ACS Chemical Neuroscience

Nerve Growth Factor (NGF) supports neuronal survival, plasticity, and growth by binding to p75NTR and TrkA receptors. There is a strong link between NGF and the cholinergic hippocampus, and changes in NGF pathways are observed in Alzheimer's disease (AD). Research shows NGF's neuroprotective and regenerative effects on cholinergic neurons, with positive results in AD models and clinical studies. However, NGF therapy faces challenges: limited blood-brain barrier crossing and dose-dependent pain. To address pain, a mutated NGF called CHF6467 was developed. Thanks to the R100E mutation, it prevents binding to p75NTR while maintaining TrkA affinity, which helps reduce pain side effects. Understanding CHF6467's mechanism remains a challenge. In this context, untargeted metabolomics is effective for uncovering unforeseen responses, making it suitable for assessing CHF6467's overall effects. Building on our previous research and recognizing the importance of amyloid-{beta} peptide as a critical pathological marker of AD, we used NMR-metabolomics to study the effect of CHF6467 on SH-SY5Y cells. The study examined metabolomic profiles of cells treated with CHF6467, with and without A{beta}(1-42), using NMR. Results show CHF6467 influences the metabolic changes caused by A{beta}(1-42), inducing biochemical effects consistent with the promotion of phospholipid precursors, reduced glutamate excitotoxicity, and restored energy metabolism.

Sleep disorders and wakefulness constitute a pronounced and pervasive health risk that contributes to numerous cerebral pathologies such as stroke, depression, and neurodegenerative disorders. The hippocampus (HC) plays vital roles in learning and memory and is especially susceptible to the pathological insults imposed by sleep deprivation (SD). While SD disrupts neuronal network signaling and triggers inflammatory processes, the impact of SD on metabolism within the HC presently remains poorly understood. In this study, we assessed the progressive and cumulative effects of partial SD in the live mouse HC CA1 region using two-photon microscopy. Using a custom-designed implantable cannula enabling direct HC visualization and administration of dyes and pharmacological agents directly to HC tissue, we longitudinally monitored spontaneous neuronal activity and partial pressure of oxygen (pO2) within HC CA1 tissue before and during a 7-day period of partial SD and after a 7- day period of recovery. Our results revealed a progressive decline in spontaneous neural activity, alongside sustained elevation in tissue pO2; during the 7-day partial SD period. Notably, after 7 days of recovery, neuronal activity did not return to baseline, and tissue oxygenation continued to increase. Our findings emphasize chronic SD's cumulative and enduring impairments to neuronal function and metabolism in the HC and reveal uncoupling between metabolic and functional recovery that outlasts the sleep restriction period.

Allosteric modulation of G protein-coupled receptors (GPCR) is a rapidly advancing area of drug discovery with considerable therapeutic potential. In this study, we used various bioluminescence resonance energy transfer (BRET) assay configurations to investigate the differential activity of LY3154207, a dopamine D1 receptor (D1R)- positive allosteric modulator (PAM), in potentiating D1R-mediated signaling pathways. Our data showed that LY3154207 demonstrated clear bias toward {beta}-arrestin recruitment over G-protein engagement. Among the G-protein subtypes, LY3154207 preferentially potentiated Gs signaling induced by DA. Interestingly, when tested for its effect on the Gs-selective D1R agonist DHX and the Golf-selective agonist TAV, LY3154207 further enhanced the selectivity of these compounds, suggesting a probe-dependent effect. We also studied the structural mechanism underlying this subtype selectivity and found that W123 and R130 in the intracellular loop 2 (ICL2) of D1R were crucial for the activity of LY3154207. Furthermore, the N domain of the G-protein appeared to make minor contributions to this G-protein subtype selectivity of LY3154207. Lastly, our data demonstrated that LY3154207 induced cAMP production in the absence of the orthosteric ligand, indicating that this compound is an ago-PAM.

