Neurobiology of Disease最新文献

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and progressive loss of motor neurons, leading to gradual paralysis and death within 2 to 5 years after diagnosis. The exact underlying pathogenic mechanism(s) remain elusive. This is particularly the case for sporadic ALS (sALS), representing 90 % of cases, as modelling a sporadic disease is extremely difficult. We used human induced pluripotent stem cell (hiPSC)-derived motor neurons from sALS patients to investigate early disease mechanisms. The earliest phenotype that we observed were profound axonal defects including impaired axonal transport, defective axonal outgrowth and a reduced formation of neuromuscular junctions. Transcriptomic profiling revealed significant dysregulation in axon guidance pathways, with upregulation of specific axonal regeneration-inhibiting genes, such as EphA4 and DCC in sALS motor neurons. Our findings suggest that dysregulation of axon guidance pathways contributes to axonal defects and that this could play a crucial role in the pathogenesis of sALS.

S100 calcium-binding protein A9 (S100A9, also known as calgranulin B) is expressed and secreted by myeloid cells under inflammatory conditions, and S100A9 can amplify inflammation. There is a large increase in S100A9 expression in the brains of patients with neurodegenerative diseases, such as Alzheimer's disease, and S100A9 has been suggested to contribute to neurodegeneration, but the mechanisms are unclear. Here we investigated the effects of extracellular recombinant S100A9 protein on microglia, neurons and synapses in primary rat brain neuronal-glial cell cultures. Incubation of cell cultures with 250-500 nM S100A9 caused neuronal loss without signs of apoptosis or necrosis, but accompanied by exposure of the "eat-me" signal - phosphatidylserine on neurons. S100A9 caused activation of microglial inflammation as evidenced by an increase in the microglial number, morphological changes, release of pro-inflammatory cytokines, and increased phagocytic activity. At lower concentrations, 10-100 nM S100A9 induced synaptic loss in the cultures. Depletion of microglia from the cultures prevented S100A9-induced neuronal and synaptic loss, indicating that neuronal and synaptic loss was mediated by microglia. These results suggest that extracellular S100A9 may contribute to neurodegeneration by activating microglial inflammation and phagocytosis, resulting in loss of synapses and neurons. This further suggests the possibility that neurodegeneration may be reduced by targeting S100A9 or microglia.

The adenosine triphosphate-binding cassette transporter A7 (ABCA7) gene is ranked as one of the top susceptibility loci for Alzheimer's disease (AD). While ABCA7 mediates lipid transport across cellular membranes, ABCA7 loss of function has been shown to exacerbate amyloid-β (Aβ) pathology and compromise microglial function. Our family-based study uncovered an extremely rare ABCA7 p.A696S variant that was substantially segregated with the development of AD in 3 African American families. Using the knockin mouse model, we investigated the effects of ABCA7-A696S substitution on amyloid pathology and brain immune response in 5xFAD transgenic mice. Importantly, our study demonstrated that ABCA7-A696S substitution reduces amyloid plaque-associated microgliosis and increases dystrophic neurites around amyloid deposits compared to control mice. We also found increased X-34-positive amyloid plaque burden in 5xFAD mice with ABCA7-A696S substitution, while there was no evident difference in insoluble Aβ levels between mouse groups. Thus, ABCA7-A696S substitution may disrupt amyloid compaction resulting in aggravated neuritic dystrophy due to insufficient microglia barrier function. In addition, we observed that ABCA7-A696S substitution disturbs the induction of proinflammatory cytokines interleukin 1β and interferon γ in the brains of 5xFAD mice, although some disease-associated microglia gene expression, including Trem2 and Tyrobp, are upregulated. Lipidomics also detected higher total lysophosphatidylethanolamine levels in the brains of 5xFAD mice with ABCA7-A696S substitution than controls. These results suggest that ABCA7-A696S substitution might compromise the adequate innate immune response to amyloid pathology in AD by modulating brain lipid metabolism, providing novel insight into the pathogenic mechanisms mediated by ABCA7. ONE SENTENCE SUMMARY: A rare Alzheimer's disease risk ABCA7 p.A696S variant compromises microglial response to amyloid pathology.

