Neurotherapeutics最新文献

Alzheimer's disease (AD) is associated with memory and cognitive impairment caused by progressive degeneration of neurons. The events leading to neuronal death are associated with the accumulation of aggregating proteins in neurons and glia of the affected brain regions, in particular extracellular deposition of amyloid plaques and intracellular formation of tau neurofibrillary tangles. Moreover, the accumulation of pathological tau proteoforms in the brain concurring with disease progression is a key feature of multiple neurodegenerative diseases, called tauopathies, like frontotemporal dementia (FTD) where autosomal dominant mutations in the tau encoding MAPT gene provide clear evidence of a causal role for tau dysfunction. Observations from disease models, post-mortem histology, and clinical evidence have demonstrated that pathological tau undergoes abnormal post-translational modifications, misfolding, oligomerization, changes in solubility, mislocalization, and intercellular spreading. Despite extensive research, there are few disease-modifying or preventative therapeutics for AD and none for other tauopathies. Challenges faced in tauopathy drug development include an insufficient understanding of pathogenic mechanisms of tau proteoforms, limited specificity of agents tested, and inadequate levels of brain exposure, altogether underscoring the need for innovative therapeutic modalities. In recent years, the development of experimental therapeutic modalities, such as targeted protein degradation (TPD) strategies, has shown significant and promising potential to promote the degradation of disease-causing proteins, thereby reducing accumulation and aggregation. Here, we review all modalities of TPD that have been developed to target tau in the context of AD and FTD, as well as other approaches that with innovation could be adapted for tau-specific TPD.

Repulsive Guidance Molecule A (RGMa) is well-recognized for its role in axon guidance. Recent studies have unveiled its diverse functions under pathological conditions within the central nervous system, such as spinal cord injury, multiple sclerosis, and Parkinson's disease. In this study, we explored the involvement of RGMa and the therapeutic effects of an anti-RGMa neutralizing antibody in a mouse model of vascular dementia (VaD). The VaD mouse model was established using the bilateral common carotid artery stenosis (BCAS) method. Immunohistochemical analysis revealed that these mice exhibited increased RGMa expression in the hippocampus, which coincided with reduced neurogenesis and impaired cholinergic innervation. These alterations manifested as cognitive impairments in the BCAS mice. Significantly, treatment with anti-RGMa neutralizing antibody reversed these pathological changes and cognitive deficits. Our findings suggest that RGMa plays a pivotal role in VaD pathology within the hippocampus and propose the anti-RGMa antibody as a promising therapeutic avenue for treating VaD.

Non-invasive brain stimulation (NIBS) technology such as transcranial magnetic stimulation (TMS) represents a promising treatment for neuropathic pain. However, neural circuitries underlying analgesia remain to be established, which is largely limiting treatment responses. Using TMS and electroencephalogram co-registration (TMS-EEG), this study quantified the circuitry abnormalities in neuropathic pain and their associations with pain symptoms. A group of 21 neuropathic pain individuals and 21 healthy controls were assessed with TMS-EEG delivering to the primary motor cortex (M1). With source modelling, local current density and current propagation were analysed with significant current density (SCD) and scattering (SCS) respectively. The SCS and SCD data converged on higher activities in neuropathic pain individuals than healthy controls, within the emotional affective (perigenual anterior cingulate cortex, pgACC), sensory nociceptive (primary somatosensory cortex, S1), and the attentional cognitive (anterior insula, aINS; supracallosal anterior cingulate cortex, scACC) structures of pain. Moreover, current propagation to the pgACC was associated with lower pain-related negative emotions, while current propagation to the aINS with higher pain-related negative emotions. Using concurrent TMS-EEG, our data identified abnormal pain circuitries that could be utilised to improve treatment efficacy with brain stimulation technologies.