The dopamine D2 receptor is a principal target of antipsychotic and antiparkinsonian drugs, yet well-characterized fluorescent ligands for the D2 receptor remain scarce compared with its relative, the D3 receptor. Here we show that fluorescent ligands developed for the D3 subtype can be repurposed as tools for studying the D2 receptor pharmacology. Using a machine-learning-assisted, live-cell fluorescence microscopy assay, we screened twelve fluorescent probes and identified eight ligands that bound specifically to the D2 receptor at 10 nM. Four ligands exhibited classical saturable binding, yielding Kd in the nanomolar range, whereas the remaining probes displayed unsaturated, time-dependent binding profiles. Kinetic analyses revealed substantial differences in association and dissociation behavior, highlighting the importance of time-resolved measurements. Competition binding with dopamine and haloperidol yielded affinity estimates consistent with literature values. These results expand the toolkit of validated D2 receptor fluorescent probes and support cross-receptor repurposing as a strategy for fluorescent ligand development.

Light-gated K+ channelrhodopsins (KCRs) are recognized as an ideal neuronal silencing tool in optogenetics. KCRs contain functionally important residues for a light-driven H+ pump bacteriorhodopsin, but their roles have been unclear. Utilizing electrophysiological methods, we demonstrate that KCRs function as a light-driven H+ pump in the absence of K+. Transport experiments using pH electrodes further elucidated the function of the H+-pump, which operates even in the presence of K+. The hypothesis that the H+ pump exerts a blocking effect on K+ transport in KCRs has been postulated. Furthermore, we ascertained that there was conversion of KCRs from the H+ pump into the H+ channel by light, yet this conversion was never reversed. However, the addition of K+ resulted in the formation of the K+ channel. KCRs exhibit three distinct functional states, H+ pump, H+ channel, and K+ channel. These multifaceted functions are modulated by environmental ions and light.

Environmental microplastics and nanoplastics (MNPs) are emerging contaminants that accumulate in human tissues, including the brain, yet their mechanistic impact on the nervous system remains poorly understood. Converging postmortem evidence indicates increased MNP burden in brains from individuals with dementia, suggesting a potential link between plastic accumulation and disorders of the nervous system. However, whether MNPs directly contribute to brain aging and ensuing neurodegenerative processes, or disrupt neurodevelopment, is unknown. Here, we show that exposure to environmentally relevant MNPs induces cellular senescence and innate immune transcriptional programs in human brain organoids. Using region-specific cortical organoids, we demonstrate that synthetic polystyrene (PS), polyethylene terephthalate (PET), low-density polyethylene (LDPE), and high-density polyethylene (HDPE), as well as environmental ocean-derived MNPs (eMNPs) isolated from the coast of Hawaii, elicit a robust neuroinflammatory response. Transcriptomic analyses revealed activation of senescence-associated secretory phenotype (SASP) pathways. MNP exposure further disrupted neurodevelopmental trajectories, impairing neuroectodermal differentiation and redirecting lineage commitment toward mesoderm-like states, with concomitant enrichment of choroid plexus-like populations and a marked imbalance in neuronal and glial differentiation. These developmental alterations occurred in parallel with a pro-inflammatory and senescent microenvironment, suggesting coordinated disruption of developmental and aging programs. Importantly, high-density multielectrode array recordings revealed that MNP exposure altered electrophysiological activity and neuronal network dynamics, demonstrating that MNP-driven perturbations translate into dysfunctional neurological outcomes. Collectively, our findings identify MNPs as potent disruptors of human neurophysiology, linking plastic exposure to altered developmental trajectories, cellular senescence, neuroinflammation, and impaired neuronal network activity, providing mechanistic insights into how plastic accumulation may contribute to impaired brain dynamics.

