Increased Tau Phosphorylation and Impaired Presynaptic Function in Hypertriglyceridemic ApoB-100 Transgenic Mice

Lénárt, Nikolett; Szegedi, Viktor; Juhász, Gábor; Kasztner, Aniko; Horváth, János; Bereczki, Erika; Tóth, Melinda E.; Penke, Botond; Sántha, Miklós

doi:10.1371/journal.pone.0046007

Cited by 21 publications

(23 citation statements)

References 40 publications

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“…An increase of Tau phosphorylation and aggregation is toxic for neurons, causing nurodegeneration [ 46 - 49 ]. Also, tau phosphorylation impairs presynaptic function in hypertriglyceridemic mice [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Rapamycin suppresses brain aging in senescence-accelerated OXYS rats

Kolosova

Vitovtov

Muraleva

et al. 2013

Aging

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Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span in C elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning and memory deficits develop by 3 months. Here we show that rapamycin treatment (0.1 or 0.5 mg/kg as a food mixture daily from the age of 1.5 to 3.5 months) decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wistar rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci. Levels of Tau and phospho-Tau (T181) were increased in OXYS rats (compared with Wistar). Rapamycin significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. Importantly, rapamycin treatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex, indicating that some downstream events were compensatory preserved, explaining the lack of toxicity. We conclude that rapamycin in low chronic doses can suppress brain aging.

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Section: Discussionmentioning

confidence: 99%

Rapamycin suppresses brain aging in senescence-accelerated OXYS rats

Kolosova

Vitovtov

Muraleva

et al. 2013

Aging

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“…Previously, we generated a mouse model of human atherosclerosis using transgenic mice overexpressing the human APOB-100 protein in different tissues such as the liver, heart and brain ( Bjelik et al, 2006 ; Csont et al, 2007 ; Lénárt et al, 2012 ). Apolipoprotein B-100 (APOB-100) is a large, 512 kDa glycoprotein that circulates in the plasma as the major protein component of low density lipoprotein (LDL) and very low density lipoproteins (VLDL).…”

Section: Introductionmentioning

confidence: 99%

Cerebrovascular Pathology in Hypertriglyceridemic APOB-100 Transgenic Mice

Hoyk

Tóth

Lénárt

et al. 2018

Front. Cell. Neurosci.

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Hypertriglyceridemia is not only a serious risk factor in the development of cardiovascular diseases, but it is linked to neurodegeneration, too. Previously, we generated transgenic mice overexpressing the human APOB-100 protein, a mouse model of human atherosclerosis. In this model we observed high plasma levels of triglycerides, oxidative stress, tau hyperphosphorylation, synaptic dysfunction, cognitive impairment, increased neural apoptosis and neurodegeneration. Neurovascular dysfunction is recognized as a key factor in the development of neurodegenerative diseases, but the cellular and molecular events linking cerebrovascular pathology and neurodegeneration are not fully understood. Our aim was to study cerebrovascular changes in APOB-100 transgenic mice. We described the kinetics of the development of chronic hypertriglyceridemia in the transgenic animals. Increased blood-brain barrier permeability was found in the hippocampus of APOB-100 transgenic mice which was accompanied by structural changes. Using transmission electron microscopy, we detected changes in the brain capillary endothelial tight junction structure and edematous swelling of astrocyte endfeet. In brain microvessels isolated from APOB-100 transgenic animals increased Lox-1, Aqp4, and decreased Meox-2, Mfsd2a, Abcb1a, Lrp2, Glut-1, Nos2, Nos3, Vim, and in transgenic brains reduced Cdh2 and Gfap-σ gene expressions were measured using quantitative real-time PCR. We confirmed the decreased P-glycoprotein (ABCB1) and vimentin expression related to the neurovascular unit by immunostaining in transgenic brain sections using confocal microscopy. We conclude that in chronic hypertriglyceridemic APOB-100 transgenic mice both functional and morphological cerebrovascular pathology can be observed, and this animal model could be a useful tool to study the link between cerebrovascular pathology and neurodegeneration.

