| First Author | Sagare AP | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 21 | Pages | 15154-66 |
| PubMed ID | 23580652 | Mgi Jnum | J:199624 |
| Mgi Id | MGI:5503294 | Doi | 10.1074/jbc.M112.439570 |
| Citation | Sagare AP, et al. (2013) A lipoprotein receptor cluster IV mutant preferentially binds amyloid-beta and regulates its clearance from the mouse brain. J Biol Chem 288(21):15154-66 |
| abstractText | Soluble low density lipoprotein receptor-related protein-1 (sLRP1) binds ~70% of amyloid beta-peptide (Abeta) in human plasma. In Alzheimer disease (AD) and individuals with mild cognitive impairment converting to AD, plasma sLRP1 levels are reduced and sLRP1 is oxidized, which results in diminished Abeta peripheral binding and higher levels of free Abeta in plasma. Experimental studies have shown that free circulating Abeta re-enters the brain and that sLRP1 and/or its recombinant wild type cluster IV (WT-LRPIV) prevent Abeta from entering the brain. Treatment of Alzheimer APPsw(+/0) mice with WT-LRPIV has been shown to reduce brain Abeta pathology. In addition to Abeta, LRPIV binds multiple ligands. To enhance LRPIV binding for Abeta relative to other LRP1 ligands, we generated a library of LRPIV-derived fragments and full-length LRPIV variants with glycine replacing aspartic acid residues 3394, 3556, and 3674 in the calcium binding sites. Compared with WT-LRPIV, a lead LRPIV-D3674G mutant had 1.6- and 2.7-fold higher binding affinity for Abeta40 and Abeta42 in vitro, respectively, and a lower binding affinity for other LRP1 ligands (e.g. apolipoprotein E2, E3, and E4 (1.3-1.8-fold), tissue plasminogen activator (2.7-fold), matrix metalloproteinase-9 (4.1-fold), and Factor Xa (3.8-fold)). LRPIV-D3674G cleared mouse endogenous brain Abeta40 and Abeta42 25-27% better than WT-LRPIV. A 3-month subcutaneous treatment of APPsw(+/0) mice with LRPIV-D3674G (40 mug/kg/day) reduced Abeta40 and Alphabeta42 levels in the hippocampus, cortex, and cerebrospinal fluid by 60-80% and improved cerebral blood flow responses and hippocampal function at 9 months of age. Thus, LRPIV-D3674G is an efficient new Abeta clearance therapy. |