Amyloid {beta}-protein (A{beta}), which is known for its role in Alzheimer's disease (AD), is also involved in several physiological functions. Of the two predominant isoforms, A{beta}40 and A{beta}42, the latter is more aggregation-prone and more active in health and disease. In the brain, A{beta} interacts with free lipids, which may affect its assembly pathways. Here, thioflavin T (ThT) fluorescence spectroscopy is combined with molecular dynamics (MD) to investigate A{beta}40 and A{beta}42 co-assembly with free dimyristoylphosphatidylcholine (DMPC) and DMPC/cholesterol (CHOL) lipids. ThT measurements at several protein-to-lipid (PL) ratios show isoform- and lipid composition-dependent kinetics of A{beta} fibril formation with clear isoform-dependent lipid effects at a PL ratio of 1:5. Early co-assembly stages of six A{beta}40/A{beta}42 with DMPC and DMPC/CHOL lipids at this PL ratio are then examined by MD. MD results indicate that lipids alter the secondary structure more and interact more avidly with A{beta}40 than with A{beta}42. In turn, A{beta}40 increases the planar order of lipid bicelles more than A{beta}42. Unlike A{beta}40, A{beta}42 decreases the nematic order of CHOL. In DMPC/CHOL lipids, A{beta}42 but not A{beta}40 exhibits two A{beta}-lipid interaction modes associated with mutually exclusive A{beta}42-lipid and A{beta}42-A{beta}42 interactions. Our MD findings provide a plausible explanation for an experimentally observed increase in the lag time for A{beta}40 fibril formation in DMPC lipids and even more so in DMPC/CHOL lipids that contrasts with much smaller effects of lipids on A{beta}42 fibril formation and offer additional atomistic-level insights into A{beta} co-assembly with lipids amenable to experimental testing.

Amyloid[beta]; (A[beta];) plaques are a hallmark of Alzheimer[prime]s disease (AD). A human cellular neuronal model that recaptures A[beta];-induced pathology is critical for advancing AD research. However, comprehensive proteomic profiling of A[beta];-induced cellular model remains elusive. In this study, we investigated the proteomic changes in induced pluripotent stem cell (iPSC)-derived neurons (iNs) exposed to synthetic A[beta]; (1-42) peptides (A[beta];42A) to improve our understanding of the cellular responses of A[beta]; aggregates and to establish a human-related platform for AD research. A[beta];42A formed extracellular aggregates around neuronal soma and neurites, impaired neurite outgrowth, and induced the expression of multiple AD-associated genes, such as APOE, BACE1, ADAM10. To define the molecular landscape of A[beta];-induced neuronal dysfunction, we performed proteomic analyses of whole-cell lysates as well as soma- and neurite-enriched fractions. Proteomic profiling revealed extensive gene alterations in pathways associated with synaptic function, neuronal maintenance, and AD pathogenesis, such as the upregulation of APOE. Importantly, the A[beta];42A-iNs system recapitulated molecular signatures observed in AD brain tissue and cerebrospinal fluid. Representative protein changes, including APOE upregulation and its colocalization with A[beta]; aggregates, were further validated in postmortem human AD brain tissue. Together, these findings manifest that the A[beta];42A-iNs system reproduces multiple cellular and molecular features of AD and exhibits strongly consensus with clinical observations. It provides a valuable platform for investigating A[beta];-driven neurodegeneration and for the discovery of therapeutic targets for AD.

