Human Apolipoprotein E2, E3, and E4 Isoform-Specific Transgenic Mice: Human-like Pattern of GlialandNeuronal Immunoreactivity in Central Nervous System Not Observed in Wild-Type Mice

Xu, Pu; Schmechel, Donald E.; Rothrock-Christian, Tracie; Burkhart, D; Qiu, Hao; Popko, Brian; Sullivan, Patrick M.; Maeda, Nobuyo; Saunders, Ann M.; Roses, Allen D.; Gilbert, John R.

doi:10.1006/nbdi.1996.0023

Cited by 160 publications

(133 citation statements)

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“…However, numerous subsequent studies have demonstrated that CNS neurons can also express apoE, albeit at lower levels than astrocytes (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47). Both apoE protein and mRNA are found in cortical and hippocampal neurons in humans (42) and in transgenic mice expressing human apoE under the control of the human apoE promoter (43). In rats treated with kainic acid, apoE expression is induced in hippocampal neurons that survive excitotoxic stress, as determined by both in situ hybridization and anti-apoE immunohistochemistry (44).…”

Section: Discussionmentioning

confidence: 99%

“…Our results demonstrate that the carboxylterminal-truncated fragments of apoE4 elicited AD-like neurodegeneration and behavioral deficits in transgenic mice. Because apoE is synthesized by neurons under diverse pathological conditions (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47), intraneuronal proteolytic processing of apoE could trigger apoE4-related neuropathology and promote the development of AD.…”

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confidence: 99%

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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.

305

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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Section: Discussionmentioning

confidence: 99%

mentioning

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.

305

365

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“…However, CNS neurons express apoE under physiological and pathological conditions (101)(102)(103)(104)(105)(106)(107)(108)(109)(110). ApoE mRNA is found in cortical and hippocampal neurons in humans (106) and in transgenic mice expressing human apoE under the control of the human apoE promoter (109). Treatment with kainic acid induces apoE synthesis in hippocampal neurons in rats (111), and apoE is expressed in neurons in cerebral infarct patients (112).…”

Section: Sites Of Synthesis In the Nervous Systemmentioning

confidence: 99%

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

Mahley

Weisgraber

Huang

2006

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

822

801

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The premise of this review is that apolipoprotein (apo) E4 is much more than a contributing factor to neurodegeneration. ApoE has critical functions in redistributing lipids among CNS cells for normal lipid homeostasis, repairing injured neurons, maintaining synaptodendritic connections, and scavenging toxins. In multiple pathways affecting neuropathology, including Alzheimer's disease, apoE acts directly or in concert with age, head injury, oxidative stress, ischemia, inflammation, and excess amyloid ␤ peptide production to cause neurological disorders, accelerating progression, altering prognosis, or lowering age of onset. We envision that unique structural features of apoE4 are responsible for apoE4-associated neuropathology. Although the structures of apoE2, apoE3, and apoE4 are in dynamic equilibrium, apoE4, which is detrimental in a variety of neurological disorders, is more likely to assume a pathological conformation. Importantly, apoE4 displays domain interaction (an interaction between the N-and C-terminal domains of the protein that results in a compact structure) and molten globule formation (the formation of stable, reactive intermediates with potentially pathological activities). In response to CNS stress or injury, neurons can synthesize apoE. ApoE4 uniquely undergoes neuron-specific proteolysis, resulting in bioactive toxic fragments that enter the cytosol, alter the cytoskeleton, disrupt mitochondrial energy balance, and cause cell death. Our findings suggest potential therapeutic strategies, including the use of ''structure correctors'' to convert apoE4 to an ''apoE3-like'' molecule, protease inhibitors to prevent the generation of toxic apoE4 fragments, and ''mitochondrial protectors'' to prevent cellular energy disruption. mitochondria ͉ neurodegeneration ͉ cytoskeleton ͉ protein folding A polipoprotein (apo) E plays a fundamental role in the maintenance and repair of neurons, but its three isoforms differ in their abilities to accomplish these critical tasks (1-3). ApoE4 is associated with a wide variety of neuropathological processes. We hypothesize that different insults associated with a variety of disorders, in concert with apoE4, can lead to neuropathology. We believe that those processes are mediated by the cellular origin of apoE (astrocytes, neurons, or microglia), the nature of various injurious factors (''second hits''), and the structure of apoE4. Thus, understanding the structure and function of the apoE isoforms will yield new strategies for treating neuropathologies.Although apoE is involved in many neuropathologies, we will focus on its role in Alzheimer's disease (AD). We will consider the unique structural features that distinguish apoE4 from apoE3 and apoE2, the sites of synthesis and normal roles of apoE in the nervous system, and the pathological roles of apoE4 with or without amyloid ␤ (A␤) peptide. The evidence suggests that apoE4 is considerably more than a simple contributing factor in AD pathogenesis. ApoE and NeuropathologyApoE4's involvement in neuropathology is we...

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“…The 4 allele of the gene encoding apolipoprotein E (apoE) has been linked to late-onset familial and sporadic Alzheimer's disease (AD) and has a gene-dose effect on the risk and age of onset of the disease (Corder et al, 1993;Saunders et al, 1993;Roses, 1996;Tang et al, 1998;Romas et al, 2002). Individuals with two copies of the 4 allele have a 50 -90% chance of developing AD by the age of 85, compared with ϳ45% for those with one allele (Corder et al, 1993;Farrer et al, 1997) and 20% for the general population (Corder et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus

Xu¹,

Bernardo²,

Walker³

et al. 2006

J. Neurosci.

413

333

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To study the profile and regulation of apolipoprotein E (apoE) expression in the CNS, we generated mice in which apoE expression can be detected in vivo with unprecedented sensitivity and resolution. cDNA encoding enhanced green fluorescent protein (EGFP) with a stop codon was inserted by gene targeting into the apoE gene locus (EGFP apoE ) immediately after the translation initiation site. Insertion of EGFP into one apoE allele provides a real-time location marker of apoE expression in vivo; the remaining allele is sufficient to maintain normal cellular physiology. In heterozygous EGFP apoE mice, EGFP was highly expressed in hepatocytes and peritoneal macrophages. EGFP was also expressed in brain astrocytes; however some astrocytes (ϳ25%) expressed no EGFP, suggesting that a subset of these cells does not express apoE. EGFP was expressed in Ͻ10% of microglia after kainic acid treatment, suggesting that microglia are not a major source of brain apoE. Although hippocampal neurons did not express EGFP under normal conditions, kainic acid treatment induced intense expression of EGFP in injured neurons, demonstrating apoE expression in neurons in response to excitotoxic injury. The neuronal expression was confirmed by in situ hybridization of mouse apoE mRNA and by anti-apoE immunostaining. Smooth muscle cells of large blood vessels and cells surrounding small vessels in the CNS also strongly expressed EGFP, as did cells in the choroid plexus. EGFP apoE reporter mice will be useful for studying the regulation of apoE expression in the CNS and might provide insights into the diverse mechanisms of apoE4-related neurodegeneration.

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Human Apolipoprotein E2, E3, and E4 Isoform-Specific Transgenic Mice: Human-like Pattern of GlialandNeuronal Immunoreactivity in Central Nervous System Not Observed in Wild-Type Mice

Cited by 160 publications

References 0 publications

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

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

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus

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