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Alzheimer's disease (AD) is one of the most progressive and prevalent types of neurodegenerative diseases in the aging population (aged >65 years) and is considered a major factor for dementia, affecting 55 million people worldwide. In the current scenario, drug-based therapies have been employed for the treatment of Alzheimer's disease but are only able to provide symptomatic relief to patients rather than a permanent solution from Alzheimer's. Recent advancements in stem cell research unlock new horizons for developing effective and highly potential therapeutic approaches due to their self-renewal, self-replicating, regenerative, and high differentiation capabilities. Stem cells come in multiple lineages such as embryonic, neural, and induced pluripotent, among others. Among different kinds of stem cells, mesenchymal stem cells are the most investigated for Alzheimer's treatment due to their multipotent nature, low immunogenicity, ability to penetrate the blood-brain barrier, and low risk of tumorigenesis, immune & inflammatory modulation, etc. They have been seen to substantially promote neurogenesis, synaptogenesis by secreting neurotrophic growth factors, as well as in ameliorating the Aβ and tau-mediated toxicity. This review covers the pathophysiology of AD, new medications, and therapies. Further, it will focus on the advancements and benefits of Mesenchymal Stem Cell therapies, their administration methods, clinical trials concerning AD progression, along with their future prospective., (Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.)

There are complex interactions between the gut and the brain. With increasing research on the relationship between gut microbiota and brain function, accumulated clinical and preclinical evidence suggests that gut microbiota is intimately involved in the pathogenesis of neurodegenerative diseases (NDs). Increasingly studies are beginning to focus on the association between gut microbiota and central nervous system (CNS) degenerative pathologies to find potential therapies for these refractory diseases. In this review, we summarize the changes in the gut microbiota in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis and contribute to our understanding of the function of the gut microbiota in NDs and its possible involvement in the pathogenesis. We subsequently discuss therapeutic approaches targeting gut microbial abnormalities in these diseases, including antibiotics, diet, probiotics, and fecal microbiota transplantation (FMT). Furthermore, we summarize some completed and ongoing clinical trials of interventions with gut microbes for NDs, which may provide new ideas for studying NDs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The diagnosis of neurodegenerative diseases (NDDs) remains challenging, and existing therapeutic approaches demonstrate little efficacy. NDD drug delivery can be achieved through the utilization of nanostructures, hence enabling multimodal NDD theranostics. Nevertheless, both biomembrane and non-biomembrane nanostructures possess intrinsic shortcomings that must be addressed by hybridization to create novel nanostructures with versatile applications in NDD theranostics. Hybrid nanostructures display improved biocompatibility, inherent targeting capabilities, intelligent responsiveness, and controlled drug release. This paper provides a concise overview of the latest developments in hybrid nanostructures for NDD theranostics and emphasizes various engineering methodologies for the integration of diverse nanostructures, including liposomes, exosomes, cell membranes, and non-biomembrane nanostructures such as polymers, metals, and hydrogels. The use of a combination technique can significantly augment the precision, intelligence, and efficacy of hybrid nanostructures, therefore functioning as a more robust theranostic approach for NDDs. This paper also addresses the issues that arise in the therapeutic translation of hybrid nanostructures and explores potential future prospects in this field., (© 2024. The Author(s).)

Safely and efficiently controlling gene expression is a long-standing goal of biomedical research, and CRISPR/Cas system can be harnessed to create powerful tools for epigenetic editing. Adeno-associated-viruses (AAVs) represent the delivery vehicle of choice for therapeutic platform. However, their small packaging capacity isn't suitable for large constructs including most CRISPR/dCas9-effector vectors. Thus, AAV-based CRISPR/Cas systems have been delivered via two separate viral vectors. Here we develop a compact CRISPR/dCas9-based repressor system packaged in AAV as a single optimized vector. The system comprises the small Staphylococcus aureus (Sa)dCas9 and an engineered repressor molecule, a fusion of MeCP2's transcription repression domain (TRD) and KRAB. The dSaCas9-KRAB-MeCP2(TRD) vector platform repressed robustly and sustainably the expression of multiple genes-of-interest, in vitro and in vivo, including ApoE, the strongest genetic risk factor for late onset Alzheimer's disease (LOAD). Our platform broadens the CRISPR/dCas9 toolset available for transcriptional manipulation of gene expression in research and therapeutic settings., (© 2024. The Author(s).)

