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Kinases are an intensively studied drug target class in current pharmacological research as evidenced by the large number of kinase inhibitors being assessed in clinical trials. Kinase-targeted therapies have potential for treatment of a broad array of indications including central nervous system (CNS) disorders. In addition to the many variables which contribute to identification of a successful therapeutic molecule, drug discovery for CNS-related disorders also requires significant consideration of access to the target organ and specifically crossing the blood-brain barrier (BBB). To date, only a small number of kinase inhibitors have been reported that are specifically designed to be BBB permeable, which nonetheless demonstrates the potential for success. This review considers the potential for kinase inhibitors in the context of unmet medical need for neurodegenerative disease. A subset of kinases that have been the focus of clinical investigations over a ten-year period have been identified and discussed individually. For each kinase target, the data underpinning the validity of each in the context of neurodegenerative disease is critically evaluated. Selected molecules for each kinase are identified with information on modality, binding site and CNS penetrance, if known. Current clinical development in neurodegenerative disease are summarized.

Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release of IL-1β. Extracellular ATP is a strong activator of NLRP3 by inducing K + efflux as a key signaling event, suggesting that K + -permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K + channels and P2X7 receptors, but their interactions and potential therapeutic role in the human brain are unknown. Using a novel specific inhibitor of THIK-1 in combination with patch-clamp electrophysiology in slices of human neocortex, we found that THIK-1 generated the main tonic K + conductance in microglia that sets the resting membrane potential. Extracellular ATP stimulated K + efflux in a concentration-dependent manner only via P2X7 and metabotropic potentiation of THIK-1. We further demonstrated that activation of P2X7 was mandatory for ATP-evoked IL-1β release, which was strongly suppressed by blocking THIK-1. Surprisingly, THIK-1 contributed only marginally to the total K + conductance in the presence of ATP, which was dominated by P2X7. This suggests a previously unknown, K + -independent mechanism of THIK-1 for NLRP3 activation. Nuclear sequencing revealed almost selective expression of THIK-1 in human brain microglia, while P2X7 had a much broader expression. Thus, inhibition of THIK-1 could be an effective and, in contrast to P2X7, microglia-specific therapeutic strategy to contain neuroinflammation. Graphical Abstract

One of the most recently identified serotonin (5-hydroxytryptamine (5-HT)) receptor subtypes is the 5-HT 6 receptor. Although in-depth localization studies reveal an exclusive distribution of 5-HT 6 mRNA in the central nervous system, the precise biological role of this receptor still remains unknown. In the present series of experiments, we report the pharmacological and neurochemical characterization of two novel and selective 5-HT 6 receptor agonists. WAY-181187 and WAY-208466 possess high affinity binding (2.2 and 4.8 nM, respectively) at the human 5-HT 6 receptor and profile as full receptor agonists (WAY-181187: EC 50 =6.6 nM, E max =93%; WAY-208466: EC 50 =7.3 nM; E max =100%). In the rat frontal cortex, acute administration of WAY-181187 (3–30 mg/kg, subcutaneous (s.c.)) significantly increased extracellular GABA concentrations without altering the levels of glutamate or norepinephrine. Additionally, WAY-181187 (30 mg/kg, s.c.) produced modest yet significant decreases in cortical dopamine and 5-HT levels. Subsequent studies showed that the neurochemical effects of WAY-181187 in the frontal cortex could be blocked by pretreatment with the 5-HT 6 antagonist, SB-271046 (10 mg/kg, s.c.), implicating 5-HT 6 receptor mechanisms in mediating these responses. Moreover, the effects of WAY-181187 on catecholamines were attenuated by an intracortical infusion of the GABA A receptor antagonist, bicuculline (10 μM), confirming a local relationship between 5-HT 6 receptors and GABAergic systems in the frontal cortex. In the dorsal hippocampus, striatum, and amygdala, WAY-181187 (10–30 mg/kg, s.c.) elicited robust elevations in extracellular levels of GABA without producing similar effects on concentrations of norepinephrine, serotonin, dopamine, or glutamate. In contrast to these brain regions, WAY-181187 had no effect on the extracellular levels of GABA in the nucleus accumbens or thalamus. Additional studies showed that WAY-208466 (10 mg/kg, s.c.) preferentially elevated cortical GABA levels following both acute and chronic (14 day) administration, indicating that neurochemical tolerance does not develop following repeated 5-HT 6 receptor stimulation. In hippocampal slice preparations ( in vitro ), 5-HT 6 receptor agonism attenuated stimulated glutamate levels elicited by sodium azide and high KCl treatment. Furthermore, in the rat schedule-induced polydipsia model of obsessive compulsive disorder (OCD), acute administration of WAY-181187 (56–178 mg/kg, po) decreased adjunctive drinking behavior in a dose-dependent manner. In summary, WAY-181187 and WAY-208466 are novel, selective, and potent 5-HT 6 receptor agonists displaying a unique neurochemical signature in vivo . Moreover, these data highlight a previously undescribed role for 5-HT 6 receptors to modulate basal GABA and stimulated glutamate transmission, as well as reveal a potential therapeutic role for this receptor in the treatment of some types of anxiety-related disorders (eg OCD).

