Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer’s disease (AD), with recent proteomic studies highlighting disrupted glial metabolism in AD. We report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function in mouse preclinical models of AD by restoring astrocyte metabolism. Activation of astrocytic IDO1 by amyloid β and tau oligomers increases KYN and suppresses glycolysis in an aryl hydrocarbon receptor–dependent manner. In amyloid and tau models, IDO1 inhibition improves hippocampal glucose metabolism and rescues hippocampal long-term potentiation in a monocarboxylate transporter–dependent manner. In astrocytic and neuronal cocultures from AD subjects, IDO1 inhibition improved astrocytic production of lactate and uptake by neurons. Thus, IDO1 inhibitors presently developed for cancer might be repurposed for treatment of AD.

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.

Significance: Dravet syndrome (DS) is a severe childhood epileptic encephalopathy characterized by intractable seizures and comorbidities, including a high rate of premature mortality. DS is mainly caused by loss-of-function mutations of the Scn1a gene encoding sodium channel Na _v 1.1 that is predominantly expressed in inhibitory parvalbumin-containing (PV) interneurons. Decreased Na _v 1.1 impairs PV cell function, causing DS phenotypes. Effective pharmacological therapy targeting defective PV interneurons is currently not available. This study demonstrated that early treatment with a partial TrkB receptor agonist, LM22A-4, increased Na _v 1.1 expression, improved PV interneuron function, and reduced seizure occurrence and mortality rate in DS mice, suggesting a potential therapy for DS.

INTRODUCTION: Tropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid beta (Aβ) toxicity. Upregulating TrkB/C signaling could reduce Alzheimer's disease (AD)‐related degenerative signaling, memory loss, and synaptic dysfunction.METHODS: PTX‐BD10‐2 (BD10‐2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish‐APP mutant mice (APP^L/S) and wild‐type controls. Effects on memory and hippocampal long‐term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA sequencing.RESULTS: In APP^L/S mice, BD10‐2 treatment improved memory and LTP deficits. This was accompanied by normalized phosphorylation of protein kinase B (Akt), calcium‐calmodulin–dependent kinase II (CaMKII), and AMPA‐type glutamate receptors containing the subunit GluA1; enhanced activity‐dependent recruitment of synaptic proteins; and increased excitatory synapse number. BD10‐2 also had potentially favorable effects on LTP‐dependent complement pathway and synaptic gene transcription.DISCUSSION: BD10‐2 prevented APP^L/S/Aβ‐associated memory and LTP deficits, reduced abnormalities in synapse‐related signaling and activity‐dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response.Highlights: Small molecule modulation of tropomyosin related kinase B (TrkB) and C (TrkC) restores long‐term potentiation (LTP) and behavior in an Alzheimer's disease (AD) model. Modulation of TrkB and TrkC regulates synaptic activity‐dependent transcription. TrkB and TrkC receptors are candidate targets for translational therapeutics. Electrophysiology combined with transcriptomics elucidates synaptic restoration. LTP identifies neuron and microglia AD‐relevant human‐mouse co‐expression modules.

Brain-derived neurotropic factor (BDNF) is expressed by skeletal muscle as a myokine. Our previous work showed that the active precursor, proBDNF, is the predominant form of BDNF expressed in skeletal muscle, and that following skeletal muscle injury, proBDNF levels are significantly increased. However, the function of the muscle-derived proBDNF in injury-induced inflammation has yet to be fully understood. Using a model of tourniquet-induced ischemia–reperfusion (IR) injury of the hindlimb, this study presents, for the first time, strong and novel evidence that following IR injury, proBDNF is released from skeletal muscle into circulation as an endocrine signaling molecule. Further, this study shows that 1 day post-IR injury, the proBDNF receptor, p75^NTR, is upregulated 12-fold in splenic monocytes, which are known to be quickly mobilized to the injury site. We demonstrate that p75^NTR plays a role in the activation of splenic monocytes, and that treatment with a p75^NTR small-molecule modulator, LM11A-31, significantly reduced monocyte inflammatory responses upon lipopolysaccharide stimulation. Overall, the present study establishes proBDNF as a myokine that plays a significant role in skeletal muscle injury-induced inflammation through its receptor, p75^NTR, which may be modulated using LM11A-31 as potential translational therapeutic against injury and inflammation.

In tauopathies, such as Alzheimer’s disease (AD), oligomeric tau (oTau) can induce tau hyperphosphorylation and further oligomerization, contributing to dendrite and dendritic spine degeneration. The p75 neurotrophin receptor (p75 ^NTR ), which regulates signaling that overlaps with tauopathy-related degenerative pathways, is a promising therapeutic target. LM11A-31, a small-molecule p75 ^NTR modulator, downregulates p75 ^NTR’ s degenerative signaling and upregulates signaling that promotes dendritic and synaptic integrity. In a tauopathy mouse model, LM11A-31 reversed spine loss in hippocampal pyramidal neurons and improved performance on behavioral tests of hippocampal function. In a Phase 2a randomized, placebo-controlled AD clinical trial, LM11A-31 slowed the progression of synaptic degeneration biomarkers. In the present study, we tested the hypothesis that LM11A-31 enhances resilience of spines and dendrites to pathological forms of tau and/or inhibits the formation and accumulation of pathological tau species. We found that LM11A-31 prevented degeneration of spines and dendrites in cultured hippocampal neurons exposed to recombinant oTau or oTau-containing hippocampal extract fractions from PS19 tauopathy mice. Treating PS19 mice with LM11A-31 reduced the degeneration-promoting activity in oTau-containing hippocampal extract fractions. In cultured hippocampal neurons, LM11A-31 inhibited excess tau phosphorylation and aggregation induced by oTau and counteracted oTau-induced abnormalities in RhoA, PKC, LIMK1, and cofilin signaling, a signaling module known to regulate spine integrity. The ability of LM11A-31 to confer resilience to dendritic spines was partially dependent on LIMK1 activity. These findings demonstrate that small-molecule modulation of p75 ^NTR by LM11A-31 both reduces the accumulation of pathological tau species and promotes resilience against oTau-induced dendritic spine degeneration, exemplifying a “dual-mechanism” therapeutic approach for tauopathies.