Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release

Abstract

The discovery of the neuronal expression of the serine protease tissue-type plasminogen activator (tPA) has opened new avenues of research, with important implications in the physiopathology of the central nervous system. For example, the interaction of tPA with synaptic receptors (NMDAR, LRP1, Annexin II, and EGFR) and its role in the maturation of BDNF have been reported to influence synaptic plasticity and neuronal survival. However, the mechanisms regulating the neuronal trafficking of tPA are unknown. Here, using high-resolution live cell imaging and a panel of innovative genetic approaches, we first unmasked the dynamic characteristics of the dendritic and axonal trafficking of tPA-containing vesicles under different paradigms of neuronal activation or inhibition. We then report a constitutive exocytosis of tPA- and VAMP2-positive vesicles, dramatically increased in conditions of neuronal activation, with a pattern which was mainly dendritic and thus post-synaptic. We also observed that the synaptic release of tPA led to an increase of the exocytosis of VGlut1 positive vesicles containing glutamate. Finally, we described alterations of the trafficking and exocytosis of neuronal tPA in cultured cortical neurons prepared from tau-22 transgenic mice (a preclinical model of Alzheimer’s disease (AD)). Altogether, these data provide new insights about the neuronal trafficking of tPA, contributing to a better knowledge of the tPA-dependent brain functions and dysfunctions.

Vascular Dysfunction in Alzheimer’s Disease: Alterations in the Plasma Contact and Fibrinolytic Systems

“…A study using primary hippocampal neurons in culture suggests that tPA can cause tau phosphorylation through an ERK (extracellular signal-regulated kinase) signaling mechanism independent of plasmin [ 63 ]. Another group used primary neurons from the THY-Tau22 AD mouse model to show that tau affects the transport of tPA-containing vesicles in neurons [ 86 ]. However, further in vivo studies are necessary to better understand the role of tPA in tau pathology in AD.…”

Low-density lipoprotein receptor-related protein-1 (LRP1) in the glial lineage modulates neuronal excitability

“…Interestingly, the prominent LRP1 ligand tPA interacts with the GluN1 N-terminal domain and can elicit cytotoxicity ( Nicole et al, 2001 ; Samson et al, 2008 ; Varangot et al, 2023 ). This notion has been elaborated further in that tPA interaction with GluN1 promotes the extra-synaptic diffusion of NMDARs without increasing the membrane located pool of the receptor ( Lesept et al, 2016 ).…”