Models Of Neurodegenerative Diseases Research Articles

Mitochondrial dysfunction of induced pluripotent stem cells-based neurodegenerative disease modeling and therapeutic strategy.

Neurodegenerative diseases (NDDs) are disorders in which neurons are lost owing to various factors, resulting in a series of dysfunctions. Their rising prevalence and irreversibility have brought physical pain to patients and economic pressure to both individuals and society. However, the pathogenesis of NDDs has not yet been fully elucidated, hampering the use of precise medication. Induced pluripotent stem cell (IPSC) modeling provides a new method for drug discovery, and exploring the early pathological mechanisms including mitochondrial dysfunction, which is not only an early but a prominent pathological feature of NDDs. In this review, we summarize the iPSC modeling approach of Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis, as well as outline typical mitochondrial dysfunction and recapitulate corresponding therapeutic strategies.

Synaptic Loss in Frontotemporal Dementia Revealed by [11 C]UCB-J Positron Emission Tomography.

Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [11 C]UCB-J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity. Eleven participants with clinically probable bvFTD and 25 age- and sex-matched healthy controls were included. Participants underwent dynamic [11 C]UCB-J PET, structural magnetic resonance imaging, and a neuropsychological battery, including the revised Addenbrooke Cognitive Examination, and INECO frontal screening. General linear models compared [11 C]UCB-J binding potential maps and gray matter volume between groups, and assessed associations between synaptic density and clinical severity in patients. Analyses were also performed using partial volume corrected [11 C]UCB-J binding potential from regions of interest (ROIs). Patients with bvFTD showed severe synaptic loss compared to controls. [11 C]UCB-J binding was reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex, and medial temporal lobe. Synaptic loss in the frontal and cingulate regions correlated significantly with cognitive impairments. Synaptic loss was more severe than atrophy. Results from ROI-based analyses mirrored the voxelwise results. In accordance with preclinical models, and human postmortem evidence, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to severity. [11 C]UCB-J PET could support translational studies and experimental medicine strategies for new disease-modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142-154.

Apelin/APJ system: an emerging therapeutic target for neurological diseases.

Apelin, an endogenous ligand for the G protein-coupled receptor APJ, is extensively expressed in various systems, especially the nervous system. This article reviews the role of apelin/APJ system in neurological diseases. In detail, apelin/APJ system can relieve acute brain injury including subarachnoid hemorrhage, traumatic brain injury, and ischemic stroke. Also, apelin/APJ system has therapeutic effects on chronic neurodegenerative disease models, involving the regulation of neurotrophic factors, neuroendocrine, oxidative stress, neuroinflammation, neuronal apoptosis, and autophagy. In addition, through different routes of administration, apelin/APJ system has a biphasic effect on depression, epilepsy, and pain. However, apelin/APJ system exacerbates the proliferation and invasion of glioblastoma. Thus, apelin/APJ system is expected to be a therapeutic target for the treatment of nervous system diseases.

Immuno(T)herapy for age-related diseases.

During the last decade, the stimulation of T-cell function by the blockage of immunosuppressive checkpoints has experienced an outstanding impact in the treatment of cancer. Development of the chimeric antigen receptor T-cell technology has also emerged as a powerful alternative for patients suffering from oncological processes, especially those affected by hematological neoplasms. Recent evidence suggest that the use of immunotherapy could be extended to non-oncological diseases and could be especially relevant for age-associated disorders, opening exciting therapeutic options for a wide range of diseases of the elderly. Here we comment on the emergence of T-cell-based immunotherapies as feasible approaches that could revolutionize the future of GeroScience.

