The apolipoprotein receptor LRP3 compromises APP levels

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...

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Autores principales:	Inmaculada Cuchillo-Ibañez, Matthew P. Lennol, Sergio Escamilla, Trinidad Mata-Balaguer, Lucía Valverde-Vozmediano, Inmaculada Lopez-Font, Isidro Ferrer, Javier Sáez-Valero
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	sAPP ApoER2 ApoER2-ICD Beta-amyloid Alzheimer’s disease Chloroquine Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/0d07f7ff82b34f70b1698695455e552b
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spelling	oai:doaj.org-article:0d07f7ff82b34f70b1698695455e552b2021-11-08T11:15:33ZThe apolipoprotein receptor LRP3 compromises APP levels10.1186/s13195-021-00921-51758-9193https://doaj.org/article/0d07f7ff82b34f70b1698695455e552b2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13195-021-00921-5https://doaj.org/toc/1758-9193Abstract 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.Inmaculada Cuchillo-IbañezMatthew P. LennolSergio EscamillaTrinidad Mata-BalaguerLucía Valverde-VozmedianoInmaculada Lopez-FontIsidro FerrerJavier Sáez-ValeroBMCarticlesAPPApoER2ApoER2-ICDBeta-amyloidAlzheimer’s diseaseChloroquineNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENAlzheimer’s Research & Therapy, Vol 13, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	sAPP ApoER2 ApoER2-ICD Beta-amyloid Alzheimer’s disease Chloroquine Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
spellingShingle	sAPP ApoER2 ApoER2-ICD Beta-amyloid Alzheimer’s disease Chloroquine Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 Inmaculada Cuchillo-Ibañez Matthew P. Lennol Sergio Escamilla Trinidad Mata-Balaguer Lucía Valverde-Vozmediano Inmaculada Lopez-Font Isidro Ferrer Javier Sáez-Valero The apolipoprotein receptor LRP3 compromises APP levels
description	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.
format	article
author	Inmaculada Cuchillo-Ibañez Matthew P. Lennol Sergio Escamilla Trinidad Mata-Balaguer Lucía Valverde-Vozmediano Inmaculada Lopez-Font Isidro Ferrer Javier Sáez-Valero
author_facet	Inmaculada Cuchillo-Ibañez Matthew P. Lennol Sergio Escamilla Trinidad Mata-Balaguer Lucía Valverde-Vozmediano Inmaculada Lopez-Font Isidro Ferrer Javier Sáez-Valero
author_sort	Inmaculada Cuchillo-Ibañez
title	The apolipoprotein receptor LRP3 compromises APP levels
title_short	The apolipoprotein receptor LRP3 compromises APP levels
title_full	The apolipoprotein receptor LRP3 compromises APP levels
title_fullStr	The apolipoprotein receptor LRP3 compromises APP levels
title_full_unstemmed	The apolipoprotein receptor LRP3 compromises APP levels
title_sort	apolipoprotein receptor lrp3 compromises app levels
publisher	BMC
publishDate	2021
url	https://doaj.org/article/0d07f7ff82b34f70b1698695455e552b
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The apolipoprotein receptor LRP3 compromises APP levels

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