Role of tissue plasminogen activator receptor LRP in hippocampal long-termpotentiation

The low-density lipoprotein (LDL) receptor-related protein (LRP) is a multi functional endocytic receptor that is expressed abundantly in neurons of th e CNS. Both LRP and several of its ligands, including tissue plasminogen ac tivator (tPA), apolipoprotein E/lipoproteins, alpha(2)-macroglobulin, and t he beta-amyloid precursor protein, have been implicated in various neuronal functions and in the pathogenesis of Alzheimer's disease. It has been repo rted that induction of tPA expression may contribute to activity-dependent synaptic plasticity in the hippocampus and cerebellum. In addition, long-te rm 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 slic es with receptor-associated protein (RAP), an antagonist for ligand interac tions 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 labe ling and ligand binding analyses showed that both tPA and LRP are synthesiz ed by hippocampal neurons and that LRP is the major cell surface receptor t hat binds tPA. Finally, we found that tPA binding to LRP in hippocampal neu rons enhances the activity of cyclic AMP-dependent protein kinase, a key mo lecule that is known to be involved in L-LTP. Taken together, our results d emonstrate that interactions between tPA and cell surface LRP are important for hippocampal L-LTP.