Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance.
Apolipoprotein E (APOE) is the strongest genetic risk factor for Alzheimer's disease (AD). Previous studies suggest that the effect of apoE on amyloid-beta (A beta) accumulation plays a major role in AD pathogenesis. Therefore, understanding proteins that control apoE metabolism may provide new targets for regulating A beta 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 A beta clearance, and decrease A beta 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 A beta aggregation and enhanced A beta 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.
Kim
Jungsu
J
Department of Neurology, Developmental Biology, Hope Center for Neurological Disorders, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Castellano
Joseph M
JM
Jiang
Hong
H
Basak
Jacob M
JM
Parsadanian
Maia
M
Pham
Vi
V
Mason
Stephanie M
SM
Paul
Steven M
SM
Holtzman
David M
DM
D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001057:Apolipoproteins E / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D053764:Presenilin-1; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D039481:CD11b Antigen; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011973:Receptors, LDL; D017493:Leukocyte Common Antigens