Adolescence is characterized by increased novelty seeking, impulsivity, locomotion and risk-taking, behaviours that facilitate the transition to adulthood but may also increase vulnerability to psychiatric illness. Maturation of dopamine (DA) transmission within the striatum is thought to contribute to these behavioural changes. However, the developmental trajectory of striatal DA release remains unclear, with conflicting evidence regarding age- and sex-dependent changes, particularly across dorsal and ventral striatal regions. Complicating interpretation, many studies classify mice younger than 2 months as 'adults,' potentially obscuring important developmental differences. Here, we examined how age, sex and striatal subregion influence DA release during adolescence and early adulthood. DA release was measured in dorsal and ventral striatal brain slices from male and female C57BL/6J mice at 2 and 4 months of age, corresponding to adolescence and young adulthood. Ultrafast imaging of the genetically encoded DA sensor, dLight, was used to quantify extracellular DA transients evoked by low- and high-frequency electrical stimulation. Glutamatergic and cholinergic transmission was pharmacologically blocked to isolate DA release intrinsic to dopaminergic axons. DA release measures were related to exploratory and locomotor behaviour. We identified a male-specific increase in dorsal striatal DA release between 2 and 4 months of age that coincided with increased locomotion and risk-taking. In contrast, DA release in the ventral striatum did not show comparable age- or sex-dependent changes. These differences were not attributable to altered glutamatergic or cholinergic contributions to DA release. Together, these findings demonstrate that maturation of striatal DA transmission is region- and sex-dependent, with prominent developmental changes occurring in the dorsal striatum during the transition from adolescence to adulthood. These findings help reconcile conflicting reports of developmental DA release and emphasize the importance of considering age, sex and striatal subregion when defining mature dopaminergic function in rodents.

TWIK-related halothane-inhibited potassium channel 1 (THIK1) is a two-pore domain potassium (K2P) channel highly expressed in microglia that contributes to microglial homeostasis and neuroinflammatory responses. Pharmacological inhibition of THIK1 suppresses tonic K+ currents and attenuates NLRP3-dependent IL-1{beta} release, highlighting THIK1 as a potential therapeutic target for neuroinflammatory disorders. However, the structural basis of THIK1 inhibition remains unclear. Here we report cryo-electron microscopy (cryo-EM) structures of full-length human THIK1 in complex with C101248, a commercially available tool compound, and CVN293, a clinical-stage inhibitor that has completed Phase I evaluation. The two inhibitors occupy a similar site within the inner vestibule formed by TM2 and TM4 beneath the selectivity filter. Consistent with their closely related chemical scaffolds and shared binding site, both inhibitors remodel the Y273 inner gate but differ in their effects on the C-terminal gate. Electrophysiological analyses further demonstrate that the C-terminal gate contributes differently to inhibition by the two compounds. Together, our findings show how chemically related inhibitors exert different effects on THIK1 despite engaging a common binding site.

Experimental surgery is one of the most fundamental fields of biomedical research, recreating clinical conditions on living organisms similar to clinical patients, to facilitate the design of novel therapies. For modeling neurological and psychiatric disorders, the majority of operative techniques mandatorily include craniotomy for consecutive interactions with the open brain. The most wide-spread methodology involves stereotactic surgery in rodents, implementing a specific head holder, attached to the coordinate table, providing the precise animal head positioning according to the brain structures topology. Despite the high efficiency, such systems require complex instrumental skills and long procedure duration per animal even for simple implantation protocols. Hence, novel alternative model species could be a valuable supplementary tool for such manipulations. Therefore, the zebrafish (Danio rerio) fits perfectly, due to its low cost, easy husbandry, rapid development, optic transparency, and high genetic and physiological similarity to rodents and humans. Furthermore, the everted zebrafish telencephalon provides excellent accessibility to critical mammalian-like structures involved in emotion processing and cognition. However, conventional avian- or rodent-inspired craniotomies in adult zebrafish often trigger inadvertent disruption of the brain vessels network, resulting in high operative mortality. A novel, geometry-driven, non-lethal cranial window protocol preserving neurovascular integrity and ensuring 90-100% post-operative survival is presented to overcome above mentioned limitations. This rapid, simple, and high reproducible technique opens new avenues for precise region-specific in vivo neurosurgery, high-throughput psychopharmacological screening, and neurostimulation in a powerful non-mammalian model species

