Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer's disease mouse model

Background

Apolipoprotein 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 Findings

To 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.

Conclusions

Our 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.