Human and Murine ApoE Markedly Alters Aβ Metabolism before and after Plaque Formation in a Mouse Model of Alzheimer's Disease

Fagan, Anne M.; Watson, Melanie; Parsadanian, Maia; Bales, Kelly R.; Paul, Steven M.; Holtzman, David M.

doi:10.1006/nbdi.2002.0483

Cited by 259 publications

(209 citation statements)

References 65 publications

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“…We found previously that PDAPP mice expressing human APOE3 or APOE4 do not develop A␤ deposition until ϳ15 months of age, when PDAPP:E4 mice in particular begin depositing A␤ and amyloid (Holtzman et al, 2000;Fagan et al, 2002). In contrast, after TBI, we found that a high percentage of braininjured PDAPP:E4 mice had A␤ deposition by 12-13 months of age.…”

Section: A␤ Analysis Frequency and Pattern Of A␤ Depositionmentioning

confidence: 57%

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Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

et al. 2002

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The ⑀4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). These factors may act synergistically, in that APOE4ϩ individuals are more likely to develop dementia after TBI. Because the mechanism underlying these effects is unclear, we questioned whether APOE4 and TBI interact either through effects on amyloid-␤ (A␤) or by enhancing cell death/tissue injury. We assessed the effects of TBI in PDAPP mice (transgenic mice that develop AD-like pathology) expressing human APOE3 (PDAPP: E3), human APOE4 (PDAPP:E4), or no APOE (PDAPP:EϪ/Ϫ). Mice were subjected to a unilateral cortical impact injury at 9-10 months of age and allowed to survive for 3 months. A␤ load, hippocampal/cortical volumes, and hippocampal CA3 cell loss were quantified using stereological methods. All of the groups contained mice with A␤-immunoreactive deposits (56% PDAPP: E4, 20% PDAPP:E3, 75% PDAPP:EϪ/Ϫ), but thioflavine-Spositive A␤ (amyloid) was present only in the molecular layer of the dentate gyrus in the PDAPP:E4 mice (44%). In contrast, our previous studies showed that in the absence of TBI, PDAPP:E3 and PDAPP:E4 mice have little to no A␤ deposition at this age. After TBI, all of the A␤ deposits present in PDAPP:E3 and PDAPP: EϪ/Ϫ mice were diffuse plaques. In contrast to the effect of APOE4 on amyloid, PDAPP:E3, PDAPP:E4, and PDAPP:EϪ/Ϫ mice did not differ in the amount of brain tissue or cell loss. These data support the hypothesis that APOE4 influences the neurodegenerative cascade after TBI via an effect on A␤.Key words: Alzheimer's disease; amyloid; APP; traumatic brain injury; apoE; hippocampus The ⑀4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). It was first found that APOE4 was a risk factor for AD in 1993 (Strittmatter et al., 1993), and numerous studies have confirmed this association. Several studies have found that individuals who sustained moderate to severe head injury are more likely to develop dementia and AD (Mayeux et al., 1993(Mayeux et al., , 1995Plassman et al., 2000). These risk factors appear to act synergistically, in that individuals who are APOE4ϩ are even more likely to develop dementia if they sustain TBI at some time in their life. For example, APOE4ϩ individuals were 10 times more likely to develop AD after TBI than those who were APOE4Ϫ, whereas APOE4 in the absence of injury was associated with only twice the risk (Mayeux et al., 1995;Tang et al., 1996).Although the mechanisms underlying these effects are unclear, some evidence suggests that both APOE4 and TBI may influence the risk of AD via interactions with the amyloid-␤ (A␤) peptide.For example, A␤ deposition can be found in ϳ30% of people who die shortly after TBI (Roberts et al., 1991(Roberts et al., , 1994; a significant percentage of these patients are APOE4ϩ (Nicoll et al., 1995(Nicoll et al., , 1996. In addition, analysis of CSF from TBI patients revealed elevated levels of ...

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Section: A␤ Analysis Frequency and Pattern Of A␤ Depositionmentioning

confidence: 57%

“…1). This is notable because A␤ deposition in the ML of PDAPP mice coincides with the onset of fibrillar A␤ deposition and neuritic plaque formation (Holtzman et al, 2000;Fagan et al, 2002). Thus, only the PDAPP:E4 mice developed neuritic plaque formation after TBI at this age.…”

Section: A␤ Analysis Frequency and Pattern Of A␤ Depositionmentioning

confidence: 93%

Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

et al. 2002

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“…E3 . E2) (Holtzman et al 2000a;Fagan et al 2002;Fryer et al 2005b). In addition to the isoform-specific effects of human apoE on parenchymal Ab pathology, crossing human apoE knockin mice to Tg2576 mice resulted in a relative shift of Ab deposition from the brain parenchyma to arterioles in the form of CAA in apoE4 expressing mice relative to apoE3 or mouse apoE (Fryer et al 2005b).…”

Section: Genetic Clinical and Biomarker Observations On Relationshimentioning

confidence: 99%

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Holtzman

Herz²,

2012

Cold Spring Harbor Perspectives in Medicine

675

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“…A large body of evidence suggests that at least part of the effect of APOE isoforms on AD and CAA risk is mediated by interactions of apoE with the amyloid-h (Ah) peptide, the primary constituent of amyloid plaques that accumulate in the brain of AD patients (reviewed in Holtzman, 2001). ApoE, in an isoform-specific fashion, regulates the time of onset and amount of Ah deposition via effects on Ah clearance and fibrillogenesis in APP transgenic mice (Bales et al, 1997;DeMattos et al, 2004;Fagan et al, 2002;Holtzman et al, 2000). In addition, it has been proposed that apoE may also influence AD and other central nervous system (CNS) disorders by influencing additional biological processes such as neural repair and inflammation (Buttini et al, 1999;Lynch et al, 2003;Teter, 2000).…”

Section: Introductionmentioning

confidence: 99%

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β

Morikawa

Fryer

Sullivan

et al. 2005

Neurobiology of Disease

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The apolipoprotein E (apoE) genotype is an important genetic risk factor for Alzheimer's disease (AD). In the central nervous system (CNS), most apoE is produced by astrocytes and is present in unique high-density lipoprotein (HDL)-like particles that have distinct properties from apoE derived from other sources. To develop an efficient system to produce astrocyte-derived apoE in large quantities, we produced and characterized immortalized cell lines from primary astrocyte cultures derived from human APOE knock-in mice. APOE2, APOE3, and APOE4 expressing cell lines were established that secrete apoE in HDL-like particles at similar levels, cholesterol composition, and size as those produced by primary astrocytes. In physiological buffers, astrocyte-secreted apoE3 and E4 associated equally well with amyloid-B. Under the same conditions, only a small fraction of AB formed sodium dodecyl sulfate (SDS)-stable complexes with apoE (E3 N E4). These immortalized astrocytes will be useful for studying mechanisms underlying the isoform-specific effects of apoE in the CNS. D 2004 Elsevier Inc. All rights reserved.

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Human and Murine ApoE Markedly Alters Aβ Metabolism before and after Plaque Formation in a Mouse Model of Alzheimer's Disease

Cited by 259 publications

References 65 publications

Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β

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