Wnt signals regulate cell proliferation, migration and differentiation during development, as well as synaptic transmission and plasticity in the adult brain. Abnormal Wnt signaling is central to a number of brain pathologies. We review here, the significance of this pathway focused in the contribution of the most frequent alterations in receptors, secretable modulators and downstream targets in Alzheimer's disease (AD) and Glioblastoma (GBM). β-catenin and GSK3 levels are pivotal in the neurodegeneration associated to AD contributing to memory deficits, tau phosphorylation, increased β-amyloid production and modulation of Apolipoprotein E in the brain. In consequence, β-catenin and GSK3 are targets for potential treatments in AD. Also, Wnt pathway components and secreted molecules interfering with this signaling contribute to the progression of tumoral cells. Wnt pathway activation is a bad prognosis in brain cancer; however, mutations in WNT or Frizzled (FZD) genes do not account for the cases of GBM. Instead, recent studies indicate that epigenetic modifications contribute to the development of GBMs opening novel strategies to study GBM progression.

Cell competition causes apoptosis of suboptimal cells: Their dregs are removed by hemocytes, thus preserving tissue homeostasis Recent results show that, during the process known as cell competition, winner cells identify and kill viable cells from a growing population without requiring engulfment. The engulfment machinery is mainly required in circulating macrophages (hemocytes) after the discrimination between winners and losers is completed and the losers have been killed and extruded from the epithelium. Those new results leave us with the question as to which molecules allow winner cells to recognize and impose cell death on the loser cells during cell competition.

A network of communicating tumour cells established by tumour microtubes (TMs) is supposed to mediate relevant aspects of progression and resistance of incurable gliomas. Moreover, neuronal activity has been shown to foster malignant behavior of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here, we report an unexpected direct communication channel between neurons and glioma cells in multiple disease models as well as in astrocytomas and glioblastomas (GBs) of adult patients: functional bona fide chemical synapses formed between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses (NGS) show a typical synaptic ultrastructure, are located on TM networks, and produce depolarizing postsynaptic currents mediated by glutamate receptors of the AMPA subtype. AMPA-type glutamate receptors (AMPAR) are expressed by a molecularly and morphologically distinct subpopulation of network-integrated glioma cells. Increased neuronal activity under epileptic conditions ex vivo or neuronal optogenetic stimulation in vivo enhanced, while general anesthesia diminished synchronized calcium transients in TM-connected glioma networks. Accordingly, anesthesia reduced invasiveness of TM-positive tumour cells in mice. Genetic perturbation of AMPAR or chronic AMPAR inhibition by perampanel decreased glioma invasion and proliferation in mice and deletion of GluRII in Drosophila glioma increased survival. These findings reveal a hitherto unappreciated direct synaptic communication between neurons and glioma cells that appears relevant for brain tumour biology, implying new avenues for glioma treatment.

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