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Title

ApoER2 processing by presenilin-1 modulates reelin expression

AuthorsBalmaceda, Valeria; Cuchillo-Ibáñez, Inmaculada; Pujadas, Lluís; García Ayllón, María Salud; Saura, Carlos A.; Nimpf, Johannes; Soriano, Eduardo; Sáez-Valero, Javier
KeywordsTranscription
Alzheimer's disease
Reelin
Issue DateApr-2014
PublisherFederation of American Societies for Experimental Biology
CitationFASEB Journal - Federation of American Societies for Experimental Biology 28(4): 1543-1554 (2014)
AbstractThe reelin signaling protein and its downstream components have been associated with synaptic plasticity and neurotransmission. The reelin signaling pathway begins with the binding of reelin to the transmembrane lipoprotein receptor apolipoprotein E receptor 2 (ApoER2), which in turns induces the sequential cleavage of ApoER2 by the sequential action of α- and γ-secretases. Using conditional-knockout mice of the catalytic component of the γ-secretase complex, presenilin 1 (PS1), we demonstrated increased brain ApoER2 and reelin protein and transcript levels, with no changes in the number of reelin-positive cells. Using the human SH-SY5Y neuroblastoma cell line, we showed that ApoER2 processing occurs in the presence of PS1, producing an intracellular ApoER2 C-terminal fragment. In addition, the pharmacologic inhibition of γ-secretase in SH-SY5Y cells led to increased reelin levels. Overexpression of ApoER2 decreased reelin mRNA levels in these cells. A luciferase reporter gene assay and nuclear fractionation confirmed that increased amounts of intracellular fragment of ApoER2 suppressed reelin expression at a transcriptional level. Chromatin immunoprecipitation experiments corroborated that the intracellular fragment of ApoER2 bound to the RELN promoter region. Our study suggests that PS1/γ-secretase-dependent processing of the reelin receptor ApoER2 inhibits reelin expression and may regulate its signaling. © FASEB.
Publisher version (URL)http://dx.doi.org/10.1096/fj.13-239350
URIhttp://hdl.handle.net/10261/103455
DOI10.1096/fj.13-239350
Identifiersdoi: 10.1096/fj.13-239350
e-issn: 1530-6860
issn: 0892-6638
Appears in Collections:(IN) Artículos
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