Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 16 No. 3 • March 2013


LDLR (LDL Receptor) Overexpression Enhances the Rate of Amyloid Beta Clearance

Amyloid Beta Clearance from the Brain in a Mouse Model of Beta-amyloidosis

A new paper1 reports that amyloid-beta is removed from the brain via apoE and that the apoE4 form, which is associated with an increased risk for Alzheimer’s disease as compared to other forms of apoE, exhibited the slowest rate of amyloid beta clearance from the brain as compared to the other forms of apoE. LDLR is known to play an important role in the periphery in mediating removal of cholesterol and cholesterol esters, but the authors note that little is known about its function in the brain. In this paper, the authors explain that recent work has identified LDLR as a major apoE receptor in the CNS that “profoundly affects the accumulation of amyloid beta.” In this new paper,1 the authors found that LDLR regulates clearance from the brain of exogenously administered amyloid beta across the blood-brain barrier.

The researchers created a mouse that overexpresses LDLR in the setting of CNS expression of human amyloid beta and the PDAPP mouse model of beta-amyloidosis. “We found that LDLR overexpression in young PDAPP mice markedly decreases apoE and decreases amyloid beta deposition in aged PDAPP mice.”1 They found, moreover, that LDLR overexpression significantly increased the appearance rate of endogenously produced human amyloid beta from brain to blood, suggesting, the authors stated, that this is a mechanism whereby LDLR regulates brain amyloid beta accumulation by eliminating it from brain to blood.

The researchers say, in their final paragraph, that LDLR has very few identified ligands for modulating the expression of LDLR and that affords an opportunity for discovery to identify innovative avenues for Alzheimer’s disease prevention and treatment.

Natural Products That Upregulate LDLR in the Periphery

Some natural products are known to upregulate LDLR in the periphery, thus acting as a mechanism to remove cholesterol from the circulation. That includes a green tea catechin extract that upregulates the LDLR in the rat liver,2 Mulberry extracts that were shown to exhibit a hypolipidemic effect on liver cells,3 and the medicinal plant goldenseal that is a natural LDL-lowering agent.4 However, whether these peripheral forms of LDLR would also have an effect in the brain of removing amyloid beta was not discussed in these papers.

References

  1. Castellano et al. Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Amyloid beta clearance in a mouse model of beta-amyloidosis. Proc Nat Acad Sci USA. 109(38):15502-7 (2012).
  2. Bursill and Roach. A green tea catechin extract upregulates the hepatic low-density lipoprotein receptor in rats. Lipids. 42:621-7 (2007).
  3. Liu et al. Effects of mulberry (Morus alba L.) extract on lipid homeostasis in vitro and in vivo. J Agric Food Chem. 57:7605-11 (2009).
  4. Abidi et al. The medicinal plant goldenseal is a natural LDL-lowering agent with multiple bioactive components and new action mechanisms. J Lipid Res. 47:2134-47 (2006).

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