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Tissue-type plasminogen activator (tPA) is a protease known for its fibrinolytic action but is also involved in physiological and pathophysiological aging processes; including amyloid elimination and synaptic plasticity. The aim of the study was to investigate the role of tPA in cognitive and brain aging. Therefore, we assessed the links between tPA plasma concentration and cognition, structural MRI, FDG-PET and Flobetapir-PET neuroimaging in 155 cognitively unimpaired adults (CUA, aged 20-85 years old) and 32 patients with Alzheimer's disease (ALZ). A positive correlation was found between tPA and age in CUA (p < 0.001), with males showing higher tPA than females (p = 0.05). No significant difference was found between ALZ patients and cognitively unimpaired elders (CUE). Plasma tPA in CUA negatively correlated with global brain volume. No correlation was found with brain FDG metabolism or amyloid deposition. Age-related tPA changes were associated to changes in blood pressure, glycemia and body mass index. Within the ALZ patients, tPA didn't correlate with any cognitive or neuroimaging measures, but only with physiological measures. Altogether our study suggests that increased tPA plasma concentration with age is related to neuronal alterations and cardiovascular risk factors.

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X221119288 for Persistent neuroinflammation and behavioural deficits after single mild traumatic brain injury by Antoine Drieu, Anastasia Lanquetin, Paul Prunotto, Zuhal Gulhan, Swannie Pédron, Gloria Vegliante, Daniele Tolomeo, Sophie Serrière, Johnny Vercouillie, Laurent Galineau, Clovis Tauber, Bertrand Kuhnast, Marina Rubio, Elisa R Zanier, Damien Levard, Sylvie Chalon, Denis Vivien and Carine Ali in Journal of Cerebral Blood Flow & Metabolism

Additional file 1: Figure S1. Characterization of a tPA-reporter viral construct in the dentate gyrus. Figure S2. Plat-GFP reporter expression in the cortex after LPS treatment. Figure S3. Plat-GFP reporter expression in excitatory neurons in the cortex. Figure S4. tPA mRNA is expressed in PV interneurons enwrapped with PNNs. Figure S5. Conditional depletion of tPA in PV interneurons. Figure S6. PNN-like structures in vitro. Figure S7. Interneuron-derived tPA promotes PNN degradation through plasmin. Figure S8. tPA/plasmin mediated PNNs degradation is MMP-independent. Table S1. Sequences of PCR primers. Supplementary materials and methods.

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X221119288 for Persistent neuroinflammation and behavioural deficits after single mild traumatic brain injury by Antoine Drieu, Anastasia Lanquetin, Paul Prunotto, Zuhal Gulhan, Swannie Pédron, Gloria Vegliante, Daniele Tolomeo, Sophie Serrière, Johnny Vercouillie, Laurent Galineau, Clovis Tauber, Bertrand Kuhnast, Marina Rubio, Elisa R Zanier, Damien Levard, Sylvie Chalon, Denis Vivien and Carine Ali in Journal of Cerebral Blood Flow & Metabolism

Additional file 1: Figure S1. In contrast to tPA coupled to Alexa, Alexa alone is not taken-up by CPECs in vivo. A, Experimental design: mice were injected intravenously with of tPA555 and Alexa488 (50µg each), brains were harvested 30min later for immunohistochemistry. B, Representative confocal photomicrographs (n=4) of CPs sections with tPA555 (magenta), Alexa488 (green) and DAPI (blue) staining; scale bar 50µm (upper panels) and 10µm in the magnified inserts (lower panels). Figure S2. CPECs internalized tPA by clathrin-coated endocytosis vesicles. A, Confocal photomicrographs (representative of n=6 slices) of CPs sections with tPA555 (left bottom, magenta), TTR (left top, white) and AP2 (right top, green) staining; scale bar 50µm and 10µm in the magnified inserts. B, Image analysis of confocal photomicrographs using the Imaris Microscopy Image Analysis Software to study the colocalization between tPA555 and AP2 staining (yellow, right). tPA endocytosis (white arrow); scale bar 10µm. Figure S3. Existence of an efflux pathway for tPA. A, Experimental design: mice received an intra-cerebroventricular injection of tPA555 (1µl at 0.9mg/ml), and brains were harvested 10, 30 or 60min later for immunohistochemistry. B, Representative confocal photomicrographs (n=4) of CPs sections with tPA555 (magenta), LRP1 (green), TTR (white) and DAPI (blue) staining; scale bar 50µm and 10µm in the magnified inserts. Figure S4. Evolution of tPA555 levels in the blood and CSF. A, Experimental design illustrating that mice were injected intravenously with 50µg of tPA555 and BSA488, CSF, blood and brains were harvested 15, 30, or 45min later for protein analysis by electrophoresis (2µl of CSF and 1 µl of plasma were resolved for each animal). B, Representative electrophoreses and C, corresponding quantification for tPA555 levels in the plasma and in the CSF (mean ±SEM, n=5). ** significant difference (p

International audience; Pituitary adenylate cyclase-activating polypeptide (PACAP) and tissue plasminogen activator (tPA) play important roles in neuronal migration and survival. However, a direct link between the neurotrophic effects of PACAP and tPA has never been investigated. In this study, we show that, in PC12 cells, PACAP induced a 9.85-fold increase in tPA gene expression through activation of the protein kinase A- and protein kinase C-dependent signaling pathways. In immature cerebellar granule neurons (CGN), PACAP stimulated tPA mRNA expression and release of proteolytically active tPA. Immunocytochemical labeling revealed the presence of tPA in the cytoplasm and processes of cultured CGN. The inhibitory effect of PACAP on CGN motility was not affected by the tPA substrate plasminogen or the tPA inhibitor plasminogen activator inhibitor-1. In contrast, plasminogen activator inhibitor-1 significantly reduced the stimulatory effect of PACAP on CGN survival. Altogether, these data indicate that tPA gene expression is activated by PACAP in both tumoral and normal neuronal cells. The present study also demonstrates that PACAP stimulates the release of tPA which promotes CGN survival by a mechanism dependent of its proteolytic activity.