Inflammation is considered a mechanistic driver of Alzheimer's disease, thought to increase tau phosphorylation, the first step to the formation of neurofibrillary tangles (NFTs). To further understand how inflammation impacts the development of tau pathology, we used (hTau) mice, which express all six, non-mutated, human tau isoforms, but with an altered ratio of tau isoforms favoring 3R tau due to the concomitant loss of murine tau (mTau) that is predominantly 4R. Such an imbalance pattern has been related to susceptibility to NFTs formation, but whether or not this also affects susceptibility to systemic inflammation and related changes in tau phosphorylation is not known. To reduce the predominance of 3R tau by increasing 4R tau availability, we bred hTau mice on a heterozygous mTau background and compared the impact of systemic inflammation induced by lipopolysaccharide (LPS) in hTau mice hetero- or homozygous mTau knockout. Three-month-old male wild-type (Wt), mTau , mTau , hTau/mTau , and hTau/mTau mice were administered 100, 250, or 330 μg/kg of LPS or its vehicle phosphate buffer saline (PBS) [intravenously ( .), = 8-9/group]. Sickness behavior, reflected by behavioral suppression in the spontaneous alternation task, hippocampal tau phosphorylation, measured by western immunoblotting, and circulating cytokine levels were quantified 4 h after LPS administration. The persistence of the LPS effects (250 μg/kg) on these measures, and food burrowing behavior, was assessed at 24 h post-inoculation in Wt, mTau , and hTau/mTau mice ( = 9-10/group). In the absence of immune stimulation, increasing 4R tau levels in hTau/mTau exacerbated pS202 and pS396/404 tau phosphorylation, without altering total tau levels or worsening early behavioral perturbations characteristic of hTau/mTau mice. We also show for the first time that modulating 4R tau levels in hTau mice affects the response to systemic inflammation. Behavior was suppressed in all genotypes 4 h following LPS administration, but hTau/mTau exhibited more severe sickness behavior at the 100 μg/kg dose and a milder behavioral and cytokine response than hTau/mTau mice at the 330 μg/kg dose. All LPS doses decreased tau phosphorylation at both epitopes in hTau/mTau mice, but pS202 levels were selectively reduced at the 100 μg/kg dose in hTau/mTau mice. Behavioral suppression and decreased tau phosphorylation persisted at 24 h following LPS administration in hTau/mTau mice.

