Role of tissue plasminogen activator receptor LRP in hippocampal long- term potentiation

Min Zhuo, David M. Holtzman, Yonghe Li, Hiroshi Osaka, Joe DeMaro, Mark Jacquin, Guojun D Bu

Research output: Contribution to journalArticle

232 Citations (Scopus)

Abstract

The low-density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional endocytic receptor that is expressed abundantly in neurons of the CNS. Both LRP and several of its ligands, including tissue plasminogen activator (tPA), apolipoprotein E/lipoproteins, α 2-macroglobulin, and the β-amyloid precursor protein, have been implicated in various neuronal functions and in the pathogenesis of Alzheimer's disease. It has been reported that induction of tPA expression may contribute to activity- dependent synaptic plasticity in the hippocampus and cerebellum. In addition, long-term potentiation (LTP) is significantly decreased in mice lacking tPA. Here we demonstrate that tPA receptor LRP is abundantly expressed in hippocampal neurons and participates in hippocampal LTP. Perfusion of hippocampal slices with receptor-associated protein (RAP), an antagonist for ligand interactions with LRP, significantly reduced late-phase LTP (L-LTP). In addition, RAP also blocked the enhancing effect of synaptic potentiation by exogenous tPA in hippocampal slices prepared from tPA knock-out mice. Metabolic labeling and ligand binding analyses showed that both tPA and LRP are synthesized by hippocampal neurons and that LRP is the major cell surface receptor that binds tPA. Finally, we found that tPA binding to LRP in hippocampal neurons enhances the activity of cyclic AMP-dependent protein kinase, a key molecule that is known to be involved in L-LTP. Taken together, our results demonstrate that interactions between tPA and cell surface LRP are important for hippocampal L-LTP.

Original languageEnglish (US)
Pages (from-to)542-549
Number of pages8
JournalJournal of Neuroscience
Volume20
Issue number2
StatePublished - Jan 15 2000
Externally publishedYes

Fingerprint

Low Density Lipoprotein Receptor-Related Protein-1
Long-Term Potentiation
Tissue Plasminogen Activator
Neurons
Ligands
LDL-Receptor Related Proteins
Apolipoprotein E2
Macroglobulins
Neuronal Plasticity
Amyloid beta-Protein Precursor
LDL Receptors
Cell Surface Receptors
Cyclic AMP-Dependent Protein Kinases
Knockout Mice
Cerebellum
Lipoproteins
Hippocampus
Alzheimer Disease
Proteins
Perfusion

Keywords

  • Alzheimer's disease
  • Hippocampus
  • LRP
  • LTP
  • PKA
  • tPA

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Zhuo, M., Holtzman, D. M., Li, Y., Osaka, H., DeMaro, J., Jacquin, M., & Bu, G. D. (2000). Role of tissue plasminogen activator receptor LRP in hippocampal long- term potentiation. Journal of Neuroscience, 20(2), 542-549.

Role of tissue plasminogen activator receptor LRP in hippocampal long- term potentiation. / Zhuo, Min; Holtzman, David M.; Li, Yonghe; Osaka, Hiroshi; DeMaro, Joe; Jacquin, Mark; Bu, Guojun D.

In: Journal of Neuroscience, Vol. 20, No. 2, 15.01.2000, p. 542-549.

Research output: Contribution to journalArticle

Zhuo, M, Holtzman, DM, Li, Y, Osaka, H, DeMaro, J, Jacquin, M & Bu, GD 2000, 'Role of tissue plasminogen activator receptor LRP in hippocampal long- term potentiation', Journal of Neuroscience, vol. 20, no. 2, pp. 542-549.
Zhuo M, Holtzman DM, Li Y, Osaka H, DeMaro J, Jacquin M et al. Role of tissue plasminogen activator receptor LRP in hippocampal long- term potentiation. Journal of Neuroscience. 2000 Jan 15;20(2):542-549.
Zhuo, Min ; Holtzman, David M. ; Li, Yonghe ; Osaka, Hiroshi ; DeMaro, Joe ; Jacquin, Mark ; Bu, Guojun D. / Role of tissue plasminogen activator receptor LRP in hippocampal long- term potentiation. In: Journal of Neuroscience. 2000 ; Vol. 20, No. 2. pp. 542-549.
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