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The short-chain fatty acid butyrate prevents gut-brain amyloid-β pathology and neuroinflammation in an Alzheimer mouse model.
Amyloid-β (Aβ) plays a critical role in Alzheimer's disease (AD) and its accumulation in the brain is pivotal to disease progression and precedes memory and neuronal loss. Besides the severely handicapping brain symptoms, AD patients display early gastro-intestinal (GI) manifestations such as upper and lower GI dysmotility, in particular constipation. Although there is increasing evidence of Aβ accumulation in the gut, its pathogenic effects on enteric nervous system (ENS) connectivity and gut function as well as underlying pathophysiological mechanisms are poorly understood. Furthermore, studies have reported a gut to brain transmission of Aβ that causes memory deficits in mice. Therefore, identifying therapeutics which can reduce Aβ accumulation in the gut at an early stage of the disease could have the advantage of slowing or even reversing disease progression before severe alterations or irreversible damages at both intestinal and brain levels. Hence, in this study, we investigated the capacity of the short-fatty acid butyrate to restore Aβ-driven alteration of ENS connectivity and gut-brain functions in the SAMP8 mouse model of AD. Here we show that SAMP8 mice display a gut amyloid pathology, an alteration of ENS connectivity and gut defects prior to memory decline. BACE1, an Aβ-producing enzyme, expression and activity are increased whereas neprilysin, an Aβ-degrading enzyme, is decreased in the gut of SAMP8 mice, indicating a rise in the Amyloid Precursor Protein (APP) holoprotein processing and a reduction of Aβ clearance which promote an amyloidosis. In primary ENS cultures, Aβ causes a degradation of synaptic-associated proteins EphB2 and synaptophysin, leading to an alteration of ENS connectivity. In wild-type mice, intra-colon delivery of Aβ alters ENS connectivity and causes subsequent GI symptoms, recapitulating the phenotype of the SAMP8 mouse model of aging and AD. Moreover, Aβ impairs ENS connectivity in human induced pluripotent stem cell (iPSC)-derived intestinal organoids and explant cultures of human colon, indicating that Aβ causes ENS lesions in models of the human gut. Butyrate, a short-chain fatty acid derived from bacterial metabolism, reduces Aβ secretion and preserves enteric neuronal connectivity in vitro and in vivo, and blocks Aβ accumulation in the gut, brain and plasma in SAMP8 mice. In addition, butyrate ameliorates neuroinflammation and prevents gut dysfunction and memory deficit. Collectively, these findings suggest that Aβ promotes gut symptoms through alteration of ENS connectivity and butyrate counteracts these impairments with an amelioration of neuroinflammation and memory function in AD model.
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The N6-Methyladenosine-Modified Pseudogene HSPA7 Correlates With the Tumor Microenvironment and Predicts the Response to Immune Checkpoint Therapy in Glioblastoma.
BACKGROUND: Glioblastoma (GBM), one of the most aggressive tumors of the brain, has no effective or sufficient therapies. Identifying robust biomarkers for the response to immune checkpoint blockade (ICB) therapy, a promising treatment option for GBM patients, is urgently needed. METHODS: We comprehensively evaluated lncRNA m6A modification patterns in m6A-sequencing (m6A-seq) data for GBM tissues and systematically investigated the immune and stromal regulators of these m6A-regulated lncRNAs. We used the single-sample gene-set enrichment analysis (ssGSEA) algorithm to investigate the difference in enriched tumor microenvironment (TME) infiltrating cells and the functional annotation of HSPA7 in individual GBM samples. Further, we validated that HSPA7 promoted the recruitment of macrophages into GBM TME in vitro, as well as in our GBM tissue section. We also explored its impact on the efficacy of ICB therapy using the patient-derived glioblastoma organoid (GBO) model. RESULTS: Here, we depicted the first transcriptome-wide m6A methylation profile of lncRNAs in GBM, revealing highly distinct lncRNA m6A modification patterns compared to those in normal brain tissues. We identified the m6A-modified pseudogene HSPA7 as a novel prognostic risk factor in GBM patients, with crucial roles in immunophenotype determination, stromal activation, and carcinogenic pathway activation. We confirmed that HSPA7 promoted macrophage infiltration and SPP1 expression via upregulating the YAP1 and LOX expression of glioblastoma stem cells (GSCs) in vitro and in our clinical GBM tumor samples. We also confirmed that knockdown of HSPA7 might increase the efficiency of anti-PD1 therapy utilizing the GBO model, highlighting its potential as a novel target for immunotherapy. CONCLUSIONS: Our results indicated that HSPA7 could be a novel immunotherapy target for GBM patients.
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Brain Organoids: Filling the Need for a Human Model of Neurological Disorder.
