Dataset Information

LDLR expression and localization are altered in mouse and human cell culture models of Alzheimer's disease.

ABSTRACT:

Background

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common form of dementia. The major molecular risk factor for late-onset AD is expression of the epsilon-4 allele of apolipoprotein E (apoE), the major cholesterol transporter in the brain. The low-density lipoprotein receptor (LDLR) has the highest affinity for apoE and plays an important role in brain cholesterol metabolism.

Methodology/principal findings

Using RT-PCR and western blotting techniques we found that over-expression of APP caused increases in both LDLR mRNA and protein levels in APP transfected H4 neuroglioma cells compared to H4 controls. Furthermore, immunohistochemical experiments showed aberrant localization of LDLR in H4-APP neuroglioma cells, Abeta-treated primary neurons, and in the PSAPP transgenic mouse model of AD. Finally, immunofluorescent staining of LDLR and of gamma- and alpha-tubulin showed a change in LDLR localization preferentially away from the plasma membrane that was paralleled by and likely the result of a disruption of the microtubule-organizing center and associated microtubule network.

Conclusions/significance

These data suggest that increased APP expression and Abeta exposure alters microtubule function, leading to reduced transport of LDLR to the plasma membrane. Consequent deleterious effects on apoE uptake and function will have implications for AD pathogenesis and/or progression.

SUBMITTER: Abisambra JF

PROVIDER: S-EPMC2797391 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Publications

LDLR expression and localization are altered in mouse and human cell culture models of Alzheimer's disease.

Abisambra Jose F JF Fiorelli Tina T Padmanabhan Jaya J Neame Peter P Wefes Inge I Potter Huntington H

PloS one 20100101 1

<h4>Background</h4>Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common form of dementia. The major molecular risk factor for late-onset AD is expression of the epsilon-4 allele of apolipoprotein E (apoE), the major cholesterol transporter in the brain. The low-density lipoprotein receptor (LDLR) has the highest affinity for apoE and plays an important role in brain cholesterol metabolism.<h4>Methodology/principal findings</h4>Using RT-PCR and western blotting tec ...[more]

PMID: 20049331

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Project description:Circadian symptoms have long been observed in Alzheimer's disease (AD) and often appear before cognitive symptoms, but the mechanisms underlying circadian alterations in AD are poorly understood. We studied circadian re-entrainment in AD model mice using a "jet lag" paradigm, observing their behavior on a running wheel after a 6 h advance in the light:dark cycle. Female 3xTg mice, which carry mutations producing progressive amyloid beta and tau pathology, re-entrained following jet lag more rapidly than age-matched wild type controls at both 8 and 13 months of age. This re-entrainment phenotype has not been previously reported in a murine AD model. Because microglia are activated in AD and in AD models, and inflammation can affect circadian rhythms, we hypothesized that microglia contribute to this re-entrainment phenotype. To test this, we used the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397, which rapidly depletes microglia from the brain. Microglia depletion did not alter re-entrainment in either wild type or 3xTg mice, demonstrating that microglia activation is not acutely responsible for the re-entrainment phenotype. To test whether mutant tau pathology is necessary for this behavioral phenotype, we repeated the jet lag behavioral test with the 5xFAD mouse model, which develops amyloid plaques, but not neurofibrillary tangles. As with 3xTg mice, 7-month-old female 5xFAD mice re-entrained more rapidly than controls, demonstrating that mutant tau is not necessary for the re-entrainment phenotype. Because AD pathology affects the retina, we tested whether differences in light sensing may contribute to altered entrainment behavior. 3xTg mice demonstrated heightened negative masking, a circadian behavior measuring responses to different levels of light, and re-entrained dramatically faster than WT mice in a jet lag experiment performed in dim light. 3xTg mice show a heightened sensitivity to light as a circadian cue that may contribute to accelerated photic re-entrainment. Together, these experiments demonstrate novel circadian behavioral phenotypes with heightened responses to photic cues in AD model mice which are not dependent on tauopathy or microglia.

Dataset Information

LDLR expression and localization are altered in mouse and human cell culture models of Alzheimer's disease.

Background

Methodology/principal findings

Conclusions/significance

Publications

LDLR expression and localization are altered in mouse and human cell culture models of Alzheimer's disease.

Similar Datasets

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