Folium Hibisci Mutabilis extract, a potent autophagy enhancer, exhibits neuroprotective properties in multiple models of neurodegenerative diseases

BackgroundProtein aggregates are considered key pathological features in neurodegenerative diseases (NDs). The induction of autophagy can effectively promote the clearance of ND-related misfolded proteins. ObjectiveIn this study, we aimed to screen natural autophagy enhancers from traditional Chinese medicines (TCMs) presenting potent neuroprotective potential in multiple ND models. MethodsThe autophagy enhancers were broadly screened in our established herbal extract library using the transgenic Caenorhabditis elegans (C. elegans) DA2123 strain. The neuroprotective effects of the identified autophagy enhancers were evaluated in multiple C. elegans ND models by measuring Aβ-, Tau-, α-synuclein-, and polyQ40-induced pathologies. In addition, PC-12 cells and 3 × Tg-AD mice were employed to further validate the neuroprotective ability of the identified autophagy enhancers, both in vitro and in vivo. Furthermore, RNAi bacteria and autophagy inhibitors were used to evaluate whether the observed effects of the identified autophagy enhancers were mediated by the autophagy-activated pathway. ResultsThe ethanol extract of Folium Hibisci Mutabilis (FHME) was found to significantly increase GFP::LGG-1-positive puncta in the DA2123 worms. FHME treatment markedly inhibited Aβ, α-synuclein, and polyQ40, as well as prolonging the lifespan and improving the behaviors of C. elegans, while siRNA targeting four key autophagy genes partly abrogated the protective roles of FHME in C. elegans. Additionally, FHME decreased the expression of AD-related proteins and restored cell viability in PC-12 cells, which were canceled by cotreatment with 3-methyladenine (3-MA) or bafilomycin A1 (Baf). Moreover, FHME ameliorated AD-like cognitive impairment and pathology, as well as activating autophagy in 3 × Tg-AD mice. ConclusionFHME was successfully screened from our natural product library as a potent autophagy enhancer that exhibits a neuroprotective effect in multiple ND models across species through the induction of autophagy. These findings offer a new and reliable strategy for screening autophagy inducers, as well as providing evidence that FHME may serve as a possible therapeutic agent for NDs.

Development of microglia-targeting adeno-associated viral vectors as tools to study microglial behavior in vivo

Here we describe the microglia-targeting adeno-associated viral (AAV) vectors containing a 1.7-kb putative promoter region of microglia/macrophage-specific ionized calcium-binding adaptor molecule 1 (Iba1), along with repeated miRNA target sites for microRNA (miR)-9 and miR-129-2-3p. The 1.7-kb genomic sequence upstream of the start codon in exon 1 of the Iba1 (Aif1) gene, functions as microglia preferential promoter in the striatum and cerebellum. Furthermore, ectopic transgene expression in non-microglial cells is markedly suppressed upon adding two sets of 4-repeated miRNA target sites for miR-9 and miR-129-2-3p, which are expressed exclusively in non-microglial cells and sponged AAV-derived mRNAs. Our vectors transduced ramified microglia in healthy tissues and reactive microglia in lipopolysaccharide-treated mice and a mouse model of neurodegenerative disease. Moreover, live fluorescent imaging allowed the monitoring of microglial motility and intracellular Ca2+ mobilization. Thus, microglia-targeting AAV vectors are valuable for studying microglial pathophysiology and therapies, particularly in the striatum and cerebellum.

Neuroprotective action of α-Klotho against LPS-activated glia conditioned medium in primary neuronal culture

