Studies showing that neurotrophin binding to p75^NTRcan promote cell survival in the absence of Trk (tropomyosin-related kinase) receptors, together with recent structural data indicating that NGF may bind to p75^NTRin a monovalent manner, raise the possibility that small molecule p75^NTRligands that positively regulate survival might be found. A pharmacophore designed to capture selected structural and physical chemical features of a neurotrophin domain known to interact with p75^NTRwas applied toin silicoscreening of small molecule libraries. Small, nonpeptide, monomeric compounds were identified that interact with p75^NTR. In cells showing trophic responses to neurotrophins, the compounds promoted survival signaling through p75^NTR-dependent mechanisms. In cells susceptible to proneurotrophin-induced death, compounds did not induce apoptosis but inhibited proneurotrophin-mediated death. These studies identify a unique range of p75^NTRbehaviors that can result from isolated receptor liganding and establish several novel therapeutic leads.

P75 neurotrophin receptor (p75^NTR) signaling pathways substantially overlap with degenerative networks active in Alzheimer disease (AD). Modulation of p75^NTR with the first-in-class small molecule LM11A-31 mitigates amyloid-induced and pathological tau-induced synaptic loss in preclinical models. Here we conducted a 26-week randomized, placebo-controlled, double-blinded phase 2a safety and exploratory endpoint trial of LM11A-31 in 242 participants with mild to moderate AD with three arms: placebo, 200 mg LM11A-31 and 400 mg LM11A-31, administered twice daily by oral capsules. This trial met its primary endpoint of safety and tolerability. Within the prespecified secondary and exploratory outcome domains (structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography and cerebrospinal fluid biomarkers), significant drug–placebo differences were found, consistent with the hypothesis that LM11A-31 slows progression of pathophysiological features of AD; no significant effect of active treatment was observed on cognitive tests. Together, these results suggest that targeting p75^NTR with LM11A-31 warrants further investigation in larger-scale clinical trials of longer duration. EU Clinical Trials registration: 2015-005263-16; ClinicalTrials.gov registration: NCT03069014.

The p75 neurotrophin receptor (p75^NTR) influences the proliferation, survival, and differentiation of neuronal precursors and its expression is induced in injured brain, where it regulates cell survival. Here, we test the hypotheses that pharmacologic modulation of p75^NTR signaling will promote neural progenitor survival and proliferation, and improve outcomes of traumatic brain injury (TBI). LM11A-31, an orally available, blood-brain barrier-permeant small-molecule p75^NTR signaling modulator, significantly increased proliferation and survival, and decreased JNK phosphorylation, in hippocampal neural stem/progenitor cells in culture expressing wild-type p75^NTR, but had no effect on cells expressing a mutant neurotrophin-unresponsive form of the receptor. The compound also enhanced the production of mature neurons from adult hippocampal neural progenitors in vitro. In vivo, intranasal administration of LM11A-31 decreased postinjury hippocampal and cortical neuronal death, neural progenitor cell death, gliogenesis, and microglial activation, and enhanced long-term hippocampal neurogenesis and reversed spatial memory impairments. LM11A-31 diminished the postinjury increase of SOX2-expressing early progenitor cells, but protected and increased the proliferation of endogenous polysialylated-neural cell adhesion molecule positive intermediate progenitors, and restored the long-term production of mature granule neurons. These findings suggest that modulation of p75^NTR actions using small molecules such as LM11A-31 may constitute a potent therapeutic strategy for TBI. Stem Cells 2013;31:2561–2574

