Behavioral Phenotyping of GFAP-ApoE3 and -ApoE4 Transgenic Mice: ApoE4 Mice Show Profound Working Memory Impairments in the Absence of Alzheimer's-like Neuropathology

Hartman, Richard E.; Wozniak, David F.; Nardi, A.; Olney, John W.; Sartorius, Leah; Holtzman, David M.

doi:10.1006/exnr.2001.7715

Cited by 147 publications

(104 citation statements)

References 35 publications

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“…This is consistent with the situation in humans as old age is the most important risk factor for developing Alzheimer disease. Several studies have also demonstrated impairments in spatial learning and memory in various types of apoE4 mice at 12 months of age and older (41) (15-18 months) (42). Therefore, it is not quite surprising that our 12-month old Arg-61 mice displayed some level of cognitive deficits as previously reported by Zhong et al (18).…”

Section: Discussionsupporting

confidence: 81%

Cognitive Deficits and Disruption of Neurogenesis in a Mouse Model of Apolipoprotein E4 Domain Interaction

Adeosun

Hou

Zheng

et al. 2014

Journal of Biological Chemistry

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Background: Domain interaction may be the principal pathogenic feature of apoE4 in Alzheimer disease. Results: Young and old mice with mutations causing apoE4 domain interaction showed impaired cognition and a disruption in neurogenesis. Conclusion: Domain interaction mediates apoE4 neuro-pathologies and cognitive phenotype. Significance: Domain interaction is a viable prophylactic target against apoE4 cognitive phenotype and increased susceptibility to Alzheimer disease.

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Section: Discussionsupporting

confidence: 81%

Cognitive Deficits and Disruption of Neurogenesis in a Mouse Model of Apolipoprotein E4 Domain Interaction

Adeosun

Hou

Zheng

et al. 2014

Journal of Biological Chemistry

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“…In contrast, these impairments were not seen in mice expressing human apoE3 in astrocytes [9]. No cognitive impairments were seen in 10-13 month-old GFAP-apoE4 male mice in spatial learning and memory in the water maze [9]. Consistent with these data, no impairments in water maze performance were seen in 6 or 18-month-old apoE4 male mice expressing human apoE4 in neurons [17,18].…”

supporting

confidence: 69%

“…Hartman and colleagues showed that 11-14 month-old transgenic male mice expressing human apoE4 in astrocytes under control of the glial fibrillary acidic protein (GFAP) promoter showed impairments in radial arm maze performance when compared to wild-type and mouse apoE deficient mice (Apoe −/− ) [9]. In contrast, these impairments were not seen in mice expressing human apoE3 in astrocytes [9]. No cognitive impairments were seen in 10-13 month-old GFAP-apoE4 male mice in spatial learning and memory in the water maze [9].…”

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confidence: 99%

Impairments in spatial memory retention of GFAP-apoE4 female mice

Meer

Acevedo

Raber

2007

Behavioural Brain Research

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The human apolipoprotein E isoforms, apoE2, apoE3, and apoE4, have differential effects on brain function. Compared to apoE3, apoE4 increases the risk of age-related cognitive decline in humans and female mice expressing apoE in neurons. Here we show impaired spatial memory retention in female mice expressing apoE4 in astrocytes compared to those expressing apoE3 in astrocytes or lacking apoE. Thus, apoE4 impairs cognition whether expressed in neurons or astrocytes. Keywordswater maze; passive avoidance; rotorod; apolipoprotein E; transgenic miceHuman apolipoprotein E is a protein encoded by three distinct alleles: ε2, ε3 and ε4. The major resulting proteins, apoE2, apoE3 and apoE4 play an important role in the redistribution and metabolism of lipoproteins and cholesterol. In the brain, apoE is involved in development, regeneration, neurite extension and neuroprotection [11]. ApoE is associated with the pathological hallmarks of Alzheimer's disease (AD) and the severity of AD pathology is influenced by APOE genotype. ApoE4 also has detrimental effects on AD-like pathology in patients with other conditions, including progressive nuclear palsy [20] and Down's syndrome [4]. The detrimental effects of apoE4 are not limited to AD. Compared to apoE3, apoE4 also increases the risk of developing cognitive impairments after neurotrauma, ischemia, cardiopulmonary bypass surgery, human immunodeficiency virus infection, and cognitive impairments that occur with the normal aging and in the context of Parkinson's disease (for review, [15]). Various mechanisms have been proposed to mediate the differential effects of apoE isoforms on brain function, including effects on cholesterol transport, the metabolism amyloid β peptide, cell signaling by lipoprotein receptors, on proteolysis of apoE, and androgen receptor function (for review, [15]). Most synthesis of apoE in the brain takes place in glial cells, in particular astrocytes. However, neurons are also able to generate apoE, particularly following injury [1,5,8,21,22]. In addition, apoE can be secreted from astrocytes and be taken up by neurons. The cellular source of apoE might be important for isoform-dependent effects of apoE on brain function. Proteolytic apoE fragments and tangle-like inclusions were seen