Parkinson's disease (PD) is a prevalent movement disorder characterized by mitochondrial dysfunction and dopaminergic neuronal loss in the substantia nigra of the midbrain. Currently, there are no effective treatments to cure or slow the progression of PD, highlighting an urgent need for new therapeutic strategies. Emerging evidence suggests that mesenchymal stem cells (MSCs) and fibroblast growth factor 21 (FGF21) are potential candidates for PD treatment. This study investigates a therapeutic strategy involving FGF21 delivered via mouse MSCs in the PD model of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and dopaminergic SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP⁺). FGF21-overexpressing MSCs were administered intranasally, either before or after MPTP treatment in mice. Intranasally delivered FGF21-overexpressing MSCs efficiently migrated to the injured substantia nigra, ameliorated MPTP-induced PD-like motor deficits, reinstated dopaminergic neurons in the substantia nigra and nerve terminals in the striatum, as well as normalized brain-derived neurotrophic factor (BDNF) and FGF21 levels. In contrast, MSCs not overexpressing FGF21 showed limited or no impact on these parameters. In a PD cellular model of MPP⁺-treated SH-SY5Y cells, FGF21-overexpressing MSCs showed enhanced PD cell viability. Treatment with conditioned medium from FGF21-overexpressing MSCs or exogenous FGF21 prevented cell death, reduced mitochondrial reactive oxygen species (ROS), and restored neuroprotective proteins, including phospho-Akt, BDNF, and Bcl-2. These findings indicate that intranasal delivery of FGF21-overexpressing MSCs holds promise as a potential PD therapy, likely through activating the Akt-BDNF-Bcl-2 pathway, normalizing mitochondrial dysfunction, and mitigating dopaminergic neurodegeneration. Further clinical investigations are essential to validate these promising findings.

Microglia play a dual role in neuroinflammatory disorders that affect millions of people worldwide. These specialized cells are responsible for the critical clearance of debris and toxic proteins through endocytosis. However, activated microglia can secrete pro-inflammatory mediators, potentially exacerbating neuroinflammation and harming adjacent neurons. TREM2, a cell surface receptor expressed by microglia, is implicated in the modulation of neuroinflammatory responses. In this study, we investigated if and how Dehydroervatamine (DHE), a natural alkaloid, reduced the inflammatory phenotype of microglia and suppressed neuroinflammation. Our findings revealed that DHE was directly bound to and activated TREM2. Moreover, DHE effectively suppressed the production of pro-inflammatory cytokines, restored mitochondrial function, and inhibited NLRP3 inflammasome activation via activating the TREM2/DAP12 signaling pathway in LPS-stimulated BV2 microglial cells. Notably, silencing TREM2 abolished the suppression effect of DHE on the neuroinflammatory response, mitochondrial dysfunction, and NF-κB/NLRP3 pathways in vitro. Additionally, DHE pretreatment exhibited remarkable neuroprotective effects, as evidenced by increased neuronal viability and reduced apoptotic cell numbers in SH-SY5Y neuroblastoma cells co-cultured with LPS-stimulated BV2 microglia. Furthermore, in our zebrafish model, DHE pretreatment effectively alleviated behavioral impairments, reduced neutrophil aggregation, and suppressed neuroinflammation in the brain by regulating TREM2/NF-κB/NLRP3 pathways after intraventricular LPS injection. These findings provide novel insights into the potent protective effects of DHE as a promising novel TREM2 agonist against LPS-induced neuroinflammation, revealing its potential therapeutic role in the treatment of central nervous system diseases associated with neuroinflammation.

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene encoding a mutant huntingtin (mHtt) protein. mHtt aggregates within neurons causing degeneration primarily in the striatum. There is currently a need for disease-modifying treatments for HD. Many therapeutic studies have focused on lowering mHtt levels by reducing its production or enhancing its clearance. One way to clear mHtt aggregates is to promote autophagy, which is disrupted in HD. Our previous studies showed that the small molecule p75 neurotrophin receptor (p75^NTR) ligand, LM11A-31, prevented HD-related neuropathologies and behavioral deficits in multiple HD mouse models. This study investigated whether modulating p75^NTR with LM11A-31, would reduce mHtt aggregates via autophagic/lysosomal mechanisms in HD models. LM11A-31 decreased mHtt aggregates in human neuroblastoma SH-SY5Y cells expressing mHtt (exon 1 with 74 CAG repeats) and in the striatum of R6/2 and zQ175dn mouse models of HD. The LM11A-31 associated decrease in mHtt aggregates in vitro was accompanied by increased autophagic/lysosomal activity as indicated by altered levels of relevant markers including p62/SQSTM1 and the lysosomal protease, mature cathepsin D, and increased autophagy flux. In R6/2 and/or zQ175dn striatum, LM11A-31 increased AMPK activation, normalized p62/SQSTM1 and LC3II levels, and enhanced LAMP1 and decreased LC3B association with mHtt. Thus, LM11A-31 reduces mHtt aggregates and may do so via engaging autophagy/lysosomal systems. LM11A-31 has successfully completed a Phase 2a clinical trial for mild-to-moderate Alzheimer's disease and our results here strengthen its potential as a candidate for HD clinical testing.