The α-Klotho is an anti-aging protein that, when overexpressed, extends the life span in humans and mice. It has an anti-inflammatory and protective action on renal cells by inhibiting NF-κB activation and production of inflammatory cytokines in response to TNF-α. Furthermore, studies have shown the neuroprotective effect of α-Klotho against neuroinflammation on different conditions, such as aging, animal models of neurodegenerative diseases, and ischemic brain injury. This work aimed to evaluate the effects of α-Klotho protein on primary glial cell culture against the proinflammatory challenge with LPS and how this could interfere with neuronal health. Cortical mixed glial cells and purified astrocytes were pretreated with α- α-Klotho and stimulated with LPS followed by TNFα, IL-1β, IL-6, IFN-γ levels, and NF-κB activity analysis. Conditioned medium from cortical mixed glia culture treated with LPS (glia conditioned medium (GCM) was used to induce neuronal death of primary cortical neuronal culture and evaluate if GCM-KL (medium from glia culture pretreated α-Klotho followed by LPS stimulation) or GCM + LPS in the presence of KL can reverse the effect. LPS treatment in glial cells induced an increase in proinflammatory mediators such as TNF-α, IL-1β, IL-6, and IFN-γ, and activation of astrocyte NF-κB. GCM treated-cortical neuronal culture induced a concentration-dependent neuronal death. Pretreatment with α-Klotho decreased TNF-α and IL-6 production, reverted NF-κB activation, and decreased neuronal death induced by GCM. In addition, KL incubation together with GCM + LPS completely reverts the neuronal toxicity induced by low concentration of GCM-LPS. These data suggest an anti-inflammatory and neuroprotective effect of α-Klotho protein in the CNS. This work demonstrated the therapeutic potential of α-Klotho in pathological processes which involves a neuroinflammatory component.

Neuronal mitochondrial morphology is significantly affected by both fixative and oxygen level during perfusion.

Neurons in the brain have a uniquely polarized structure consisting of multiple dendrites and a single axon generated from a cell body. Interestingly, intracellular mitochondria also show strikingly polarized morphologies along the dendrites and axons: in cortical pyramidal neurons (PNs), dendritic mitochondria have a long and tubular shape, while axonal mitochondria are small and circular. Mitochondria play important roles in each compartment of the neuron by generating adenosine triphosphate (ATP) and buffering calcium, thereby affecting synaptic transmission and neuronal development. In addition, mitochondrial shape, and thereby function, is dynamically altered by environmental stressors such as oxidative stress or in various neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Although the importance of altered mitochondrial shape has been claimed by multiple studies, methods for studying this stress-sensitive organelle have not been standardized. Here we address pertinent steps that influence mitochondrial morphology during experimental processes. We demonstrate that fixative solutions containing only paraformaldehyde (PFA), or that introduce hypoxic conditions during the procedure, induce dramatic fragmentation of mitochondria both in vitro and in vivo. This disruption was not observed following the use of glutaraldehyde (GA) addition or oxygen supplementation, respectively. Finally, using pre-formed fibril α-synuclein treated neurons, we show fixative choice can alter experimental outcomes. Specifically, α-synuclein-induced mitochondrial remodeling could not be observed with PFA only fixation as fixation itself caused mitochondrial fragmentation. Our study provides optimized methods for examining mitochondrial morphology in neurons and demonstrates that fixation conditions are critical when investigating the underlying cellular mechanisms involving mitochondria in physiological and neurodegenerative disease models.

Zebrafish: A Pharmacological Model for Learning and Memory Research.

Learning and memory are essential to organism survival and are conserved across various species, especially vertebrates. Cognitive studies involving learning and memory require using appropriate model organisms to translate relevant findings to humans. Zebrafish are becoming increasingly popular as one of the animal models for neurodegenerative diseases due to their low maintenance cost, prolific nature and amenability to genetic manipulation. More importantly, zebrafish exhibit a repertoire of neurobehaviors comparable to humans. In this review, we discuss the forms of learning and memory abilities in zebrafish and the tests used to evaluate the neurobehaviors in this species. In addition, the pharmacological studies that used zebrafish as models to screen for the effects of neuroprotective and neurotoxic compounds on cognitive performance will be summarized here. Lastly, we discuss the challenges and perspectives in establishing zebrafish as a robust model for cognitive research involving learning and memory. Zebrafish are becoming an indispensable model in learning and memory research for screening neuroprotective agents against cognitive impairment.

A systematic review of the effect of photobiomodulation on the neuroinflammatory response in animal models of neurodegenerative diseases.

