Intrathecal delivery of AAV-NDNF ameliorates disease progression of ALS mice.

Amyotrophic lateral sclerosis (ALS) is a uniformly lethal neurodegenerative disease characterized by progressive deterioration of motor neurons and neuromuscular denervation. Adeno-associated virus (AAV)-mediated delivery of trophic factors is being considered as a potential disease-modifying therapeutic avenue. Here we show a marked effect of AAV-mediated over-expression of neuron-derived neurotrophic factor (NDNF) on SOD1G93A ALS model mice. First, we adopt AAV-PHP.eB capsid to enable widespread expression of target proteins in the brain and spinal cord when delivered intrathecally. Then we tested the effects of AAV-NDNF on SOD1G93A mice at different stages of disease. Interestingly, AAV-NDNF markedly improved motor performance and alleviated weight loss when delivered at early post-symptomatic stage. Injection in the middle post-symptomatic stages still improved the locomotion ability, although it did not alleviate the loss of body weight. Injection in the late stage also extended the life span of SOD1G93A mice. Furthermore, NDNF expression promoted the survival of spinal motoneurons, reduced abnormal protein aggregation, and preserved the innervated neuromuscular functions. We further analyzed the signaling pathways of NDNF expression and found that it activates cell survival and growth-associated mammalian target of rapamycin signaling pathway and downregulates apoptosis-related pathways. Thus, intrathecally AAV-NDNF delivery has provided a potential strategy for the treatment of ALS.

Advances and Applications of Brain Organoids.

Understanding the fundamental processes of human brain development and diseases is of great importance for our health. However, existing research models such as non-human primate and mouse models remain limited due to their developmental discrepancies compared with humans. Over the past years, an emerging model, the "brain organoid" integrated from human pluripotent stem cells, has been developed to mimic developmental processes of the human brain and disease-associated phenotypes to some extent, making it possible to better understand the complex structures and functions of the human brain. In this review, we summarize recent advances in brain organoid technologies and their applications in brain development and diseases, including neurodevelopmental, neurodegenerative, psychiatric diseases, and brain tumors. Finally, we also discuss current limitations and the potential of brain organoids.

Generation of vascularized brain organoids to study neurovascular interactions.

Brain organoids have been used to recapitulate the processes of brain development and related diseases. However, the lack of vasculatures, which regulate neurogenesis and brain disorders, limits the utility of brain organoids. In this study, we induced vessel and brain organoids, respectively, and then fused two types of organoids together to obtain vascularized brain organoids. The fused brain organoids were engrafted with robust vascular network-like structures and exhibited increased number of neural progenitors, in line with the possibility that vessels regulate neural development. Fusion organoids also contained functional blood-brain barrier-like structures, as well as microglial cells, a specific population of immune cells in the brain. The incorporated microglia responded actively to immune stimuli to the fused brain organoids and showed ability of engulfing synapses. Thus, the fusion organoids established in this study allow modeling interactions between the neuronal and non-neuronal components in vitro, particularly the vasculature and microglia niche.

Understanding how the organs form and how their cells behave is essential to finding the causes and treatment for developmental disorders, as well as understanding certain diseases. However, studying most organs in live animals or humans is technically difficult, expensive and invasive. To address this issue, scientists have developed models called 'organoids' that recapitulate the development of organs using stem cells in the lab. These models are easier to study and manipulate than the live organs. Brain organoids have been used to recapitulate brain formation as well as developmental, degenerative and psychiatric brain conditions such as microcephaly, autism and Alzheimer's disease. However, these brain organoids lack the vasculature (the network of blood vessels) that supplies a live brain with nutrients and regulates its development, and which has important roles in brain disorders. Partly due to this lack of blood vessels, brain organoids also do not develop a blood brain barrier, the structure that prevents certain contents of the blood, including pathogens, toxins and even certain drugs from entering the brain. These characteristics limit the utility of existing brain organoids. To overcome these limitations, Sun, Ju et al. developed brain organoids and blood vessel organoids independently, and then fused them together to obtain vascularized brain organoids. These fusion organoids developed a robust network of blood vessels that was well integrated with the brain cells, and produced more neural cell precursors than brain organoids that had not been fused. This result is consistent with the idea that blood vessels can regulate brain development. Analyzing the fusion organoids revealed that they contain structures similar to the blood-brain barrier, as well as microglial cells (immune cells specific to the brain). When exposed to lipopolysaccharide ­ a component of the cell wall of certain bacteria ­ these cells responded by initiating an immune response in the fusion organoids. Notably, the microglial cells were also able to engulf connections between brain cells, a process necessary for the brain to develop the correct structures and work normally. Sun, Ju et al. have developed a new organoid system that will be of broad interest to researchers studying interactions between the brain and the circulatory system. The development of brain-blood-barrier-like structures in the fusion organoids could also facilitate the development of drugs that can cross this barrier, making it easier to treat certain conditions that affect the brain. Refining this model to allow the fusion organoids to grow for longer times in the lab, and adding blood flow to the system will be the next steps to establish this system.

Emerging neurotropic features of SARS-CoV-2.

The prevailing coronavirus disease-19 (COVID-19) caused by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has presented some neurological manifestations including hyposmia, hypogeusia, headache, stroke, encephalitis, Guillain-Barre syndrome, and some neuropsychiatric disorders. Although several cell types in the brain express angiotensin-converting enzyme-2 (ACE2), the main SARS-CoV-2 receptor, and other related proteins, it remains unclear whether the observed neurological manifestations are attributed to virus invasion into the brain or just comorbidities caused by dysregulation of systemic factors. Here, we briefly review the neurological manifestations of SARS-CoV-2, summarize recent evidence for the potential neurotropism of SARS-CoV-2, and discuss the potential mechanisms of COVID-19-associated neurological diseases.

The CTNNBIP1-CLSTN1 fusion transcript regulates human neocortical development.

Fusion transcripts or RNAs have been found in both disordered and healthy human tissues and cells; however, their physiological functions in the brain development remain unknown. In the analysis of deposited RNA-sequence libraries covering early to middle embryonic stages, we identify 1,055 fusion transcripts present in the developing neocortex. Interestingly, 98 fusion transcripts exhibit distinct expression patterns in various neural progenitors (NPs) or neurons. We focus on CTNNBIP1-CLSTN1 (CTCL), which is enriched in outer radial glial cells that contribute to cortex expansion during human evolution. Intriguingly, downregulation of CTCL in cultured human cerebral organoids causes marked reduction in NPs and precocious neuronal differentiation, leading to impairment of organoid growth. Furthermore, the expression of CTCL fine-tunes Wnt/ß-catenin signaling that controls cortex patterning. Together, this work provides evidence indicating important roles of fusion transcript in human brain development and evolution.

A Qualitative Analysis Based on Relative Expression Orderings Identifies Transcriptional Subgroups for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease. However, few studies have investigated the heterogeneous gene expression patterns in AD. OBJECTIVE AND METHODS: We examined the gene expression patterns in four brain regions of AD based on the within-sample relative expression orderings (REOs). Gene pairs with significantly reversed REOs in AD samples compared to non-AD controls were identified for each brain region using Fisher's exact test, and filtered according to their transcriptional differences between AD samples. Subgroups of AD were classified by cluster analysis. RESULTS: REO-based gene expression profiling analyses revealed that transcriptional differences, as well as distinct disease subsets, existed within AD patients. For each brain region, two main subgroups were classified: one subgroup reported differentially expressed genes overlapped with the age-related genes, and the other was related to neuroinflammation. CONCLUSION: AD transcriptional subgroups might help understand the underlying pathogenesis of AD, and lend support to a personalized approach to AD management.