Inflammatory bowel disease (IBD) has the potential to induce neuroinflammation, which may increase the risk of developing neurodegenerative disorders. Ultrasound stimulation to the abdomen is a potential treatment for dextran sulfate sodium (DSS)-induced acute colitis. The present study aimed to investigate whether abdominal low-intensity pulsed ultrasound (LIPUS) can alleviate DSS-induced neuroinflammation through the microbiota-gut-brain axis. Male mice were fed DSS to induce ulcerative colitis. LIPUS stimulation was then applied to the abdomen at intensities of 0.5 and 1.0 ​W/cm². Mouse biological samples were analyzed, and behavior was evaluated. [¹⁸F]FEPPA PET/CT imaging was employed to track and quantify inflammation in the abdomen and brain. Changes in the gut microbiota composition were analyzed using 16S rRNA sequencing. Abdominal LIPUS significantly inhibited the DSS-induced inflammatory response, repaired destroyed crypts, and partially preserved the epithelial barrier. [¹⁸F]FEPPA accumulation in the colitis-induced neuroinflammation in the abdomen and specific brain regions significantly decreased after LIPUS treatment. LIPUS maintained intestinal integrity by increasing zonula occludens and occludin levels, reduced lipopolysaccharide-binding protein and lipopolysaccharide levels in the serum, and improved behavioral dysfunctions. Moreover, LIPUS, at an intensity of 0.5 ​W/cm², reshaped the gut microbiota in colitis-induced mice by increasing the relative abundance of the Firmicutes and decreasing the relative abundance of the Bacteroidota. Our findings demonstrated that abdominal LIPUS stimulation has the potential to be a novel therapeutic strategy to improve colitis-induced behavioral disorders through microbiota-gut-brain axis signaling.

Intrathecal drug administration represents a promising method to deliver biologics effectively to the central nervous system (CNS). However, little is known about the tolerability and pharmacokinetics of intrathecally applied antibodies. Hence, the focus of this study was to evaluate the toxicity, pharmacokinetic, and pharmacodynamic properties of an intrathecally administered human monoclonal antibody against the growth inhibitory CNS membrane protein Nogo-A in the non-human primate (NHP). The antibody was repeatedly injected into the lumbar cerebrospinal fluid (CSF) sack of NHPs, Macaca fascicularis (N ​= ​18), at three dose levels (placebo, 75 and 150 ​mg antibody/injection, n ​= ​6/group). CSF and serum samples were collected for pharmacokinetic analysis. The health status was constantly monitored to detect any treatment-related abnormalities. After sacrifice, the CNS tissues were evaluated by immunohistochemistry and biochemistry to study the antibody distribution and target interaction in the spinal cord and brain. No treatment-related side effects were observed, and the treatment was well tolerated by NHPs. After administration, the antibody was rapidly cleared from the CSF with a half-life of 6.4 ​h and accumulated in the serum where it showed a half-life of 13.7 days. The antibody distributed over the spinal cord and brain, penetrated into the CNS parenchyma where it bound to Nogo-A expressing neurons and oligodendrocytes, and induced significant (P ​< ​0.05) downregulation of the target antigen Nogo-A. Collectively, these results support the direct administration of therapeutic antibodies into the CSF and are of relevance for the antibody-based therapeutics currently in development for different CNS diseases.

Innate immunity protein interferon induced transmembrane protein 3 (IFITM3) is a transmembrane protein that has a wide array of functions, including in viral infections, Alzheimer's Disease (AD), and cancer. As an interferon stimulated gene (ISG), IFITM3's expression is upregulated by type-I, II, and III interferons. Moreover, the antiviral activity of IFITM3 is modulated by post-translational modifications. IFITM3 functions in innate immunity to disrupt viral fusion and entry to the plasma membrane as well as prevent viral escape from endosomes. As a γ-secretase modulatory protein, IFITM3 distinctly modulates the processing of amyloid precursor protein (APP) to generate amyloid beta peptides (Aβ) and Notch1 cleavages. Increased IFITM3 expression, which can result from aging, cytokine activation, inflammation, and infection, can lead to an upregulation of γ-secretase for Aβ production that causes a risk of AD. Therefore, the prevention of IFITM3 upregulation has potential in the development of novel therapies for the treatment of AD.