This systematic review examines the effect of photobiomodulation (PBM), the application of red to near infrared light on body tissues, on the neuroinflammatory response and oxidative stress in animal models of neurodegenerative diseases. The research question and search protocol were prospectively registered on the PROSPERO database. Neurodegenerative diseases are becoming evermore prevalent in the ageing populations across theWestern world, with no disease-modifying or neuroprotective treatment options being available. Hence there is a real need for the development of effective treatment options for patients. Inflammatory responses and oxidative stress within the central nervous system have a strong correlation with neuronal cell death. PBM is a non-invasive therapeutic option that has shown efficacy and promising effects inanimal models of neurodegenerative disease; many studies have reported neuroprotection and improved behavioural outcomes. To the best of our knowledge, therehas been no previous study that has reviewed theanti-inflammatory and the antioxidant effect of PBM inthe context of neurodegeneration. This review has examined this relationship in animal models of a range ofneurodegenerative diseases. We found that PBM can effectively reduce glial activation, pro-inflammatory cytokine expression and oxidative stress, whilst increasing anti-inflammatory glial responses and cytokines, and antioxidant capacity. These positive outcomes accompanied the neuroprotection evident after PBM treatment. Our review provides further indication that PBM can be developed intoan effective non-pharmacological intervention for neurodegenerative diseases.

A novel rhesus macaque model of Huntington's disease recapitulates key neuropathological changes along with motor and cognitive decline.

We created a new nonhuman primate model of the genetic neurodegenerative disorder Huntington's disease (HD) by injecting a mixture of recombinant adeno-associated viral vectors, serotypes AAV2 and AAV2.retro, each expressing a fragment of human mutant HTT (mHTT) into the caudate and putamen of adult rhesus macaques. This modeling strategy results in expression of mutant huntingtin protein (mHTT) and aggregate formation in the injected brain regions, as well as dozens of other cortical and subcortical brain regions affected in human HD patients. We queried the disruption of cortico-basal ganglia circuitry for 30 months post-surgery using a variety of behavioral and imaging readouts. Compared to controls, mHTT-treated macaques developed working memory decline and progressive motor impairment. Multimodal imaging revealed circuit-wide white and gray matter degenerative processes in several key brain regions affected in HD. Taken together, we have developed a novel macaque model of HD that may be used to develop disease biomarkers and screen promising therapeutics.

Synthetic OCT Data Generation to Enhance the Performance of Diagnostic Models for Neurodegenerative Diseases.

PurposeOptical coherence tomography (OCT) has recently emerged as a source for powerful biomarkers in neurodegenerative diseases such as multiple sclerosis (MS) and neuromyelitis optica (NMO). The application of machine learning techniques to the analysis of OCT data has enabled automatic extraction of information with potential to aid the timely diagnosis of neurodegenerative diseases. These algorithms require large amounts of labeled data, but few such OCT data sets are available now.MethodsTo address this challenge, here we propose a synthetic data generation method yielding a tailored augmentation of three-dimensional (3D) OCT data and preserving differences between control and disease data. A 3D active shape model is used to produce synthetic retinal layer boundaries, simulating data from healthy controls (HCs) as well as from patients with MS or NMO.ResultsTo evaluate the generated data, retinal thickness maps are extracted and evaluated under a broad range of quality metrics. The results show that the proposed model can generate realistic-appearing synthetic maps. Quantitatively, the image histograms of the synthetic thickness maps agree with the real thickness maps, and the cross-correlations between synthetic and real maps are also high. Finally, we use the generated data as an augmentation technique to train stronger diagnostic models than those using only the real data.ConclusionsThis approach provides valuable data augmentation, which can help overcome key bottlenecks of limited data.Translational RelevanceBy addressing the challenge posed by limited data, the proposed method helps apply machine learning methods to diagnose neurodegenerative diseases from retinal imaging.

