The apolipoprotein receptor LRP3 compromises APP levels.
Por:
Cuchillo-Ibañez I, Lennol MP, Escamilla S, Mata-Balaguer T, Valverde-Vozmediano L, Lopez-Font I, Ferrer I and Sáez-Valero J
Publicada:
2 nov 2021
Ahead of Print:
2 nov 2021
Resumen:
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 ß-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 Aß42 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 (sAPPa) or non-amyloidogenic (sAPPß) pathways, as well as Aß 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 sAPPa levels. CONCLUSIONS: ApoER2/reelin signaling regulates LRP3 expression, whose levels are affected in AD; LRP3 is involved in the regulation of APP levels.
Filiaciones:
:
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández de Elche-CSIC, Sant Joan d'Alacant, Spain.
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Instituto de Investigacion Sanitaria y Biomedica de Alicante (ISABIAL), Alicante, Spain.
Lennol MP:
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández de Elche-CSIC, Sant Joan d'Alacant, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Escamilla S:
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández de Elche-CSIC, Sant Joan d'Alacant, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Mata-Balaguer T:
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández de Elche-CSIC, Sant Joan d'Alacant, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Valverde-Vozmediano L:
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández de Elche-CSIC, Sant Joan d'Alacant, Spain
:
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández de Elche-CSIC, Sant Joan d'Alacant, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain
Ferrer I:
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Instituto de Neuropatología, Hospital Universitario de Bellvitge, Universidad de Barcelona, Hospitalet de Llobregat, Barcelona, Spain
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