We have examined how ibogaine may enhance synaptic plasticity and neural repair. Extracellular efflux analysis showed that ibogaine (3, 10 or 30 M) produced a rapid (<5 minutes) and concentration-dependent suppression of mitochondrial function and glycolysis in mouse cortical neurons. Cell-based imaging demonstrated this metabolic inhibition was preceded by an elevation of the mitochondrial membrane potential and followed by increased mitochondrial reactive oxygen species levels. Like ibogaine, which blocks potassium channels, mitochondrial Kv1.3 channel (mitoKv1.3) inhibitors produce concordant changes over a similar timeframe. Following treatment with ibogaine (3, 10 or 30 M) for 4 hours, a marked concentration-dependent rebound of energy production occurred 20 hours later suggestive of metabolic preconditioning. Indeed, proteomic profiling showed that oral ibogaine (100 mg/kg) administration to female mice produced changes in spinal cord protein abundance indicative of increasing metabolic stress from 0.25-24 hours that resolved by 72 hours. This was accompanied by activation, inhibition and reactivation of synaptic plasticity and neural repair signaling pathways at 0.25, 4-24 and 72 hours, respectively. Hence, by inducing transient metabolic stress, ibogaine may re-open a neurodevelopmental window characterized by enhanced synaptic plasticity and neural repair. Ibogaine binds with high affinity to the sigma-2 receptor. Like mitoKv1-3 inhibitors and sigma-2 receptor ligands, ibogaine transiently elevated AMP-activated protein kinase (0.25 hours) and temporally suppressed mechanistic target of rapamycin and lipid synthesis pathways (0.25-24 hours) implicated in enhanced synaptic plasticity and neural repair. These findings suggest ibogaine rewires and repairs neural circuits by a metabolic preconditioning mechanism, perhaps involving mitoKv1.3 and the sigma-2 receptor.

Extracellular vesicles (EVs) play a critical role in the propagation of Tau pathology in Alzheimer's disease (AD). The selective identification and characterization of Tau seed-carrying EVs would help developing new diagnostic tools and therapeutic strategies. While pathogenic forms of Tau can be detected biochemically in EV-enriched fractions, only super-resolution fluorescence imaging provides both morphological and compositional information at the level of single EVs on account of their small size and the low number of target molecules. This was the object of our study. Post-mortem human brain-derived EVs from AD patients and non-demented control individuals were characterized in depth using biochemistry, transmission electron microscopy (TEM) and single molecule localization microscopy (SMLM). Dual-colour SMLM of immobilized EVs, displaying size distributions that were consistent with TEM, enabled statistically meaningful measurements of thousands of EVs in parallel. Owing to the high spatial resolution and capability of SMLM to detect sparse epitopes, we identified pathological Tau proteins in individual EVs from AD samples. Reconstructed super-resolution images of permeabilized EVs demonstrate that pathological Tau forms are frequent cargo proteins of EVs from AD brains. Our data illustrate the power of SMLM to determine the ultrastructure, molecular composition and topology of single EVs and EV populations.

Traumatic brain injury (TBI) is a risk factor for Alzheimer's disease (AD), and both conditions are associated with impaired glucose metabolism and mitochondrial dysfunction. We previously reported time-dependent mitochondrial dysfunction following closed-head injury (CHI) in amyloid precursor protein/presenilin 1 (APP/PS1) knock-in (KI) mice, but whether glucose-derived carbon labeling showed a corresponding temporal pattern remained unknown. We hypothesized that early deficits would involve tricarboxylic acid (TCA)-cycle metabolites, whereas chronic changes persisted upstream at the pyruvate-lactate branchpoint. Here, oral uniformly 13C-labeled glucose ([U-13C]-glucose) tracing and gas chromatography-mass spectrometry (GC-MS)-based isotopologue analysis were used to quantify first-turn glucose-derived carbon fate in cortex and hippocampus. To distinguish the effects of age at injury from those of post-injury interval, mice were analyzed 1 month after injury either at 7 or 12 months of age or 8 months after injury at 12 months of age. The most pronounced alterations occurred 8 months after CHI, when KI mice exhibited increased pyruvate and lactate labeling in the cortex and broader increases in glycolytic labeling in the hippocampus. These findings suggest that in APP/PS1 KI mice, chronic closed-head injury produced a delayed shift in glucose-derived carbon labeling centered on glycolytic and pyruvate/lactate nodes, with loss of hippocampal precursor-product coupling but without broad reduction of first-turn TCA-linked labeling.