Ayurvedic formulations amalaki rasayana and rasa sindoor improve age-associated memory deficits in mice by modulating dendritic spine densities

BackgroundEmerging reports indicate that age-associated cognitive decline begins with the transition from young to middle-aged, and this neurological condition manifests mainly due to the progressive impairment in the adaptive homeostasis process. Moreover, cognitive decline is associated with neurodegenerative changes in older adults. ObjectivePrevious studies have shown that the administration of Ayurvedic formulations restores the homeostatic pathways and ameliorates neurodegeneration in animal models of neurodegenerative diseases. Therefore, we wanted to check whether Ayurvedic formulations can rescue or delay the age-associated cognitive decline in middle-aged mice. Material and methodsWe fed two-month-old mice with amalaki aasayana (AR, 1025 mg/kg per day) or rasa sindoor (RS, 41 mg/kg per day) mixed in a gelatin-based jelly for six months. Mice eating regular chow or blank jelly served as control. Subsequently, we looked at the improvements in the cognitive and behavioural traits of the treated animals. We have also analysed the effect of these formulations on the dendritic processes of neurons, glial activation, and the formation of corpora amylacea. ResultsWe found a significant improvement in episodic, working- and reference-spatiotemporal memory in animals fed on AR or RS. Microscopic analyses revealed a significant increase in the dendritic spine density in the apical dendrites of the hippocampal pyramidal neurons. The treatment, however, did not significantly affect gliosis and corpora amylacea in the brains. ConclusionsBoth AR and RS showed beneficial effects on memory functions of the middle-aged mice, possibly due to their effect on the dendritic spine densities. Our findings provide strong evidence to conclude that formulations AR and RS can prevent or delay the onset of age-associated cognitive decline.

The Neuroprotective Effect of NEUROMIDE, a Compound Bioidentical to Commensal Bacteria Metabolites.

Simple SummaryN-Palmitoyl serinol is a commensal bacterial metabolite that acts as an endocannabinoid CB1 and GPR119 agonist. We investigated the potential of N-Palmitoyl serinol (NEUROIMIDE) to exert its neuroprotective effects via the gut–brain axis. NEUROMIDE improves cell survival and can reduce and even prevent scopolamine-induced memory impairments and passive avoidance disorder while increasing acetylcholine levels. These results suggest that the endocannabinoid system can act via the gut–brain axis.GPR119 is a novel cannabinoid receptor that is primarily expressed in the pancreas and gastrointestinal tract and has beneficial effects on glucose homeostasis exerted through the stimulation of GLP-1 secretion, as demonstrated in the rodent brain. GLP-1 also has important anti-inflammatory effects in chronic inflammatory diseases, including type 1 and 2 diabetes, asthma, psoriasis, and neurodegenerative disorders. Recently, there has been increasing interest in the effect of the gut microbiota on both the gut and the brain. However, few studies have examined how gut microbes affect brain health through the endocannabinoid system. NEUROMIDE is a compound that shares a bioidentical structure with certain commensal bacterial metabolites, acting as a CB1 and GPR119 agonist. In an in vitro system exposed to reactive oxygen species (ROS), pretreatment with NEUROMIDE resulted in a significant increase in cell viability. The ROS-exposed system also showed decreased acetylcholine and an increase in inflammatory cytokines such as IL-1β, changes that were counteracted in a dose-dependent manner in the NEUROMIDE treatment groups. To measure the effectiveness of NEUROMIDE in an in vivo system, we used scopolamine-treated mice as a neurodegenerative disease model and performed a series of passive avoidance tests to observe and quantify the cognitive impairment of the mice. Mice in the NEUROMIDE treatment group had increased latency time, thus indicating an improvement in their cognitive function. Furthermore, the NEUROMIDE treatment groups showed dose-dependent increases in acetylcholine along with decreases in TNF-α and IL-1β. These experiments demonstrate that NEUROMIDE can potentially be used for neuroprotection and the improvement of cognitive ability.

Innate immune activation without immune cell infiltration in brains of murine models of Aicardi-Goutières Syndrome.

