Stroke is the second leading cause of death and a major contributor to disability worldwide. The prevalence of stroke is highest in developing countries, with ischemic stroke being the most common type. Considerable progress has been made in our understanding of the pathophysiology of stroke and the underlying mechanisms leading to ischemic insult. Stroke therapy primarily focuses on restoring blood flow to the brain and treating stroke-induced neurological damage. Lack of success in recent clinical trials has led to significant refinement of animal models, focus-driven study design and use of new technologies in stroke research. Simultaneously, despite progress in stroke management, post-stroke care exerts a substantial impact on families, the healthcare system and the economy. Improvements in pre-clinical and clinical care are likely to underpin successful stroke treatment, recovery, rehabilitation and prevention. In this review, we focus on the pathophysiology of stroke, major advances in the identification of therapeutic targets and recent trends in stroke research.

Voltage-gated sodium channels isolated from mammalian brain are composed of alpha, beta1, and beta2 subunits. The alpha subunit forms the ion conducting pore of the channel, whereas the beta1 and beta2 subunits modulate channel function, as well as channel plasma membrane expression levels. beta1 and beta2 each contain a single, extracellular Ig-like domain with structural similarity to the neural cell adhesion molecule (CAM), myelin Po. beta2 contains strong amino acid homology to the third Ig domain and to the juxtamembrane region of F3/contactin. Many CAMs of the Ig superfamily have been shown to interact with extracellular matrix molecules. We hypothesized that beta2 may interact with tenascin-R (TN-R), an extracellular matrix molecule that is secreted by oligodendrocytes during myelination and that binds F3-contactin. We show here that cells expressing sodium channel beta1 or beta2 subunits are functionally modulated by TN-R. Transfected cells stably expressing beta1 or beta2 subunits initially recognized and then were repelled from TN-R substrates. The cysteine-rich amino-terminal domain of TN-R expressed as a recombinant peptide, termed EGF-L, appears to be responsible for the repellent effect on beta subunit-expressing cells. The epidermal growth factor-like repeats and fibronectin-like repeats 6-8 are most effective in the initial adhesion of beta subunit-expressing cells. Application of EGF-L to alphaIIAbeta1beta2 channels expressed in Xenopus oocytes potentiated expressed sodium currents without significantly altering current time course or the voltage dependence of current activation or inactivation. Thus, sodium channel beta subunits appear to function as CAMs, and TN-R may be an important regulator of sodium channel localization and function in neurons.

The release of amyloid precursor protein (APP) intracellular domain (AICD) may be triggered by extracellular cues through γ-secretase-dependent cleavage. AICD binds to Fe65, which may have a role in AICD-dependent signalling; however, the functional ligand has not been characterized. In this study, we have identified TAG1 as a functional ligand of APP. We found that, through an extracellular interaction with APP, TAG1 increased AICD release and triggered Fe65-dependent activity in a γ-secretasedependent manner. TAG1, APP and Fe65 colocalized in the neural stem cell niche of the fetal ventricular zone. Neural precursor cells from TAG1 -/-, APP -/-and TAG1 -/-;APP -/-mice had aberrantly enhanced neurogenesis, which was significantly reversed in TAG1 -/-mice by TAG1 or AICD but not by AICD mutated at the Fe65 binding site. Notably, TAG1 reduced normal neurogenesis in Fe65 +/+ mice. Abnormally enhanced neurogenesis also occurred in Fe65 -/-mice but could not be reversed by TAG1. These results describe a TAG1-APP signalling pathway that negatively modulates neurogenesis through Fe65.The γ-secretase proteolytic complex cleaves a wide spectrum of type-1 transmembrane protein substrates, including Notch and APP, by regulated intramembrane proteolysis (RIP) to release their intracellular domains 1 . Ligand-binding to the substrate protein is one mechanism by which this cleavage is regulated. When a ligand binds to Notch, RIP stimulates the release of the intracellular domain of Notch (NICD), which interacts with the transcription factor CSL (CBF1, Suppressor of Hairless and Lag1; ref. 1). Similar transcriptional activity or regulation has been proposed for the intracellular domains cleaved from other γ-secretase substrates, including AICD, which is cleaved from APP 1 . It is therefore important to understand the physiological mechanisms regulating cleavage of AICD.Glycophosphatidylinositol (GPI)-linked proteins are anchored to the outer leaflet of the plasma membrane and mediate the dynamic remodelling of membranes during cell-cell interactions. In the central nervous system (CNS), GPI-linked recognition molecules, such as TAG1, NB-3 and F3, have been implicated in key developmental events, including selective axonal fasciculation, neural cell adhesion and migration, and neurite outgrowth 2 . Recently, we identified F3 and its homologue NB-3 as functional ligands for the Notch receptor and we showed that their interaction with each other is involved in oligodendrocyte differentiation through activation of the transcriptional factor Deltex1 (refs 3, 4). Given that RIP processing of APP is strikingly similar to that of the Notch receptor 5 , knowledge of the interaction between F3 and the Notch receptor has led us to ask whether members of the F3 family may act as APP ligands. RESULTS TAG1 and APP bind to each otherTo investigate the potential interaction between APP and members of the F3 subfamily, cell adhesion assays were performed. When F3-transfected CHO (CHOF3) cells or non-transfected CHO cells were seeded onto c...