n bound to the same receptor — lipoprotein receptor-related protein 1 (LRP1) — on the surface of astrocytes that Abeta did. With APOE vying for the receptor, there was less opportunity for uptake of Abeta into the clearance pathway.
The researchers did follow-up experiments using an AD mouse model that involved manipulating the level of circulating APOE in brain interstitial fluids. More protein of the APOE4 variety led to an increase in Abeta, while the same degree of buildup did not occur with APOE2, which is a form of APOE that is protective against Alzheimer's.
“We propose that the ability of APOE to influence [Abeta] clearance or aggregation probably is mediated not through direct binding…but rather through its actions with LRP1 and other interacting receptors/transporters,” the researchers concluded. “Evidence indicates that decreasing APOE in the (central nervous system) and modulating the level and activity of APOE receptors and transporters may provide opportunities for developing AD therapeutics.”
A drug that would cause an upregulation of the LRP1 receptor, for instance, could lead to more Abeta being cleared, Dr. Holtzman said.
He said these latest findings, which his team continues to explore, highlight the cellular complexity of Alzheimer's.
Mary Jo LaDu, PhD; Leon Tai, PhD; and a team of other Alzheimer's disease researchers at the University of Illinois at Chicago cautioned that people should not discount the importance of binding between APOE and Abeta peptide on this paper alone. They said it is not clear whether the in vitro results published in the paper are relevant in vivo. Using a new laboratory assay, the researchers recently demonstrated that APOE does bind to Abeta, suggesting that APOE/Abeta complex formation may influence Abeta clearance. Their findings were published in the Feb. 22 issue of the Journal of Biological Chemistry.
“Every technique and model has strengths and weaknesses, making conclusions that eliminate one hypothesis in favor of another premature at this point, as the story continues to unfold,” Dr. LaDu and Dr. Tai wrote in an e-mail.
•. Verghese PB, Castellano JM, Holtzman DM. ApoE influences amyloid-β(Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc Natl Acad Sci. U S A. 2013; 110:(19):E1807-;16. E-pub 2013 Apr 25.
•. Tai LM, Bilousova T, Ladu MJ. Levels of soluble apolipoprotein E/amyloid-β (Aβ) complex are reduced and oligomeric Aβ Increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples. J Biol Chem. 2013; 288:5914–5926.
•. Neurology Today: “Increased LDL receptor lowers amyloid plaques via apolipoprotein E: Study offers new insight on how APOE works in Alzheimer disease”: http://bit.ly/119w0V6