Neurological disorders are among the leading causes of death worldwide, accounting for almost all onsets of dementia in the elderly, and are known to negatively affect motor ability, mental and cognitive performance, as well as overall wellbeing and happiness. Currently, most neurological disorders go untreated due to a lack of viable treatment options. The reason for this lack of options is s poor understanding of the disorders, primarily due to research models that do not translate well into the human in vivo system. Current models for researching neurological disorders, neurodevelopment, and drug interactions in the central nervous system include in vitro monolayer cell cultures, and in vivo animal models. These models have shortcomings when it comes to translating research about disorder pathology, development, and treatment to humans. Brain organoids are three-dimensional (3D) cultures of stem cell-derived neural cells that mimic the development of the in vivo human brain with high degrees of accuracy. Researchers have started developing these miniature brains to model neurodevelopment, and neuropathology. Brain organoids have been used to model a wide range of neurological disorders, including the complex and poorly understood neurodevelopmental and neurodegenerative disorders. In this review, we discuss the brain organoid technology, placing special focus on the different brain organoid models that have been developed, discussing their strengths, weaknesses, and uses in neurological disease modeling.
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Chromatin establishes an immature version of neuronal protocadherin selection during the naive-to-primed conversion of pluripotent stem cells.
In the mammalian genome, the clustered protocadherin (cPCDH) locus provides a paradigm for stochastic gene expression with the potential to generate a unique cPCDH combination in every neuron. Here we report a chromatin-based mechanism that emerges during the transition from the naive to the primed states of cell pluripotency and reduces, by orders of magnitude, the combinatorial potential in the human cPCDH locus. This mechanism selectively increases the frequency of stochastic selection of a small subset of cPCDH genes after neuronal differentiation in monolayers, 10-month-old cortical organoids and engrafted cells in the spinal cords of rats. Signs of these frequent selections can be observed in the brain throughout fetal development and disappear after birth, except in conditions of delayed maturation such as Down's syndrome. We therefore propose that a pattern of limited cPCDH-gene expression diversity is maintained while human neurons still retain fetal-like levels of maturation.
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Engineered bacterial extracellular vesicles for central nervous system diseases.
The prevalence of central nervous system (CNS) diseases is on the rise as the population ages. The presence of various obstacles, particularly the blood-brain barrier (BBB), poses a challenge for drug delivery to the CNS. An expanding body of study suggests that gut microbiota (GM) plays an important role in CNS diseases. The communication between GM and CNS diseases has received increasing attention. Accumulating evidence indicates that the GM can modulate host signaling pathways to regulate distant organ functions by delivering bioactive substances to host cells via bacterial extracellular vesicles (BEVs). BEVs have emerged as a promising platform for the treatment of CNS diseases due to their nanostructure, ability to penetrate the BBB, as well as their low toxicity, high biocompatibility, ease of modification and large-scale culture. Here, we discuss the biogenesis, internalization mechanism and engineering modification methods of BEVs. We then focus on the use and potential role of BEVs in the treatment of CNS diseases. Finally, we outline the main challenges and future prospects for the application of BEVs in CNS diseases. We hope that the comprehensive understanding of the BEVs-based gut-brain axis will provide new insights into the treatment of CNS diseases.
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Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids.
Valproic acid (VPA) exposure during pregnancy leads to a higher risk of autism spectrum disorder (ASD) susceptibility in offspring. Human dorsal forebrain organoids were used to recapitulate course of cortical neurogenesis in the developing human brain. Combining morphological characterization with massive parallel RNA sequencing (RNA-seq) on organoids to analyze the pathogenic effects caused by VPA exposure and critical signaling pathway. We found that VPA exposure in organoids caused a reduction in the size and impairment in the proliferation and expansion of neural progenitor cells (NPCs) in a dose-dependent manner. VPA exposure typically decreased the production of outer radial glia-like cells (oRGs), a subtype of NPCs contributing to mammalian neocortical expansion and delayed their fate toward upper-layer neurons. Transcriptomics analysis revealed that VPA exposure influenced ASD risk gene expression in organoids, which markedly overlapped with irregulated genes in brains or organoids originating from ASD patients. We also identified that VPA-mediated Wnt/β-catenin signaling pathway activation is essential for sustaining cortical neurogenesis and oRGs output. Taken together, our study establishes the use of dorsal forebrain organoids as an effective platform for modeling VPA-induced teratogenic pathways involved in the cortical neurogenesis and oRGs output, which might contribute to ASD pathogenesis in the developing brain.
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Non-Canonical Splicing and Its Implications in Brain Physiology and Cancer.
The advance of experimental and computational techniques has allowed us to highlight the existence of numerous different mechanisms of RNA maturation, which have been so far unknown. Besides canonical splicing, consisting of the removal of introns from pre-mRNA molecules, non-canonical splicing events may occur to further increase the regulatory and coding potential of the human genome. Among these, splicing of microexons, recursive splicing and biogenesis of circular and chimeric RNAs through back-splicing and trans-splicing processes, respectively, all contribute to expanding the repertoire of RNA transcripts with newly acquired regulatory functions. Interestingly, these non-canonical splicing events seem to occur more frequently in the central nervous system, affecting neuronal development and differentiation programs with important implications on brain physiology. Coherently, dysregulation of non-canonical RNA processing events is associated with brain disorders, including brain tumours. Herein, we summarize the current knowledge on molecular and regulatory mechanisms underlying canonical and non-canonical splicing events with particular emphasis on cis-acting elements and trans-acting factors that all together orchestrate splicing catalysis reactions and decisions. Lastly, we review the impact of non-canonical splicing on brain physiology and pathology and how unconventional splicing mechanisms may be targeted or exploited for novel therapeutic strategies in cancer.
