LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation
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Summary
This summary is machine-generated.The low density lipoprotein (LDL) receptor-related protein (LRP) mediates the cellular uptake and degradation of secreted beta-amyloid precursor protein (APP). This finding links LRP and APP metabolism to Alzheimer's disease (AD) risk factors.
Area Of Science
- Neuroscience
- Molecular Biology
- Cell Biology
Background
- Secreted beta-amyloid precursor protein (APP) containing the Kunitz proteinase inhibitor (KPI) domain, also known as protease nexin II, is internalized and degraded by cells.
- Alzheimer's disease (AD) is a neurodegenerative disorder associated with amyloid-beta (Aβ) accumulation.
Purpose Of The Study
- To identify the cellular receptor responsible for the endocytosis of secreted APP.
- To investigate the role of the low density lipoprotein (LDL) receptor-related protein (LRP) in APP metabolism.
- To explore the link between LRP, APP, and Alzheimer's disease (AD) pathophysiology.
Main Methods
- Investigated the endocytosis of secreted APP (APPs770) in cell cultures.
- Utilized receptor-associated protein (RAP) as an LRP antagonist.
- Employed LRP antibodies to block receptor function.
- Examined APP degradation in fibroblasts genetically deficient in LRP.
- Assessed the binding of different APP isoforms (APPs770 vs. APPs695) to LRP.
Main Results
- The low density lipoprotein (LDL) receptor-related protein (LRP) was identified as the primary receptor mediating the endocytosis of secreted APP.
- APPs770 degradation was significantly inhibited by LRP antagonists (RAP, LRP antibodies) and in LRP-deficient cells.
- APPs695, lacking the KPI domain, showed poor binding to LRP.
- LRP also binds apolipoprotein E (apoE)-enriched lipoproteins.
Conclusions
- LRP is the key receptor for the cellular uptake and degradation of secreted APP containing the KPI domain.
- These findings establish a direct link between LRP-mediated APP metabolism and apolipoprotein E (apoE) epsilon 4 allele, a known risk factor for Alzheimer's disease (AD).
- This study implicates a single metabolic pathway involving LRP and APP in the pathophysiology of AD.