Chronic inflammation is frequently invoked as a mechanism of neurodegeneration and yet inflammatory cell infiltrates are seldom seen in brains of these disorders. Different disciplines utilize different technologies and methodologies to describe what is immunologically defined as the innate immune response (IIR). We examined murine models of the human neurodegenerative disease Aicardi-Goutières Syndrome, where an IIR is initiated by aberrant RNA metabolism secondary to a mutation in adenosine deaminase acting on RNA gene (ADAR1). We previously showed that these mice demonstrated a deficit in RNA editing that lead to MDA-5 mediated RNA sensing pathway activation of the IIR with massive interferon stimulated gene transcription and translation. As early as 2 weeks of age, in situ hybridization demonstrated that different central nervous system (CNS) cell lineages expressed very high levels of distinct interferon stimulated genes (ISGs) in the absence of interferon and absence of immune cell infiltrates. We have expanded these studies to more completely describe the breadth of ISG expression systemically and in CNS using double label in situ hybridization. Within the CNS aberrant ISG expression was mostly limited to neurons, microglia, ependyma, choroid plexus, and endothelial cells with little expression in oligodendroglia and astrocytes except for STAT1. Wild type controls showed a similar pattern of ISG expression but only in aged mice and at levels minimally detectable by in situ hybridization. Despite months of elevated ISG expression in mutant mice, there was essentially no inflammatory infiltrate, no interferon production and minimal glial reaction. Histomorphological neurodegenerative pathology of ventricular dilatation and deep gray matter mineralization were evident in mutant mice 8-13 months of age but this did not show a spatial relationship to ISG expression. This IIR without immune cell infiltration leads to neurodegeneration through non-canonical pathways that may accentuate normal aging pathways.

The role of PKC/PKR in aging, Alzheimer's disease, and perioperative neurocognitive disorders.

BackgroundThe incidence of perioperative neurocognitive disorders (PNDs) is reportedly higher in older patients. Mitochondrial and synaptic dysfunctions have consistently been demonstrated in models of aging and neurodegenerative diseases; nonetheless, their role in PND is not well understood.MethodsThe Morris water maze and elevated plus maze tests were used to assess the learning and memory abilities of both C57BL/6 and 3×Tg-AD mice of different ages (8 and 18 months). PND was induced by laparotomy in C57BL/6 mice and 3×Tg-AD mice (8 months old). Markers associated with neuroinflammation, mitochondrial function, synaptic function, and autophagy were assessed postoperatively. The roles of protein kinase C (PKC) and double-stranded RNA-dependent protein kinase (PKR) were further demonstrated by using PKC-sensitive inhibitor bisindolylmaleimide X (BIMX) or PKR−/− mice.ResultsSignificant cognitive impairment was accompanied by mitochondrial dysfunction and autophagy inactivation in both aged C57BL/6 and 3×Tg-AD mice. Laparotomy induced a significant neuroinflammatory response and synaptic protein loss in the hippocampus. Cognitive and neuropathological changes induced by aging or laparotomy were further exacerbated in 3×Tg-AD mice. Deficits in postoperative cognition, hippocampal mitochondria, autophagy, and synapse were significantly attenuated after pharmacological inhibition of PKC or genetic deletion of PKR.ConclusionsOur findings suggest similar pathogenic features in aging, Alzheimer's disease, and PND, including altered mitochondrial homeostasis and autophagy dysregulation. In addition, laparotomy may exacerbate cognitive deficits associated with distinct neuronal inflammation, mitochondrial dysfunction, and neuronal loss independent of genetic background. The dysregulation of PKC/PKR activity may participate in the pathogenesis of these neurodegenerative diseases.

CRISPR and iPSCs: Recent Developments and Future Perspectives in Neurodegenerative Disease Modelling, Research, and Therapeutics.

