Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Protein Precursor / deficiency
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Amyloid beta-Protein Precursor / physiology*
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Animals
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Animals, Newborn
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Apolipoproteins E / metabolism*
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Brain / metabolism*
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Cell Line, Transformed
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Cholesterol / metabolism*
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Chromatin Immunoprecipitation
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Cricetinae
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Cytidine Deaminase / metabolism
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Enzyme-Linked Immunosorbent Assay / methods
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Gene Expression Regulation, Developmental / genetics
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Gene Expression Regulation, Developmental / physiology*
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Histone Acetyltransferases / pharmacology
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Humans
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Low Density Lipoprotein Receptor-Related Protein-1
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Lysine Acetyltransferase 5
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Mice
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Mice, Knockout
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Nerve Tissue Proteins / pharmacology
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Nuclear Proteins / pharmacology
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RNA, Messenger / biosynthesis
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Receptors, LDL / deficiency
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Receptors, LDL / physiology*
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Trans-Activators
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Transfection / methods
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / physiology*
Substances
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Amyloid beta-Protein Precursor
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Apbb1 protein, mouse
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Apolipoproteins E
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Low Density Lipoprotein Receptor-Related Protein-1
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Lrp1 protein, mouse
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Nerve Tissue Proteins
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Nuclear Proteins
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RNA, Messenger
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Receptors, LDL
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Trans-Activators
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Tumor Suppressor Proteins
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Cholesterol
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Histone Acetyltransferases
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Kat5 protein, mouse
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Lysine Acetyltransferase 5
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Amyloid Precursor Protein Secretases
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AICDA (activation-induced cytidine deaminase)
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Cytidine Deaminase