Cannabis is one of the most widely consumed substances in the world. Consumers seek out cannabis cultivars with varying levels of phytocannabinoids, primarily delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The effects of THC, CBD or the combination of THC:CBD have distinct outcomes on cognitive processes, cellular functions, and phytocannabinoid pharmacokinetics. The majority of research on cannabis effects on the brain has focussed on neurons, and few studies have investigated the impact of different cannabis cultivars on glia. In particular, the impact of varying levels of THC:CBD on oligodendrocyte lineage cells, which play numerous support roles in the brain essential to proper neuronal communication, is relatively unknown. This study set out to examine the acute impact of different cultivars of vaporized cannabis on oligodendrocyte lineage cells in the forceps minor of adult male and female mice. Mice were exposed to vapor from cannabis flower high in THC, high in CBD or balanced in THC:CBD over 15 minutes, and brains were fixed 30 minutes post-cannabis onset. Using immunofluorescence microscopy, we observed significant changes to oligodendrocyte progenitor cell (OPC) morphology in mice exposed to balanced cannabis, and, using correlative light and electron microscopy, we observed alterations to OPC mitochondria. The alterations observed (i.e., enlarged soma and nucleus volume, reduced density and increased area of mitochondria in the soma) in OPCs due to balanced cannabis are reminiscent of the very early changes seen during OPC differentiation. This study highlights the differing effects of cannabis cultivars on OPCs and the rapidity of the OPC response to inhaled phytocannabinoids.

Polyamines are cationic metabolites that support critical cellular processes including transcription, translation, and cell proliferation. Although polyamine synthesis and transport are emerging therapeutic targets in human disease, the polyamine transport system remains poorly understood. ATP13A2-4 were recently identified as endolysosomal polyamine exporters, transporting putrescine (PUT), spermidine (SPD), and spermine (SPM) from the vesicular lumen to the cytosol. Despite interest in pharmacologically targeting these transporters, existing assays of transporter function rely on indirect or endpoint measures that cannot resolve transport as it occurs. Here, we report the first voltage-clamp recordings of polyamine transporter activity, directly detecting ATP13A2- and ATP13A3-mediated charge movement across cell membranes. When expressed in Xenopus oocytes, these transporters localized to the plasma membrane, enabling electrophysiological measurements. Polyamines induced inward currents dependent on transporter catalytic activity, and their dose-dependence correlated with ATPase assays. ATP13A2 currents were largest in response to SPM, whereas ATP13A3 currents were largest with PUT, consistent with their established substrate preferences. Polyamine-induced currents were blocked by the polyamine transport inhibitor AMXT-1501. These findings establish ATP13A2 and ATP13A3 as electrogenic polyamine pumps and demonstrate the utility of two-electrode voltage clamp as a label-free, transporter-resolved assay to complement other approaches in polyamine transporter-targeted drug discovery.

Liquid-liquid phase separation (LLPS) of biomacromolecules has been shown to influence a large variety of biological processes via the formation of membraneless organelles. Aberrant LLPS, however, has been implicated in a number of oncological and neurodegenerative disorders. Proteins related to Alzheimer's, Parkinson's diseases and other major amyloidoses have all been shown to form these condensates. Interestingly, some amyloidogenic proteins were demonstrated to form heterotypic droplets, where both molecules coexisted within the same condensate and affected each other's aggregation. While such cross-interactions have been reported numerous times under non-LLPS conditions, the heterotypic droplet assemblies were only shown for a very limited number of amyloidogenic proteins. In this work, we examine heterotypic LLPS of prion proteins and the pro-inflammatory S100A9, whose cross-interaction under non-LLPS conditions we confirmed in a previous work. The results show that this interaction under condensation-promoting conditions enhances their aggregation, leading to the formation of a higher concentration of amyloid structures. These findings suggest that the pro-inflammatory S100A9 may have a critical role in promoting prion protein aggregation via the assembly of heterotypic condensates under high molecular crowding conditions.

