Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance

Abstract

Summary Apolipoprotein E (APOE) is the strongest genetic risk factor for Alzheimer’s disease (AD). Previous studies suggest that the effect of apoE on amyloid-β (Aβ) accumulation plays a major role in AD pathogenesis. Therefore, understanding proteins that control apoE metabolism may provide new targets for regulating Aβ levels. LDLR, a member of the LDL receptor family, binds to apoE, yet its potential role in AD pathogenesis remains unclear. We hypothesized that LDLR overexpression in the brain would decrease apoE levels, enhance Aβ clearance and decrease Aβ deposition. To test our hypothesis, we created several transgenic mice that overexpress LDLR in the brain and found that apoE levels in these mice decreased by 50–90%. Furthermore, LDLR overexpression dramatically reduced Aβ aggregation and enhanced Aβ clearance from the brain extracellular space. Plaque-associated neuroinflammatory responses were attenuated in LDLR transgenic mice. These findings suggest that increasing LDLR levels may represent a novel AD treatment strategy.

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…In contrast, another study using PDAPP-transgenic mice did not find a significant effect of Ldlr deletion on Ab level or deposition although there was a trend for increased Ab in the absence of LDLR (Fryer et al 2005a). Using a gain-of-function approach, a more recent study showed that overexpression of the LDLR in the brain of transgenic mice enhanced Ab clearance and decreased Ab deposition (Kim et al 2009b). It is not clear whether the effect of LDLR overexpression on Ab clearance is because of the reduced level of apoE in the LDLR transgenic mice, or a direct effect on Ab, or both.…”

“…Deletion of the Ldlr gene in mice increases apoE levels in brain parenchyma and CSF (Fryer et al 2005a), suggesting impaired metabolism of apoE. In contrast, overexpression of the LDLR in the brain decreases apoE levels, reflecting an increased metabolism of apoE (Kim et al 2009b). Similarly, conditional deletion of the Lrp1 gene in mouse forebrain neurons increases apoE levels (Liu et al 2007) and overexpression of a functional LRP1 minireceptor in mouse brain decreases brain apoE levels (Zerbinatti et al 2006).…”

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

“…For quantitative analysis of Aβ plaque load, thioflavin-S, or 6E10-positive signals were determined by a standardized region of interest grayscale threshold analysis (Kim et al 2009). The percentage of area occupied by thioflavin-S or 6E10 in the whole hippocampus, gray matter area, and white matter area was measured.…”

Lipid metabolism in Alzheimer’s disease

“…For example, LRP1 and LDLR play crucial roles in brain lipid metabolism and Aβ clearance [22,23,50] .…”

“…Some single-nucleotide polymorphisms in the LDLR gene are associated with a risk of AD in a gender-specific manner [47,48] . Interestingly, deletion of Ldlr in mice increases apoE levels in the brain parenchyma and cerebrospinal fluid (CSF) [49] , whereas overexpression of LDLR in the brain decreases the metabolism of apoE [50] . Similarly, conditional deletion of Lrp1 in forebrain neurons increases apoE metabolism [51] , while overexpression of a functional LRP1 mini-receptor in mouse brain decreases it [52] .…”