Impaired Neuronal Plasticity in Transgenic Mice Expressing Human Apolipoprotein E4 Compared to E3 in a Model of Entorhinal Cortex Lesion

White, F. E.; Nicoll, James A. R.; Roses, Allen D.; Horsburgh, Karen

doi:10.1006/nbdi.2001.0401

Cited by 124 publications

(69 citation statements)

References 58 publications

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“…The lower glomerular Syn density in KO mice could represent less Syn per synapse but equal numbers of synapses or fewer presynaptic endings in a glomerulus of KO mice and glial processes may be "over represented" in KO glomeruli. Together, these data strongly suggest that apoE is involved in processes governing synaptogenesis in the CNS comparable to previous reports [2,8,20,27]. In vitro studies have demonstrated that cholesterol laden apoE is a glial-derived factor that promotes synapse development in neuronal cultures [10].…”

supporting

confidence: 89%

“…ApoE levels in the OB were two fold higher than normal immediately following OE lesion, and remained elevated over a 3-week period when axons from the newly differentiated olfactory receptor neurons (ORN) grew to reestablish the synaptic connections with cells in the glomeruli [13]. The precise function of apoE in the olfactory system during normal and injury-induced remodeling is unclear; however, studies suggest a role for apoE in the synaptogenesis of the CNS [2,8,20,27]. …”

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confidence: 99%

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Impact of apoE deficiency during synaptic remodeling in the mouse olfactory bulb

Nwosu

Gairhe

Struble

et al. 2008

Neuroscience Letters

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In this study we examined the role of apoE on the rate of synaptic recovery in the olfactory bulb (OB) following olfactory epithelium (OE) lesioning in mice. We used both immunoblotting and immunohistochemical techniques to compare the density of OB synaptophysin (Syn, a synaptic marker) in apoE-gene deficient/knockout (KO) mice and wild-type (WT) mice following OE lesion. We found that the whole bulb concentrations of Syn, measured by immunoblotting, declined sharply following injury in both WT and KO mice during the degenerative phase (3-7 days). After this initial decline, the Syn concentration gradually increased to normal levels by 56 days in WT mice. In contrast, Syn concentration in KO mice did not recover by day 56 when Syn density in WT was essentially normal. Glomerular Syn density, measured by immunohistochemistry, found a lower density in KO mice at all time points post lesion. This lower concentration of whole bulb Syn parallels the slower recovery of glomerular area in KO mice. The data indicate that apoE deficiency in KO mice is associated with a delayed recovery of the glomerular area and a slower recovery in Syn concentration in the OB. Keywords apoE; synaptophysin; olfactory bulb; glia; olfactory nerve; glial proteins; transgenic mice Apolipoprotein E (apoE), a lipid transporting protein, is widely expressed in the primary olfactory pathway [6,12,13,23,25]. Previous studies from our laboratories and others have shown apoE expression in the olfactory nerve and around the glomeruli in the OB of adult mice [12,23]. ApoE levels in the OB were two fold higher than normal immediately following OE lesion, and remained elevated over a 3-week period when axons from the newly differentiated olfactory receptor neurons (ORN) grew to reestablish the synaptic connections with cells in the glomeruli [13]. The precise function of apoE in the olfactory system during normal and injury-induced remodeling is unclear; however, studies suggest a role for apoE in the synaptogenesis of the CNS [2,8,20,27].

