Abstract
BackgroundAlzheimer'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 ε-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 FindingsUsing 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, Aβ-treated primary neurons, and in the PSAPP transgenic mouse model of AD. Finally, immunofluorescent staining of LDLR and of γ- and α-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/SignificanceThese data suggest that increased APP expression and Aβ 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.
Highlights
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and the most common form of dementia
In order to assess whether potential amyloid precursor protein (APP)-induced alterations were specific to low-density lipoprotein receptor (LDLR), we immunostained for LDLR and another member of the LDLR family, LRP (LDLR-related protein-1) (Figure 2A)
While we did not observe significant changes in the distribution of LRP, we found that in H4-APP cells, LDLR had become densely concentrated in the perinuclear region
Summary
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and the most common form of dementia. Onset of the disease after age 65 is described as late-onset or sporadic AD, which accounts for over 95% of the cases and has an idiopathic etiology. Extracellular b-amyloid deposits in the cores of neuronal (senile) plaques and in vessel walls, intraneuronal neurofibrillary tangles, and neuroinflammation characterize the disease’s pathology resulting in accelerated neuron loss and dementia [1]. Mutations in the two presenilin (PS) genes encoding the catalytic core of c-secretase as well as mutations in the APP gene lead to increases or alterations in Ab, a 38–42 amino acid peptide and the seed for, and major component of amyloid pathology. The major molecular risk factor for late-onset AD is expression of the e-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
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