 sterol composition using a metabolomics approach that preserves the proportion of the different sterol intermediates. In AD, the proportion of desmosterol was found to be less than that of age-matched controls. The findings do not directly support the focus on Seladin-1, although they could reflect different stages of a slowly progressive disease.
    Journal of Alzheimer's disease: JAD 10/2012; 33(3). DOI:10.3233/JAD-2012-121453 · 3.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Animal models of Alzheimer disease (AD) are used to study the mechanisms underlying AD pathogenesis, genetic interactions with genes of interest, and environmental risk factors that cause sporadic AD as well as to test the therapeutic effects of AD drug-candidates on neuropathology and cognitive function. To attain a comparative view on the AD models developed, representative AD lines were selected and summarized with respect to transgenic constructs and AD-related pathology. In addition, age-dependent plaque deposition data available in the literature for six representative AD models such as Tg2576, PDAPP, TgAPP23, Tg-APPswe/PS1dE9, 3xTg-AD, and 5XFAD mice were reevaluated using a photographic plaque reference scale method that was introduced recently. Tg2576, PDAPP, and TgAPP23 mice, which carry the amyloid precursor protein (APP) transgene, produced initially slow, but progressively accelerated plaque deposition as they aged, resulting in logistic plaque deposition. In contrast, Tg-APPswe/PS1dE9 and 3xTg-AD mice, which carry both APP and PS1 transgenes, developed abruptly accelerated plaque formation from the beginning, resulting in logarithmic plaque deposition. 5XFAD mice, which also carry both the APP and PS1 transgenes, developed a logarithmic deposition beginning at 2 months. This comparative analysis suggests that AD models may be classified into two distinct plaque deposition groups, and that early plaque models such as APPswe/PS1dE9, 3xTg-AD and 5XFAD might be useful to study the biochemical aspects of APP metabolism, whereas late plaque models such as Tg2576, PDAPP, and TgAPP23 might be useful to study more physiological and environmental aspects of AD pathogenesis, which occur on a longer time scale.
    06/2013; 22(2):84-95. DOI:10.5607/en.2013.22.2.84