RNA binding protein dysfunction is a pathogenic feature of multiple neurological diseases, including multiple sclerosis (MS). Neurodegeneration (the loss of, or damage to neurons and axons) is the primary driver of disease progression in MS. Herein, we utilized a novel, neuron-specific model of neurodegeneration by transducing primary mouse neurons with mutant forms of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) identified from MS patients, including one within the M9-nuclear localization sequence of hnRNP A1 (A1(P275S)) and a second in the prion-like domain of hnRNP A1 (A1(F263S)) to test the hypothesis that neuronal hnRNP A1 dysfunction drives neurodegeneration in MS. Examination of hnRNP A1 localization in neurons revealed an increase in nucleocytoplasmic mislocalization in neurons transduced with A1(P275S), but not A1(F263S). Yet, both A1(F263S) and A1(P275S) induced neurodegeneration evidenced by significant reductions in total neurite length and complexity and an increase in FluoroJade-C neuronal cell body staining. RNA sequencing and differential alternative splicing analysis of mutant-expressing neurons revealed dramatic changes in alternative RNA splicing of transcripts critical to neuronal function. Further, amyloid precursor protein (APP), a marker for neurodegeneration in MS, showed differential splicing in mutant-expressing neurons, which was confirmed in MS brains with hnRNP A1 dysfunction. Overall, we have identified that hnRNP A1 plays a complex role in neuronal function and regulation by mediating the alternative splicing of neuron-specific transcripts. When neuronal hnRNP A1 function is impaired, as in disease, resultant dysfunction propagates through multiple pathways that may influence the progression of neurodegeneration in MS.

A-kinase anchoring protein 79/150 (AKAP79/150) is a crucial scaffolding protein that positions various proteins at specific synaptic sites to modulate excitatory synaptic intensity. As our understanding of AKAP79/150's biology deepens, along with its significant role in the pathophysiology of various human disorders, there is growing evidence that reveals new opportunities for therapeutic interventions. In this review, we examine the fundamental structure and primary functions of AKAP79/150, emphasizing its pathophysiological mechanisms in different nervous system disorders, particularly inflammatory pain, epilepsy, depression, and Alzheimer's disease. We also discuss its potential therapeutic implications for patients suffering from these conditions.

The consequences of non-pathogenic huntingtin (HTT) reduction in the mature brain are of substantial importance as clinical trials for numerous HTT-lowering therapies are underway; many of which are non-selective in that they reduce both mutant and wild type protein variants. In this study, we injected CaMKII-promoted AAV-Cre directly into the hippocampus of adult HTT floxed mice to explore the role of wild-type huntingtin (wtHTT) in adult hippocampal pyramidal neurons and the broader implications of its loss. Our findings reveal that wtHTT depletion results in profound macroscopic morphological abnormalities in hippocampal structure, accompanied by significant reactive gliosis. At the synaptic level, we identified a marked reduction in presynaptic terminals 1-2 months following wtHTT loss; this was contrasted by an increased density of postsynaptic mushroom spines and larger amplitudes of spontaneous excitatory postsynaptic currents, indicative of disrupted synaptic homeostasis. Furthermore, intrinsic neuronal excitability was significantly diminished in CA1 pyramidal neurons lacking wtHTT, and we observed a complete loss of NMDA receptor-dependent long-term potentiation. Unexpectedly, synapse density returned to control levels 6-8 months following wtHTT loss, despite the ongoing presence of macroscopic morphological abnormalities, altered anxiety-related behaviors and clear impairments in spatial learning and memory. Overall, these findings uncover a previously unrecognized role of wtHTT as a critical regulator of hippocampal function in the mature brain, and highlight the hippocampus as a potentially vulnerable region to the adverse effects of non-selective HTT reduction.

Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are more prevalent in males than females. Furthermore, they typically showed abnormally high delta (< 4 Hz) and low alpha (8-10 Hz) rhythms from resting-state electroencephalographic (rsEEG) activity. Here, we hypothesized that those abnormalities may depend on the patient's sex. An international database provided clinical-demographic-rsEEG datasets for cognitively unimpaired older (Healthy; N = 49; 24 females), PDD (N = 39; 13 females), and DLB (N = 38; 15 females) participants. Each group was stratified into matched female and male subgroups. The rsEEG rhythms were investigated across the individual rsEEG delta, theta, and alpha frequency bands based on the individual alpha frequency peak. The eLORETA freeware was used to estimate cortical rsEEG sources. In the Healthy group, widespread rsEEG alpha source activities were greater in the females than in the males. In the PDD group, widespread rsEEG delta source activities were lower and widespread rsEEG alpha source activities were greater in the females than in the males. In the DLB group, central-parietal rsEEG delta source activities were lower, and posterior rsEEG alpha source activities were greater in the females than in the males. These results suggest sex-dependent hormonal modulation of neuroprotective-compensatory neurophysiological mechanisms in PDD and DLB patients underlying the generation of rsEEG delta and alpha rhythms, which should be considered in the treatment of vigilance dysregulation in those patients.

Central nervous system (CNS) repair after injury is a challenging process limited by inflammation and neuronal apoptosis. This study identifies Wilms' tumor 1-associating protein (WTAP) as a pivotal regulator of neuronal protection and repair through m6A methylation of STAT3 mRNA. By employing spinal cord injury (SCI) as a representative model of CNS injury, transcriptomic analyses reveal WTAP as a key mediator of pathways related to neuronal autophagy and inflammation regulation. WTAP enhances neuronal autophagy by suppressing STAT3 expression and activity, which inhibits the NLRP3 inflammatory pathway. Functional studies demonstrate that WTAP knockdown exacerbates neuronal apoptosis, whereas overexpression improves cell viability, autophagy, and motor recovery. In vivo, WTAP promotes SCI repair via m6A-mediated suppression of STAT3 and regulation of the NLRP3 signaling pathway, highlighting its therapeutic potential for CNS injury repair.

Addiction is a chronic and severe mental disorder with high gender- and sex-specificity. However, the pathogenesis of this disorder is not fully elucidated, and no targeted pharmacotherapy is available. A growing body of evidence points out the potential involvement of the ceramide system in the pathophysiology of addiction. A pathogenic pathway for several mental disorders based on the overexpression of an enzyme involved in ceramide formation, acid sphingomyelinase (ASM), was recently proposed. Here we show a crucial role of ASM specifically overexpressing in the forebrain for various types of addiction-related behaviours in a drug- and sex-specific way. In male mice, a forebrain ASM overexpression led to enhanced alcohol consumption in a free-choice paradigm. It also diminished the reinforcing properties of alcohol and cocaine, but not that of amphetamine, ketamine, or a natural reinforcer fat/carbohydrate-rich food in the conditioned place preference (CPP) test in males. In female mice, a forebrain ASM overexpression enhanced alcohol binge-like drinking, while moderate alcohol consumption was preserved. ASM overexpression in females contributed to CPP establishment for amphetamine, but not for other psychoactive substances. Altogether, this study shows a specific involvement of forebrain ASM in the development of conditioned reinforcing effects of different types of substances with addictive properties in a sex-specific way. Our data enlarge the current knowledge on the specific molecular mechanisms of dependence from various drugs of abuse and might serve as a basis for the development of drug- and sex-specific targeted therapy.

Chronic itch remains a clinically challenging condition with limited therapeutic efficacy, posing a significant burden on patients' quality of life. Despite its prevalence, the underlying neural mechanisms remain poorly understood. In this study, we explored the synaptic relationships between neuropeptide Y (NPY) neurons and gastrin-releasing peptide receptor (GRPR) neurons in the spinal cord. Our findings reveal a direct synaptic connection whereby Npy neurons provide inhibitory modulation to Grpr neurons. Notably, during chronic itch, the activity of Grpr neurons was significantly elevated, coinciding with a decrease in Y1 receptor expression and a reduction in both the frequency and amplitude of inhibitory postsynaptic currents (IPSCs). These results suggest a decline in NPY/Y1R system function during chronic itch, leading to a decreased inhibitory influence of Npy neurons on Grpr neurons and subsequent disinhibition and excitation of the latter. This disinhibitory mechanism may underlie the enhanced responsiveness to mechanical and chemical itch stimuli in chronic itch patients.