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Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1.

Neuron | Oct 4, 2007

Mutations in the amyloid precursor protein (APP) cause early-onset Alzheimer's disease (AD), but the only genetic risk factor for late-onset AD is the varepsilon4 allele of apolipoprotein E (apoE), a major cholesterol carrier. Using Cre-lox conditional knockout mice, we demonstrate that lipoprotein receptor LRP1 expression regulates apoE and cholesterol levels within the CNS. We also found that deletion of APP and its homolog APLP2, or components of the gamma-secretase complex, significantly enhanced the expression and function of LRP1, which was reversed by forced expression of the APP intracellular domain (AICD). We further show that AICD, together with Fe65 and Tip60, interacts with the LRP1 promoter and suppresses its transcription. Together, our findings support that the gamma-secretase cleavage of APP plays a central role in regulating apoE and cholesterol metabolism in the CNS via LRP1 and establish a biological linkage between APP and apoE, the two major genetic determinants of AD.

Pubmed ID: 17920016 RIS Download

Mesh terms: Amyloid Precursor Protein Secretases | Amyloid beta-Protein Precursor | Animals | Animals, Newborn | Apolipoproteins E | Brain | Cell Line, Transformed | Cholesterol | Chromatin Immunoprecipitation | Cricetinae | Cytidine Deaminase | Enzyme-Linked Immunosorbent Assay | Gene Expression Regulation, Developmental | Histone Acetyltransferases | Humans | Mice | Mice, Knockout | Nerve Tissue Proteins | Nuclear Proteins | RNA, Messenger | Receptors, LDL | Reverse Transcriptase Polymerase Chain Reaction | Trans-Activators | Transfection | Tumor Suppressor Proteins

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Associated grants

  • Agency: NIA NIH HHS, Id: P01 AG030128
  • Agency: NIA NIH HHS, Id: R01 AG027924
  • Agency: NIA NIH HHS, Id: R01 AG027924-02
  • Agency: NHLBI NIH HHS, Id: R37 HL063762

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