Journal
NEURON
Volume 56, Issue 1, Pages 66-78Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2007.08.008
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Funding
- NHLBI NIH HHS [R37 HL063762] Funding Source: Medline
- NIA NIH HHS [R01 AG027924, R01 AG027924-02, P01 AG030128] Funding Source: Medline
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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 epsilon 4 allele of apolipoprotein E (apoE), a major cholesterol carrier. Using Crelox 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.
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