Low density lipoprotein receptor-related protein 1 promotes anti-apoptotic signaling in neurons by activating Akt survival pathway

Rodrigo A. Fuentealba, Qiang Liu, Takahisa Kanekiyo, Juan Zhang, Guojun D Bu

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

The low density lipoprotein receptor-related protein 1 (LRP1) is a multi-ligand receptor abundantly expressed in neurons. Previous work has shown that brain LRP1 levels are decreased during aging and in Alzheimer disease. Although mounting evidence has demonstrated a role for LRP1 in the metabolism of apolipoprotein E/lipoprotein and amyloid-β peptide, whether LRP1 also plays a direct role in neuronal survival is not clear. Here, we show that LRP1 expression is critical for the survival of primary neurons under stress conditions including trophic withdrawal, the presence of apoptosis inducers, or amyloid-β-induced neurotoxicity. Using lentiviral short hairpin RNA to knock down endogenous LRP1 expression, we showed that a depletion of LRP1 leads to an activation of caspase-3 and increased neuronal apoptosis, an effect that was rescued by a caspase-3 inhibitor. A correlation between decreased Akt phosphorylation and the activation of caspase-3 was demonstrated in LRP1 knocked down neurons. Notably, LRP1 knockdown decreased insulin receptor levels in primary neurons, suggesting that decreased neuronal survival might be a consequence of an impaired insulin receptor signaling pathway. Correspondingly, both insulin receptor and phospho-Akt levels were decreased in LRP1 forebrain knock-out mice. These results demonstrate that LRP1 mediates anti-apoptotic function in neurons by regulating insulin receptor and the Akt survival pathway and suggest that restoring LRP1 expression in Alzheimer disease brain might be beneficial to inhibiting neurodegeneration.

Original languageEnglish (US)
Pages (from-to)34045-34053
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number49
DOIs
StatePublished - Dec 4 2009
Externally publishedYes

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Low Density Lipoprotein Receptor-Related Protein-1
Lipoprotein Receptors
Neurons
Proteins
Insulin Receptor
Caspase 3
Amyloid
Brain
Alzheimer Disease
Chemical activation
Apoptosis
Phosphorylation
Caspase Inhibitors
Apolipoproteins E
Prosencephalon
Mountings
Metabolism
Knockout Mice
Small Interfering RNA
Lipoproteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Low density lipoprotein receptor-related protein 1 promotes anti-apoptotic signaling in neurons by activating Akt survival pathway. / Fuentealba, Rodrigo A.; Liu, Qiang; Kanekiyo, Takahisa; Zhang, Juan; Bu, Guojun D.

In: Journal of Biological Chemistry, Vol. 284, No. 49, 04.12.2009, p. 34045-34053.

Research output: Contribution to journalArticle

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