Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance.

TitleOverexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance.
Publication TypeJournal Article
Year of Publication2009
AuthorsKim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM
JournalNeuron
Volume64
Issue5
Pagination632-44
Date Published2009 Dec 10
ISSN1097-4199
KeywordsAmyloid, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Animals, Newborn, Antigens, CD11b, Antigens, CD45, Apolipoproteins E, Astrocytes, Brain, Cells, Cultured, Embryo, Mammalian, Extracellular Space, Female, Gene Expression Regulation, Humans, Mice, Mice, Transgenic, Neurons, Presenilin-1, Receptors, LDL
Abstract

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.

DOI10.1016/j.neuron.2009.11.013
Alternate JournalNeuron
PubMed ID20005821
PubMed Central IDPMC2787195
Grant ListAG034004-01A1 / AG / NIA NIH HHS / United States
AG13956 / AG / NIA NIH HHS / United States
K01 AG029524-03 / AG / NIA NIH HHS / United States
P01 NS032636-140007 / NS / NINDS NIH HHS / United States
P30 DK056341-09 / DK / NIDDK NIH HHS / United States
P30 NS057105 / NS / NINDS NIH HHS / United States
P30 NS057105-04 / NS / NINDS NIH HHS / United States
R37 AG013956-14 / AG / NIA NIH HHS / United States
R37 AG013956-15 / AG / NIA NIH HHS / United States