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: 3.19). 08/2011; 39(4):924-32. DOI: 10.1042/BST0390924
Source: PubMed


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.

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    • "It has also been proposed that ApoE4 may interfere with cholesterol transport from astrocytes to synaptic compartments, inducing synapse loss and eventually neurodegeneration (Pfrieger, 2003). Other proposed potential pathogenic mechanisms include differential effects of ApoE isoforms on tau phosphorylation, cerebral energy metabolism, neuroinflammation, neurovascular function , neurogenesis, and synaptic plasticity (Huang, 2011; Kim et al., 2014; Yu et al., 2014). Despite extensive research efforts, however, the exact role of ApoE4 in the etiology of AD remains to be fully elucidated. "
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    ABSTRACT: Mutations in Amyloid β Precursor Protein (APP) and in genes that regulate APP processing -such as PSEN1/2 and ITM2b/BRI2- cause familial dementia, such Familial Alzheimer disease (FAD), Familial Danish (FDD) and British (FBD) dementias. The ApoE gene is the major genetic risk factor for sporadic AD. Three major variants of ApoE exist in humans (ApoE2, ApoE3, and ApoE4), with the ApoE4 allele being strongly associated with AD. ITM2b/BRI2 is also a candidate regulatory node genes predicted to mediate the common patterns of gene expression shared by healthy ApoE4 carriers and late-onset AD patients not carrying ApoE4. This evidence provides a direct link between ITM2b/BRI2 and ApoE4. To test whether ApoE4 and pathogenic ITM2b/BRI2 interact to modulate learning and memory, we crossed a mouse carrying the ITM2b/BRI2 mutations that causes FDD knocked-in the endogenous mouse Itm2b/Bri2 gene (FDDKI mice) with human ApoE3 and ApoE4 targeted replacement mice. The resultant ApoE3, FDDKI/ApoE3, ApoE4, FDDKI/ApoE4 male mice were assessed longitudinally for learning and memory at 4, 6, 12, and 16-17 months of age. The results showed that ApoE4-carrying mice displayed spatial working/short-term memory deficits relative to ApoE3-carrying mice starting in early middle age, while long-term spatial memory of ApoE4 mice was not adversely affected even at 16-17 months, and that the FDD mutation impaired working/short-term spatial memory in ApoE3 -carrying mice and produced impaired long-term spatial memory in ApoE4-carrying mice in middle age. The present results suggest that the FDD mutation may differentially affect learning and memory in ApoE4 carriers and non-carriers.
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    • "The most common ApoE allele (APOE*3) is considered the normal allele exhibiting a neutral risk phenotype in the majority of the population. APOE*4, however, is associated with increased risk of cardiovascular disease, stroke and Alzheimer’s disease [5,6] and is a risk factor for cognitive impairment in old age [7] and after stroke [4]. One of the mechanisms by which ApoE isoforms contribute to the outcome after central nervous system (CNS) insult is immunomodulation, as different ApoE isoforms have been shown to regulate both systemic and CNS inflammation [8]. "
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    • "The E4 allele has been identified as a risk factor for AD in late-onset families [11]. Individuals with one copy (15% of total population) or two copies (2% of total population) of the E4 allele have an increased chance of developing AD by, respectively, 3 times and 10-20 times, compared to those not carrying any E4 alleles [11, 12]. "
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