Tau amyloid fibrils adopt disease-specific structures across tauopathies, yet the sequence determinants that favor one pathological fold over another remain poorly defined. Here we combine computational saturation mutagenesis and energetic profiling, in vitro aggregation, cryo-EM and cellular seeding assays to identify sequence changes that alter tau fold compatibility. Across six tauopathy fibril structures, approximately 12,000 substitutions revealed that mutational sensitivity is concentrated within interaction networks formed by amyloidogenic motifs rather than uniformly distributed across the fibril core. Comparison of Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) folds identified residues within the 335-363 region that differentially influence fold compatibility. The S341L/S352I double mutant accelerated aggregation and remodeled packing within the PAM4-containing amyloidogenic region, producing an alternative amyloid architecture in a minimal tau fragment. S341L/S352I biosensors preferentially responded to CTE-derived over Alzheimer's disease-derived seeds, while aggregates generated from recombinant S341L/S352I tau exhibited CTE-like cellular templating behavior. Although these assemblies are not established to reproduce the atomic CTE fold, the results demonstrate that targeted sequence changes can bias tau aggregation and propagation toward a CTE-compatible state. This framework provides a strategy for defining sequence-structure relationships in polymorphic amyloids and developing conformation-selective models and biosensors.

NOS1AP is a genetically validated driver of tau pathology in Alzheimer's disease (AD), yet the NOS1AP-tau interaction itself has remained pharmacologically untargeted. We report CAPTOR-1, a first-in-class small molecule that disrupts this interaction by binding a pocket in the N-terminal region of NOS1AP (residues 1-126). A drug-resistant NOS1AP Y16A/F42A variant that retained tau binding but exhibited a 78-fold reduction in CAPTOR-1 affinity provides genetic evidence supporting an on-target mechanism. In human iPSC-derived neurons, CAPTOR-1 dose-dependently reduces endogenous NOS1AP-tau association, tau seeding activity, and pathogenic tau phosphorylation, phenocopying genetic NOS1AP knockdown; these effects extend to neurons from patients with sporadic AD. Orally dosed CAPTOR-1 crosses the blood-brain barrier and engages NOS1AP in brain dose-dependently. Chronic oral dosing rescues pathology, synaptic function, and memory in a tauopathy model (PS19) and an amyloidosis model (APP/PS1), sparing wild-type littermates in both. This work establishes pharmacological disruption of the NOS1AP-tau interaction as a viable, disease-modifying strategy for AD and positions CAPTOR-1 as a biomarker-ready chemical probe (pTau217, neurofilament light) for translational studies.

Psychoactive drugs profoundly alter consciousness, but the neural mechanisms by which they do so remain poorly understood. Global workspace theory may provide a framework for investigating these mechanisms. The global workspace, a candidate neural substrate of consciousness, is a set of brain regions that integrate and disseminate information to the rest of the brain. According to a recent model, the integrators, or 'gateways,' are characterized by synergistic interactions with other brain regions, while the disseminators, or 'broadcasters,' exhibit redundant interactions. Here, we measured the effects of various psychoactive drugs, including 'classic' psychedelics like LSD, mescaline, and psilocybin, 'atypical' psychedelics (entactogens) like MDMA, and the stimulant D-amphetamine, on the global workspace. In a secondary analysis of resting-state functional magnetic resonance imaging (fMRI) data on all these drugs, we found that classic psychedelics are associated with significant increases in the number of gateways in the frontoparietal control and dorsal attention networks. Meanwhile, MDMA and amphetamine reduced the number of gateways in the visual and somatomotor networks. The regional topographies of both synergy and redundancy distinguished classic psychedelics from other drugs. Finally, drugs producing similar changes in synergy and redundancy also produced similar profiles of subjective effects. Overall, our findings provide the first direct evidence that psychedelics may alter the synergistic and redundant interactions that characterize the global workspace of consciousness.