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Moderate 3D orbital shaking mitigates maternal separation-induced neurodevelopmental impairments in rats.
Maternal separation during early life is a well-established model for inducing neurodevelopmental impairments and increasing hippocampal vulnerability. Externally generated mechanosensory stimulation, such as three-dimensional orbital shaking (3D-OS), has been proposed as a candidate modulatory stimulus in cellular and organoid models, but its impact on neonatal brain development under early-life stress conditions remains unknown. We investigated whether 3D-OS, applied as a controlled postnatal mechanosensory stimulation, could partially attenuate behavioural, histological, and molecular alterations induced by maternal separation in rats. Eighteen newborn Sprague Dawley rats were assigned to control (C), maternal separation (MS), or maternal separation plus orbital shaking (MSOS) groups. Maternal separation was performed 3 h/day between postnatal days 2-21; MSOS additionally received 3D-OS (25 rpm, 3 h/day) as a rocking cradle-like mechanosensory stimulation. Behavioural tests (Open Field, Novel Object Recognition, Morris Water Maze, Passive Avoidance), combined with RT-qPCR, Western blot, histology, and immunohistochemistry were conducted. Compared with MS, MSOS rats showed partial improvement in early Morris Water Maze performance and longer step-through latency in the retention phase of Passive Avoidance, whereas Open Field, Novel Object Recognition, and Western blot analyses did not reveal significant inter-group differences. Histological analysis showed reduced neuronal loss and vacuolisation in hippocampal and cortical regions of MSOS rats. RT-qPCR demonstrated reduced hippocampal FGF2 and FGFR1 expression in MS, with values in MSOS shifting toward control levels, whereas immunohistochemistry showed a receptor-specific pattern that was not fully concordant with the transcript data. Early-life 3D-OS administration alleviated maternal separation-induced cognitive decline and structural impairments and modulated hippocampal FGF2-FGFR signalling markers, proposing a neuroprotective effect of externally generated mechanosensory stimulation under early-life stress. These findings provide preclinical evidence that gentle mechanosensory stimulation may support early brain development and mitigate stress-related neurodevelopmental vulnerability.
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Dihydrofolate reductase activity controls neurogenic transitions in the developing neocortex.
One-carbon/folate (1C) metabolism supplies methyl groups required for DNA and histone methylation, and is involved in the maintenance of self-renewal in stem cells. Dihydrofolate reductase (DHFR), a key enzyme in 1C metabolism, is highly expressed in human and mouse neural progenitors at the early stages of neocortical development. Here, we have investigated the role of DHFR in the developing neocortex and report that reducing its activity in human neural organoids and mouse embryonic neocortex accelerates indirect neurogenesis, thereby affecting neuronal composition of the neocortex. Furthermore, we show that decreasing DHFR activity in neural progenitors leads to a reduction in one-carbon/folate metabolites and correlates with modifications of H3K4me3 levels. Our findings reveal an unanticipated role for DHFR in controlling specific steps of neocortex development and indicate that variations in 1C metabolic cues impact cell fate transitions.
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Functional development of midbrain and pons during human gestation and electrophysiological markers for DS intervention.
The early fetal period (GW8-20) is crucial for establishing motor and cognitive neural circuits. However, ethical constraints and limitations in current research methods have hindered our understanding of functional development in related brain regions during this period. This study presents the first functional map of midbrain-pons development in human fetuses from GW10 to GW17, systematically investigating ion channel development, the dynamic evolution of excitatory and inhibitory networks, and synaptic maturation, thereby addressing a critical developmental research gap. Employing electrophysiological techniques and Smart-seq technology, we revealed the spatiotemporal dynamics of neuronal excitability, synaptic transmission, and synaptic plasticity in the human midbrain-pons, highlighting functional developmental differences between healthy fetuses and those with Down syndrome (DS) at GW17. Our results demonstrate that the midbrain-pons complex undergoes a rapid phase of neural network maturation from GW10 to GW17, characterized by a swift increase in neuronal excitability, gradual maturation of synaptic transmission, and enhanced synaptic plasticity. In addition, during mid-gestation, the midbrain and pons follow distinct developmental trajectories, exhibiting regional specificity and non-linear maturation patterns. The midbrain-pons functional map addresses a significant gap in developmental neuroscience and challenges existing organoid models by incorporating region-specific network features into disease modeling. In DS fetuses at GW17, we observed early functional deficits, including decreased action potential firing frequency, unbalanced AMPAR/NMDAR-mediated EPSC ratio and sEPSCs/sIPSCs ratio, impaired synaptic plasticity. Electrophysiological profiling reveals that by gestational week 17, fetuses with Down syndrome already manifest signs of neural network dysfunction. By correlating early electrophysiological markers with neurodevelopmental pathology, we provide new potential markers for future prenatal diagnosis of DS and suggest a critical intervention window (GW13.5-17).