Ataxia–telangiectasia (A–T) is a rare, autosomal recessive, multisystem disorder caused by mutations in the Ataxia–Telangiectasia Mutated (ATM) gene and is characterized by a devastating and progressive neurological pathology. The cellular and molecular changes driving the neurological abnormalities associated with A-T are not well understood. Here, we applied our proprietary Nuclear Enriched Transcript Sort sequencing (NETSseq) platform to investigate changes in cell type composition and gene expression in human cerebellar post-mortem tissue from A-T and control donors. We found dysregulation in neurotransmitter signaling in granule neurons, potentially underlying the impaired motor coordination in A-T. Astrocytes and microglia have evidence of accelerated aging, with astrocytes being characterized by neurotoxic signatures, while microglia showed activation of DNA damage response pathways. Compared to single-nuclei technologies, NETSseq provided a more robust detection of genes with low abundance, a higher cell type specific expression pattern, and significantly lower levels of cross-contamination. These findings highlight the importance of NETSseq as a resource for investigating mechanisms and biological processes associated with disease, providing high-sensitivity, cell-specific insights to advance targeted therapies for neurodegenerative diseases.

Rationale Prefrontal cortex (PFC)-dependent executive function is disrupted in a range of psychiatric disorders and can be modelled in non-human primates and rodents using attentional set-shifting paradigms. There are few current pharmacological strategies for enhancing attentional set shifting, although the PFC is rich in relevant neurotransmitter targets, including 5 - hydroxytryptamine (5-HT). Although 5-HT depletion studies do not support a role for 5-HT in attentional set shifting, the effect of 5-HT activation using specific receptor agonists has not been tested. Objectives and methods This study investigated the effect of a novel, selective 5-HT 6 receptor agonist, WAY181187, in a rat model of PFC-dependent extra-dimensional (ED) attentional set shifting. The effect of this agent on immediate early gene expression in the medial PFC and other regions was also examined. Results Compared to vehicle-injected controls, WAY181187 facilitated ED set shifting but did not change other non-ED phases of the task (including intra-dimensional set shifting and reversal). This effect was blocked by the selective 5-HT 6 antagonist SB399885, which alone had no effect. WAY181187 enhanced ED set shifting even when administered after the attentional set had been acquired, thereby ruling out impairments in attentional set formation. In separate experiments, at a dose that increased ED set shifting, WAY181187 increased Fos-like immunoreactivity in the medial PFC in a SB399885-sensitive manner, suggesting a 5-HT 6 receptor-mediated activation of this region. Conclusions Through use of a novel 5-HT agonist, these experiments reveal a previously unrecognised role for 5-HT activation in PFC-dependent executive function, mediated by 5-HT 6 receptor activation.

Since the G8 dementia summit in 2013, a number of initiatives have been established with the aim of facilitating the discovery of a disease-modifying treatment for dementia by 2025. This report is a summary of the findings and recommendations of a meeting titled “Tackling gaps in developing life-changing treatments for dementia”, hosted by Alzheimer's Research UK in May 2018. The aim of the meeting was to identify, review, and highlight the areas in dementia research that are not currently being addressed by existing initiatives. It reflects the views of leading experts in the field of neurodegeneration research challenged with developing a strategic action plan to address these gaps and make recommendations on how to achieve the G8 dementia summit goals. The plan calls for significant advances in (1) translating newly identified genetic risk factors into a better understanding of the impacted biological processes; (2) enhanced understanding of selective neuronal resilience to inform novel drug targets; (3) facilitating robust and reproducible drug-target validation; (4) appropriate and evidence-based selection of appropriate subjects for proof-of-concept clinical trials; (5) improving approaches to assess drug-target engagement in humans; and (6) innovative approaches in conducting clinical trials if we are able to detect disease 10–15 years earlier than we currently do today.