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“…Furthermore, expression of neuronal apoE can be induced in human brains after cerebral infarction (47). ApoE is also expressed in primary cultured human CNS neurons (45) and in many human neuronal cell lines, including SY-5Y, Kelly, and NT2 cells (46,(55)(56)(57). CNS injury may induce neuronal expression of apoE to participate in neuronal repair or remodeling or to protect neurons from injury (44).…”

Section: Discussionmentioning

confidence: 99%

Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice

Harris

Brecht

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

307

365

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Apolipoprotein (apo) E4 increases the risk and accelerates the onset of Alzheimer's disease (AD). However, the underlying mechanisms remain to be determined. We previously found that apoE undergoes proteolytic cleavage in AD brains and in cultured neuronal cells, resulting in the accumulation of carboxyl-terminaltruncated fragments of apoE that are neurotoxic. Here we show that this fragmentation is caused by proteolysis of apoE by a chymotrypsin-like serine protease that cleaves apoE4 more efficiently than apoE3. Transgenic mice expressing the carboxylterminal-cleaved product, apoE4(⌬272-299), at high levels in the brain died at 2-4 months of age. The cortex and hippocampus of these mice displayed AD-like neurodegenerative alterations, including abnormally phosphorylated tau (p-tau) and Gallyas silverpositive neurons that contained cytosolic straight filaments with diameters of 15-20 nm, resembling preneurofibrillary tangles. Transgenic mice expressing lower levels of the truncated apoE4 survived longer but showed impaired learning and memory at 6 -7 months of age. Thus, carboxyl-terminal-truncated fragments of apoE4, which occur in AD brains, are sufficient to elicit AD-like neurodegeneration and behavioral deficits in vivo. Inhibiting their formation might inhibit apoE4-associated neuronal deficits.H uman apolipoprotein (apo) E, a 34-kDa protein composed of 299 amino acids, occurs as three major isoforms, apoE2, apoE3, and apoE4 (1-4). ApoE4 is a major risk or susceptibility factor for Alzheimer's disease (AD) (5-7). The apoE4 allele, which is found in 40-65% of cases of sporadic and familial AD, increases the occurrence and lowers the age of onset of the disease (7,8).Biochemical, cell biological, and transgenic animal studies have suggested several potential mechanisms to explain apoE4's contribution to the pathogenesis of AD. These include the modulation of the deposition and clearance of amyloid ␤ peptides and the formation of plaques (9-15), impairment of the antioxidative defense system (16), dysregulation of neuronal signaling pathways (17), disruption of cytoskeletal structure and function (18,19), and altered phosphorylation of tau and the formation of neurofibrillary tangles (NFTs) (20-23). However, the mechanisms of these apoE4-mediated detrimental effects are still largely unknown, and it is not known which are the primary effects and which are subsequent or downstream effects.The neuropathological hallmarks of AD include extracellular amyloid plaques and intracellular NFTs in the brain (24-27). The plaques consist primarily of amyloid ␤ peptides (24-26). The NFTs are composed largely of the highly phosphorylated microtubule-associated protein tau (p-tau) (25) and, to a lesser extent, of phosphorylated neurofilaments (28, 29). Both amyloid plaques and NFTs contain apoE (5, 30, 31); however, the role of apoE in the pathogenesis of these two lesions is uncertain. Histopathological and behavioral analyses of transgenic mice expressing different human apoE isoforms in the brain have revealed clear evi...

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Behavioral Phenotyping of GFAP-ApoE3 and -ApoE4 Transgenic Mice: ApoE4 Mice Show Profound Working Memory Impairments in the Absence of Alzheimer's-like Neuropathology

Cited by 147 publications

References 35 publications

Cognitive Deficits and Disruption of Neurogenesis in a Mouse Model of Apolipoprotein E4 Domain Interaction

Cognitive Deficits and Disruption of Neurogenesis in a Mouse Model of Apolipoprotein E4 Domain Interaction

Impairments in spatial memory retention of GFAP-apoE4 female mice

Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice

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