Please use this identifier to cite or link to this item: https://hdl.handle.net/11000/31207

The apolipoprotein receptor LRP3 compromises APP levels

Title:
The apolipoprotein receptor LRP3 compromises APP levels
Authors:
Cuchillo‑Ibañez, Inmaculada
Lennol, Matthew Paul  
Escamilla, Sergio  
Mata‑Balaguer, Trinidad
Valverde‑Vozmediano, Lucía
Lopez-Font, Inmaculada  
Ferrer, Isidro
Sáez-Valero, Javier  
Editor:
BMC
Issue Date:
2021-11-02
URI:
https://hdl.handle.net/11000/31207
Abstract:
Background: Members of the low-density lipoprotein (LDL) receptor family are involved in endocytosis and in transducing signals, but also in amyloid precursor protein (APP) processing and β-amyloid secretion. ApoER2/LRP8 is a member of this family with key roles in synaptic plasticity in the adult brain. ApoER2 is cleaved after the binding of its ligand, the reelin protein, generating an intracellular domain (ApoER2-ICD) that modulates reelin gene transcription itself. We have analyzed whether ApoER2-ICD is able to regulate the expression of other LDL receptors, and we focused on LRP3, the most unknown member of this family. We analyzed LRP3 expression in middle-aged individuals (MA) and in cases with Alzheimer’s disease (AD)-related pathology, and the relation of LRP3 with APP. Methods: The effects of full-length ApoER2 and ApoER2-ICD overexpression on protein levels, in the presence of recombinant reelin or Aβ42 peptide, were evaluated by microarray, qRT-PCRs, and western blots in SH-SY5Y cells. LRP3 expression was analyzed in human frontal cortex extracts from MA subjects (mean age 51.8±4.8 years) and AD-related pathology subjects [Braak neurofibrillary tangle stages I–II, 68.4±8.8 years; III–IV, 80.4 ± 8.8 years; V–VI, 76.5±9.7 years] by qRT-PCRs and western blot; LRP3 interaction with other proteins was assessed by immunoprecipitation. In CHO cells overexpressing LRP3, protein levels of full-length APP and fragments were evaluated by western blots. Chloroquine was employed to block the lysosomal/autophagy function. Results: We have identified that ApoER2 overexpression increases LRP3 expression, also after reelin stimulation of ApoER2 signaling. The same occurred following ApoER2-ICD overexpression. In extracts from subjects with AD-related pathology, the levels of LRP3 mRNA and protein were lower than those in MA subjects. Interestingly, LRP3 transfection in CHO-PS70 cells induced a decrease of full-length APP levels and APP-CTF, particularly in the membrane fraction. In cell supernatants, levels of APP fragments from the amyloidogenic (sAPPα) or non-amyloidogenic (sAPPβ) pathways, as well as Aβ peptides, were drastically reduced with respect to mock-transfected cells. The inhibitor of lysosomal/ autophagy function, chloroquine, significantly increased full-length APP, APP-CTF, and sAPPα levels. Conclusions: ApoER2/reelin signaling regulates LRP3 expression, whose levels are affected in AD; LRP3 is involved in the regulation of APP levels.
Keywords/Subjects:
sAPP
ApoER2
ApoER2-ICD
Beta-amyloid
Alzheimer’s disease
Chloroquine
Differential centrifugation
Autophagy
Type of document:
application/pdf
Access rights:
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
DOI:
https://doi.org/10.1186/s13195-021-00921-5
Appears in Collections:
Instituto de Neurociencias



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