There is a growing body of evidence suggesting that animal models can be developed to probe the specific domains of bipolar disorder (BD) using the endophenotype approach. Here we tested clinically active antimanic drugs to validate amphetamine-induced hyperactivity in Black Swiss mice as a putative model of the manic phase of BD. We also co-administered a mood stabilizer and an atypical antipsychotic drug in a manner akin to the clinical treatment regimens. Since lithium has been shown to potentially act through glycogen synthase kinase-3 (GSK3) inhibition, we evaluated the efficacy of selective GSK3 inhibitors in this model. Habituated animals were pretreated with a compound of interest before being challenged with amphetamine (2.0 mg/kg) and returned to activity cages for an additional 1.5 h. We tested lithium, sodium valproate, carbamazepine, olanzapine, ziprasidone as well as co-administered lithium and olanzapine at sub-efficacious doses. The GSK3 inhibitors tested included indirubin, alsterpaullone, TDZD-8, AR-A014418, SB-216763, and SB-627772. All mood stabilizers and antipsychotic drugs reduced hyperactivity without affecting spontaneous locomotion. While subactive doses of lithium and olanzapine were without effect, their co-administration produced robust reductions in hyperactivity. All GSK3 inhibitors were active in the model, producing selective inhibition of rearing hyperactivity. These data support the predictive validity of the model for the acute manic phase of BD and may have utility as an in-vivo model for identifying novel antimanic therapeutics.

Sporadic Alzheimer's disease (AD) is a complex and heterogenous condition, posing challenges for the development of effective therapeutics. A detailed molecular understanding of how specific brain cell types change throughout disease progression can help unravel this complexity, revealing common mechanisms of disease pathophysiology and identifying potential targets for therapeutic intervention. Cerevance's proprietary technology platform, NETSseq, enables deep gene expression (>12,000 genes detected) and paired epigenetic profiling of specific cell types from post-mortem human brain By applying NETSseq to brain tissue from control, early-, and late-sporadic AD donors, a comprehensive dataset consisting of diverse neuronal and glial cell type profiles has been generated, including a set of astrocyte RNA-seq and ATAC-seq samples. Correlative analysis of paired RNA-seq and ATAC-seq data enables the identification of putative genome regulatory regions and their corresponding regulated genes within each cell type. Analysis of control and AD astrocyte samples has revealed numerous chromatin and gene expression changes associated with disease progression, with further analysis revealing the interplay between these changes. Finally, linking these paired datasets with published GWAS AD data, both reproduces previously identified genetic associations, and reveals novel, genetically validated targets with astrocyte-specific mechanisms of action. Along with generating highly reproducible molecular profiles from specific CNS cell types, NETSseq enables the understanding of temporal dynamics of chromatin and gene expression changes across disease progression, thereby identifying relevant pathways and genes to target as novel therapeutic strategies.

CVN293 is a novel, investigational, small molecule inhibitor of the two-pore domain potassium channel KCNK13. KCNK13 is selectively expressed in microglia and mediates the potassium efflux required for activation of the NLRP3 inflammasome complex. NLRP3-mediated inflammation has been identified as a central mediator of neuroinflammation in neurodegenerative diseases. Through inhibition of KCNK13 and microglial proinflammatory processes, CVN293 has the potential to dampen neuroinflammation across neurodegenerative diseases. This Phase 1 single/multiple ascending dose (SAD/MAD) study investigated the safety, tolerability and pharmacokinetics of orally administered CVN293 in healthy subjects. Following a randomized, double-blind and placebo-controlled design, subjects received either CVN293 or placebo with SAD cohorts receiving single doses up to 1000mg (all fasted; 150mg was also tested under fed conditions). MAD cohorts received repeated doses over 14 days, up to 750mg (375mg twice daily). CSF sampling was conducted in both SAD and MAD cohorts. CVN293 was generally well-tolerated following single and 14-day multiple dosing and all subjects completed the treatment period. There were no severe or dose-limiting adverse events (AEs), treatment-related discontinuations, or clinically meaningful changes in vital signs or laboratory parameters. All related AEs were considered mild. In both the SAD and MAD phases, CVN293 plasma exposure increased in a generally dose proportional manner. Penetrance of CVN293 into the cerebrospinal fluid (CSF) was demonstrated in both the SAD (150mg) and MAD (150mg, 75mg twice daily) studies. This Phase 1 study demonstrated a favourable tolerability profile for CVN293 in healthy adults and supports the continued development of this novel KCNK13 inhibitor for neurodegenerative diseases driven by neuroinflammation.