Neurotrophin (NT) receptors are coupled to numerous signaling networks that play critical roles in neuronal survival and plasticity. Several non-peptide small molecule ligands have recently been reported that bind to and activate specific tropomyosin-receptor kinase (Trk) NT receptors, stimulate their downstream signaling, and cause biologic effects similar to, though not completely overlapping, those of the native NT ligands. Here, in silico screening, coupled with low-throughput neuronal survival screening, identified a compound, LM22B-10, that, unlike prior small molecule Trk ligands, binds to and activates TrkB as well as TrkC. LM22B-10 increased cell survival and strongly accelerated neurite outgrowth, superseding the effects of brain-derived neurotrophic factor (BDNF), NT-3 or the two combined. Additionally, unlike the NTs, LM22B-10 supported substantial early neurite outgrowth in the presence of inhibiting glycoproteins. Examination of the mechanisms of these actions suggested contributions of the activation of both Trks and differential interactions with p75(NTR), as well as a requirement for involvement of the Trk extracellular domain. In aged mice, LM22B-10 activated hippocampal and striatal TrkB and TrkC, and their downstream signaling, and increased hippocampal dendritic spine density. Thus, LM22B-10 may constitute a new tool for the study of TrkB and TrkC signaling and their interactions with p75(NTR), and provides groundwork for the development of ligands that stimulate unique combinations of Trk receptors and activity patterns for application to selected neuronal populations and deficits present in various disease states.

Brain-derived neurotrophic factor (BDNF) signaling in the dorsolateral striatum (DLS) keeps alcohol intake in moderation. For example, activation of the BDNF receptor tropomyosin receptor kinase B (TrkB) in the DLS reduces intake in rats that consume moderate amounts of alcohol. Here, we tested whether long-term excessive consumption of alcohol produces neuroadaptations in BDNF signaling in the rat DLS. We found that BDNF was no longer able to gate alcohol self-administration after a history of repeated cycles of binge alcohol drinking and withdrawal. We then elucidated the possible neuroadaptations that could block the ability of BDNF to keep consumption of alcohol in moderation. We report that intermittent access to 20% alcohol in a two-bottle choice paradigm that models excessive alcohol drinking produces a mobilization of DLS p75 neurotrophin receptor (p75NTR), whose activities oppose those of the Trk receptors, including TrkB. These neuroadaptations were not observed in the DLS of rats exposed to continuous access to 10% alcohol or in rats consuming sucrose. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of thep75NTRgene in the DLS, as well as intra-DLS infusion or systemic administration of the p75NTR modulator, LM11A-31, significantly reduced binge drinking of alcohol. Together, our results suggest that excessive alcohol consumption produces a change in BDNF signaling in the DLS, which is mediated by the recruitment of p75NTR. Our data also imply that modulators of p75NTR signaling could be developed as medications for alcohol abuse disorders.SIGNIFICANCE STATEMENTNeuroadaptations gate or drive excessive, compulsive alcohol drinking. We previously showed that brain-derived neurotrophic factor and its receptor, TrkB, in the dorsolateral striatum (DLS), are part of an endogenous system that keeps alcohol drinking in moderation. Here, we show that a history of excessive alcohol intake produces neuroadaptations in the DLS that preclude BDNF's ability to gate alcohol self-administration in rats by the recruitment of the low-affinity neurotrophin receptor, p75NTR, whose activities opposes those of the Trk receptors. Finally, we show that the administration of the p75NTR modulator, LM11A-31, significantly reduces excessive alcohol intake suggesting that the drug may be developed as a new treatment for alcohol abuse disorders.

Longitudinal preclinical and clinical studies suggest that Aβ drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling networks regulated by the p75 neurotrophin receptor (p75^NTR) substantially overlap with those linked to Aβ and to tau. Here we examine the hypothesis that modulation of p75^NTR will suppress the generation of multiple potentially pathogenic tau species and related signaling to protect dendritic spines and processes from Aβ-induced injury. In neurons exposed to oligomeric Aβ in vitro and APP mutant mouse models, modulation of p75^NTR signaling using the small-molecule LM11A-31 was found to inhibit Aβ-associated degeneration of neurites and spines; and tau phosphorylation, cleavage, oligomerization and missorting. In line with these effects on tau, LM11A-31 inhibited excess activation of Fyn kinase and its targets, tau and NMDA-NR2B, and decreased Rho kinase signaling changes and downstream aberrant cofilin phosphorylation. In vitro studies with pseudohyperphosphorylated tau and constitutively active RhoA revealed that LM11A-31 likely acts principally upstream of tau phosphorylation, and has effects preventing spine loss both up and downstream of RhoA activation. These findings support the hypothesis that modulation of p75^NTR signaling inhibits a broad spectrum of Aβ-triggered, tau-related molecular pathology thereby contributing to synaptic resilience.