Lack of LDL Receptor Enhances Amyloid Deposition and Decreases Glial Response in an Alzheimer's Disease Mouse Model

Loukia Katsouri,Spiros Georgopoulos,Michelle L Block

doi:10.1371/journal.pone.0021880

Loukia Katsouri, Spiros Georgopoulos + Show 1 more

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https://doi.org/10.1371/journal.pone.0021880

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Abstract

BackgroundApolipoprotein E (ApoE), a cholesterol carrier associated with atherosclerosis, is a major risk factor for Alzheimer's disease (AD). The low-density lipoprotein receptor (LDLR) regulates ApoE levels in the periphery and in the central nervous system. LDLR has been identified on astrocytes and a number of studies show that it modulates amyloid deposition in AD transgenic mice. However these findings are controversial on whether LDLR deletion is beneficial or detrimental on the AD-like phenotype of the transgenic mice.Methodology/Principal FindingsTo investigate the role of LDLR in the development of the amyloid related phenotype we used an APP/PS1 transgenic mouse (5XFAD) that develops an AD-like pathology with amyloid plaques, astrocytosis and microgliosis. We found that 4 months old 5XFAD transgenic mice on the LDLR deficient background (LDLR-/-) have increased amyloid plaque deposition. This increase is associated with a significant decrease in astrocytosis and microgliosis in the 5XFAD/LDLR-/- mice. To further elucidate the role of LDLR in relation with ApoE we have generated 5XFAD transgenic mice on the ApoE deficient (ApoE-/-) or the ApoE/LDLR double deficient background (ApoE-/-/LDLR -/-). We have found that ApoE deletion in the 4 months old 5XFAD/ApoE-/- mice decreases amyloid plaque formation as expected, but has no effect on astrocytosis or microgliosis. By comparison 5XFAD/ApoE-/-LDLR -/- double deficient mice of the same age have increased amyloid deposition with decreased astrocytosis and microgliosis.ConclusionsOur analysis shows that LDL deficiency regulates astrocytosis and microgliosis in an AD mouse model. This effect is independent of ApoE, as both 5XFAD/LDLR -/- and 5XFAD/ApoE-/- LDLR -/- mice show reduction in inflammatory response and increase in amyloid deposition compared to control mice. These results demonstrate that LDLR regulates glial response in this mouse model independently of ApoE and modifies amyloid deposition.

Highlights

Alzheimer’s disease (AD), the major form of dementia, is an age-related neurodegenerative disease that impairs basic cognitive functions, primarily memory
Our analysis shows that LDL deficiency regulates astrocytosis and microgliosis in an AD mouse model
This effect is independent of Apolipoprotein E (ApoE), as both 5XFAD/low-density lipoprotein receptor (LDLR) -/- and 5XFAD/ApoE-/- LDLR -/- mice show reduction in inflammatory response and increase in amyloid deposition compared to control mice

Summary

Introduction

Alzheimer’s disease (AD), the major form of dementia, is an age-related neurodegenerative disease that impairs basic cognitive functions, primarily memory. Studies using huAPP transgenic mice that develop an AD-like phenotype have shown that ApoE deletion exerts a beneficial effect on Ab-fibrillogenesis and amyloid plaque formation in the mouse brain without altering Ab-production. ApoE binds to a number of membrane receptors, known as the low density lipoprotein receptor (LDLR) family. Many of these structurally related proteins, including the LDLR and the LDL receptor-related protein 1 (LRP1), have been shown to have diverse roles ranging from cholesterol homeostasis to nervous system development [10]. LDLR has been identified on astrocytes and a number of studies show that it modulates amyloid deposition in AD transgenic mice. These findings are controversial on whether LDLR deletion is beneficial or detrimental on the AD-like phenotype of the transgenic mice

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