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supporting

confidence: 89%

mentioning

confidence: 99%

Impact of apoE deficiency during synaptic remodeling in the mouse olfactory bulb

Nwosu

Gairhe

Struble

et al. 2008

Neuroscience Letters

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“…Moreover, it has been hypothesized that because apoE is dramatically upregulated after neuronal injury, that the ability of apoE to deliver cholesterol to regenerating neurons may be an important factor in cognitive recovery from brain injury (Poirier, 1994). Multiple in vivo studies support this claim: for example, it has been demonstrated that apoE knock-out mice and 4/4 targeted replacement mice exhibit more severe neurological and cognitive deficits after closed head injury (Chen et al, 1997;Sabo et al, 2000), experimental stroke (Laskowitz et al, 1997;Sheng et al, 1998Sheng et al, , 1999, entorhinal cortex lesions (Fagan et al, 1998;White et al, 2001) and experimental allergic encephalomyelitis (Karussis et al, 2003) than controls (wild-type and 3/3 mice, respectively). Moreover, it has also been noted that the presence of the 4 allele correlates with a reduced number of dendritic spines in transgenic mice and AD patients (Ji et al, 2003;Lai et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels

Riddell¹,

Zhou²,

Atchison³

et al. 2008

J. Neurosci.

297

246

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Inheritance of the apoE4 allele (4) increases the risk of developing Alzheimer's disease; however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of 4 may lead to reduced apoE protein levels in the CNS. We therefore examined apoE protein levels in the brains, CSF and plasma of 2/2, 3/3, and 4/4 targeted replacement mice. These apoE mice showed a genotype-dependent decrease in apoE levels; 2/2 Ͼ3/3 Ͼ4/4. Next, we sought to examine the relative contributions of apoE4 and apoE3 in the 3/4 mouse brains. ApoE4 represented 30 -40% of the total apoE. Moreover, the absolute amount of apoE3 per allele was similar between 3/3 and 3/4 mice, implying that the reduced levels of total apoE in 3/4 mice can be explained by the reduction in apoE4 levels. In culture medium from 3/4 human astrocytoma or 3/3, 4/4 and 3/4 primary astrocytes, apoE4 levels were consistently lower than apoE3. Secreted cholesterol levels were also lower from 4/4 astrocytes. Pulse-chase experiments showed an enhanced degradation and reduced half-life of newly synthesized apoE4 compared with apoE3. Together, these data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels. Moreover, the genotype-dependent decrease in CNS apoE levels, mirror the relative risk of developing AD, and suggest that low levels of total apoE exhibited by 4 carriers may directly contribute to the disease progression, perhaps by reducing the capacity of apoE to promote synaptic repair and/or A␤ clearance.

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“…ApoE also appears to play a pivotal role in the redistribution of lipid and cholesterol during membrane repair, and has been postulated to be important for maintaining synaptic plasticity, especially after neuronal injury in the CNS [23][24][25]. Synthesis, transport, or uptake of cholesterol in the CNS may directly affect the development and plasticity of the synaptic circuitry.…”

Section: Apoe-cholesterol Complex and Cognitive Development: A Differmentioning

confidence: 99%

Role of apolipoprotein E4 in protecting children against early childhood diarrhea outcomes and implications for later development

et al. 2007

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SummaryOur group and others have reported a series of studies showing that heavy burdens of diarrheal diseases in the formative first two years of life in children in urban shantytowns have profound consequences of impaired physical and cognitive development lasting into later childhood and schooling. Based on these previous studies showing that apolipoprotein E4 (APOE4) is relatively common in favela children, we review recent data suggesting a protective role for the APOE4 allele in the cognitive and physical development of children with heavy burdens of diarrhea in early childhood. Despite being a marker for cognitive decline with Alzheimer's and cardiovascular diseases later in life, APOE4 appears to be important for cognitive development under the stress of heavy diarrhea. The reviewed findings provide a potential explanation for the survival advantage in evolution of the thrifty APOE4 allele and raise questions about its implications for human development under life-style changes and environmental challenges.

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Impaired Neuronal Plasticity in Transgenic Mice Expressing Human Apolipoprotein E4 Compared to E3 in a Model of Entorhinal Cortex Lesion

Cited by 124 publications

References 58 publications

Impact of apoE deficiency during synaptic remodeling in the mouse olfactory bulb

Impact of apoE deficiency during synaptic remodeling in the mouse olfactory bulb

Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels

Role of apolipoprotein E4 in protecting children against early childhood diarrhea outcomes and implications for later development

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