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“…Recently, we have shown that chronic hypertriglyceridemia led to the development of neurodegenerative changes in brains of ApoB-100 transgenic mice. These changes include hyperphosphorylation of tau protein at several sites, extensive cortical and hippocampal neuronal apoptosis, marked reduction in the number and size of the dendritic spines in the hippocampal neurons and impaired hippocampal presynaptic functions [ 8 ]. Moreover, significant enlargement of brain ventricles in a transgene dose dependent manner was demonstrated by magnetic resonance imaging [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…In spite of the well-known contribution of ApoB-100 to the development of hyperlipidemia and atherogenesis, there is less information on its presence and potential function in the brain. Previously, we have demonstrated that ApoB-100 protein is present in the cerebral cortex of mice overexpressing ApoB-100 [ 8 ] and shows microvascular/perivascular localization [ 10 ]. However, little is known about the effect of ApoB-100 on the cells of the blood–brain barrier (BBB).…”

Section: Introductionmentioning

confidence: 99%

Cultured cells of the blood–brain barrier from apolipoprotein B-100 transgenic mice: effects of oxidized low-density lipoprotein treatment

Lénárt

Walter

Bocsik

et al. 2015

Fluids Barriers CNS

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BackgroundThe apolipoprotein B-100 (ApoB-100) transgenic mouse line is a model of human atherosclerosis. Latest findings suggest the importance of ApoB-100 in the development of neurodegenerative diseases and microvascular/perivascular localization of ApoB-100 protein was demonstrated in the cerebral cortex of ApoB-100 transgenic mice. The aim of the study was to characterize cultured brain endothelial cells, pericytes and glial cells from wild-type and ApoB-100 transgenic mice and to study the effect of oxidized low-density lipoprotein (oxLDL) on these cells.MethodsMorphology of cells isolated from brains of wild type and ApoB-100 transgenic mice was characterized by immunohistochemistry and the intensity of immunolabeling was quantified by image analysis. Toxicity of oxLDL treatment was monitored by real-time impedance measurement and lactate dehydrogenase release. Reactive oxygen species and nitric oxide production, barrier permeability in triple co-culture blood–brain barrier model and membrane fluidity were also determined after low-density lipoprotein (LDL) or oxLDL treatment.ResultsThe presence of ApoB-100 was confirmed in brain endothelial cells, while no morphological change was observed between wild type and transgenic cells. Oxidized but not native LDL exerted dose-dependent toxicity in all three cell types, induced barrier dysfunction and increased reactive oxygen species (ROS) production in both genotypes. A partial protection from oxLDL toxicity was seen in brain endothelial and glial cells from ApoB-100 transgenic mice. Increased membrane rigidity was measured in brain endothelial cells from ApoB-100 transgenic mice and in LDL or oxLDL treated wild type cells.ConclusionThe morphological and functional properties of cultured brain endothelial cells, pericytes and glial cells from ApoB-100 transgenic mice were characterized and compared to wild type cells for the first time. The membrane fluidity changes in ApoB-100 transgenic cells related to brain microvasculature indicate alterations in lipid composition which may be linked to the partial protection against oxLDL toxicity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12987-015-0013-y) contains supplementary material, which is available to authorized users.

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Increased Tau Phosphorylation and Impaired Presynaptic Function in Hypertriglyceridemic ApoB-100 Transgenic Mice

Cited by 21 publications

References 40 publications

Rapamycin suppresses brain aging in senescence-accelerated OXYS rats

Rapamycin suppresses brain aging in senescence-accelerated OXYS rats

Cerebrovascular Pathology in Hypertriglyceridemic APOB-100 Transgenic Mice

Cultured cells of the blood–brain barrier from apolipoprotein B-100 transgenic mice: effects of oxidized low-density lipoprotein treatment

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