Canonical Wnt pathway and the LDL receptor superfamily in neuronal cholesterol homeostasis and function
Por:
Borrell-Pages, M, Luquero, A, Vilahur, G, Padró, T, Badimon, L
Publicada:
13 mar 2024
Ahead of Print:
1 ene 2024
Resumen:
Aims There is little information on the regulation of cholesterol homeostasis in the brain. Whether cholesterol crosses the blood-brain barrier is under investigation, but the present understanding is that cholesterol metabolism in the brain is independent from that in peripheral tissues. Lipoprotein receptors from the LDL receptor family (LRPs) have key roles in lipid particle accumulation in cells involved in vascular and cardiac pathophysiology; however, their function on neural cells is unknown.Methods and results The expression of LRP5 and the components and targets of its downstream signalling pathway, the canonical Wnt pathway, including beta-catenin, LEF1, VEGF, OPN, MMP7, and ADAM10, is analysed in the brains of Wt and Lrp5-/- mice and in a neuroblastoma cell line. LRP5 expression is increased in a time- and dose-dependent manner after lipid loading in neuronal cells; however, it does not participate in cholesterol homeostasis as shown by intracellular lipid accumulation analyses. Neurons challenged with staurosporin and H2O2 display an anti-apoptotic protective role for LRP5.Conclusions For the first time, it has been shown that neurons can accumulate intracellular lipids and lipid uptake is performed mainly by the LDLR, while CD36, LRP1, and LRP5 do not play a major role. In addition, it has been shown that LRP5 triggers the canonical Wnt pathway in neuronal cells to generate pro-survival signals. Finally, Lrp5-/- mice have maintained expression of LRP5 only in the brain supporting the biological plausible concept of the need of brain LRP5 to elicit pro-survival processes and embryonic viability.
Graphical Abstract
Filiaciones:
Borrell-Pages, M:
St Pau Inst Biomed Res IIB St Pau, Cardiovasc Program ICCC, C St Antoni Maria Claret 167, Barcelona 08025, Spain
CIBER CV, Av Monforte Lemos,3 5, Madrid 28029, Spain
Luquero, A:
St Pau Inst Biomed Res IIB St Pau, Cardiovasc Program ICCC, C St Antoni Maria Claret 167, Barcelona 08025, Spain
CIBER CV, Av Monforte Lemos,3 5, Madrid 28029, Spain
Vilahur, G:
St Pau Inst Biomed Res IIB St Pau, Cardiovasc Program ICCC, C St Antoni Maria Claret 167, Barcelona 08025, Spain
CIBER CV, Av Monforte Lemos,3 5, Madrid 28029, Spain
Padró, T:
St Pau Inst Biomed Res IIB St Pau, Cardiovasc Program ICCC, C St Antoni Maria Claret 167, Barcelona 08025, Spain
CIBER CV, Av Monforte Lemos,3 5, Madrid 28029, Spain
Badimon, L:
St Pau Inst Biomed Res IIB St Pau, Cardiovasc Program ICCC, C St Antoni Maria Claret 167, Barcelona 08025, Spain
CIBER CV, Av Monforte Lemos,3 5, Madrid 28029, Spain
Univ Autonoma Barcelona, Cardiovasc Res Chair, Pl Civ, Barcelona 08193, Spain
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