Neurodegenerative diseases are prominent causes of pain, suffering, and death worldwide. Traditional approaches modelling neurodegenerative diseases are deficient, and therefore, improved strategies that effectively recapitulate the pathophysiological conditions of neurodegenerative diseases are the need of the hour. The generation of human-induced pluripotent stem cells (iPSCs) has transformed our ability to model neurodegenerative diseases in vitro and provide an unlimited source of cells (including desired neuronal cell types) for cell replacement therapy. Recently, CRISPR/Cas9-based genome editing has also been gaining popularity because of the flexibility they provide to generate and ablate disease phenotypes. In addition, the recent advancements in CRISPR/Cas9 technology enables researchers to seamlessly target and introduce precise modifications in the genomic DNA of different human cell lines, including iPSCs. CRISPR-iPSC-based disease modelling, therefore, allows scientists to recapitulate the pathological aspects of most neurodegenerative processes and investigate the role of pathological gene variants in healthy non-patient cell lines. This review outlines how iPSCs, CRISPR/Cas9, and CRISPR-iPSC-based approaches accelerate research on neurodegenerative diseases and take us closer to a cure for neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, and so forth.

Human Brain Organoid: A Versatile Tool for Modeling Neurodegeneration Diseases and for Drug Screening.

Clinical trials serve as the fundamental prerequisite for clinical therapy of human disease, which is primarily based on biomedical studies in animal models. Undoubtedly, animal models have made a significant contribution to gaining insight into the developmental and pathophysiological understanding of human diseases. However, none of the existing animal models could efficiently simulate the development of human organs and systems due to a lack of spatial information; the discrepancy in genetic, anatomic, and physiological basis between animals and humans limits detailed investigation. Therefore, the translational efficiency of the research outcomes in clinical applications was significantly weakened, especially for some complex, chronic, and intractable diseases. For example, the clinical trials for human fragile X syndrome (FXS) solely based on animal models have failed such as mGluR5 antagonists. To mimic the development of human organs more faithfully and efficiently translate in vitro biomedical studies to clinical trials, extensive attention to organoids derived from stem cells contributes to a deeper understanding of this research. The organoids are a miniaturized version of an organ generated in vitro, partially recapitulating key features of human organ development. As such, the organoids open a novel avenue for in vitro models of human disease, advantageous over the existing animal models. The invention of organoids has brought an innovative breakthrough in regeneration medicine. The organoid-derived human tissues or organs could potentially function as invaluable platforms for biomedical studies, pathological investigation of human diseases, and drug screening. Importantly, the study of regeneration medicine and the development of therapeutic strategies for human diseases could be conducted in a dish, facilitating in vitro analysis and experimentation. Thus far, the pilot breakthrough has been made in the generation of numerous types of organoids representing different human organs. Most of these human organoids have been employed for in vitro biomedical study and drug screening. However, the efficiency and quality of the organoids in recapitulating the development of human organs have been hindered by engineering and conceptual challenges. The efficiency and quality of the organoids are essential for downstream applications. In this article, we highlight the application in the modeling of human neurodegenerative diseases (NDDs) such as FXS, Alzheimer's disease (AD), Parkinson's disease (PD), and autistic spectrum disorders (ASD), and organoid-based drug screening. Additionally, challenges and weaknesses especially for limits of the brain organoid models in modeling late onset NDDs such as AD and PD., and future perspectives regarding human brain organoids are addressed.

Response to Comment on "Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases".

Microglial FDG uptake alterations are the source of FDG-PET changes in models of neurodegenerative diseases.

Anti-Inflammatory Effects of GLP-1 Receptor Activation in the Brain in Neurodegenerative Diseases.

The glucagon-like peptide-1 (GLP-1) is a pleiotropic hormone well known for its incretin effect in the glucose-dependent stimulation of insulin secretion. However, GLP-1 is also produced in the brain and displays a critical role in neuroprotection and inflammation by activating the GLP-1 receptor signaling pathways. Several studies in vivo and in vitro using preclinical models of neurodegenerative diseases show that GLP-1R activation has anti-inflammatory properties. This review explores the molecular mechanistic action of GLP-1 RAS in relation to inflammation in the brain. These findings update our knowledge of the potential benefits of GLP-1RAS actions in reducing the inflammatory response. These molecules emerge as a potential therapeutic tool in treating neurodegenerative diseases and neuroinflammatory pathologies.