Disorders of the central nervous system (CNS) which include a wide range of neurodegenerative and neurological conditions have become a serious global issue. The presence of CNS barriers poses a significant challenge to the progress of designing effective therapeutic delivery systems, limiting the effectiveness of drugs, genes, and other therapeutic agents. Natural nanocarriers present in biological systems have inspired researchers to design unique delivery systems through biomimicry. As natural resource derived delivery systems are more biocompatible, current research has been focused on the development of delivery systems inspired by bacteria, viruses, fungi, and mammalian cells. Despite their structural potential and extensive physiological function, making them an excellent choice for biomaterial engineering, the delivery of nucleic acids remains challenging due to their instability in biological systems. Similarly, the efficient delivery of genetic material within the tissues of interest remains a hurdle due to a lack of selectivity and targeting ability. Considering that gene therapies are the holy grail for intervention in diseases, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's Disease, and Huntington's disease, this review centers around recent advances in bioinspired approaches to gene delivery for the prevention of CNS disorders.

The deposition of abnormal tau protein is characteristic of Alzheimer's disease (AD) and a class of neurodegenerative diseases called tauopathies. Physiologically, tau maintains an intrinsically disordered structure and plays diverse roles in neurons. Pathologically, tau undergoes abnormal post-translational modifications and forms oligomers or fibrous aggregates in tauopathies. In this review, we briefly introduce several tauopathies and discuss the mechanisms mediating tau aggregation and propagation. We also describe the toxicity of tau pathology. Finally, we explore the early diagnostic biomarkers and treatments targeting tau. Although some encouraging results have been achieved in animal experiments and preclinical studies, there is still no cure for tauopathies. More in-depth basic and clinical research on the pathogenesis of tauopathies is necessary., (© 2024. The Author(s).)

Neurodegenerative diseases (NDDs) affect more than 50 million people worldwide, posing a significant global health challenge as well as a high socioeconomic burden. With aging constituting one of the main risk factors for some NDDs such as Alzheimer's disease (AD) and Parkinson's disease (PD), this societal toll is expected to rise considering the predicted increase in the aging population as well as the limited progress in the development of effective therapeutics. To address the high failure rates in clinical trials, legislative changes permitting the use of alternatives to traditional pre-clinical in vivo models are implemented. In this regard, microphysiological systems (MPS) such as organ-on-a-chip (OoC) platforms constitute a promising tool, due to their ability to mimic complex and human-specific tissue niches in vitro. This review summarizes the current progress in modeling NDDs using OoC technology and discusses five critical aspects still insufficiently addressed in OoC models to date. Taking these aspects into consideration in the future MPS will advance the modeling of NDDs in vitro and increase their translational value in the clinical setting., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Protein aggregation is a common age-associated process and can be a pathological hallmark of various neurodegenerative conditions, possibly because of an age-associated decline in the activity of components of the proteostasis network. The specific molecular drivers of protein aggregation in certain cell types are not well understood, posing tremendous challenges to current research aimed at devising strategies to treat neurodegenerative diseases. This preface introduces the special issue "Aging and Neurodegeneration: from molecular mechanisms to therapeutic interventions," featuring articles that assess the drivers of pathology in the aging cell, including oxidative stress, protein glycation/aggregation, and mitochondrial impairment., (© 2024 International Society for Neurochemistry.)

Background: When commencing enteral feeding, patients and families will want to know the likelihood of returning to an oral diet. There is a paucity of data on the prognosis of patients with gastrostomies. We describe a large dataset of patients, which identifies factors influencing gastrostomy removal and assesses the likelihood of the patient having at home enteral nutrition., Methods: Retrospective data was collected on patients from Sheffield Teaching Hospitals who had received a gastrostomy and had outpatient enteral feeding between January 2016 and December 2019. Demographic data, indication and outcomes were analysed., Results: A total of 451 patients were assessed, median age: 67.7. 183/451(40.6%) gastrostomies were for head and neck cancer, 88/451 (19.5%) for stroke, 28/451 (6.2%) for Motor Neuron Disease, 32/451 (7.1%) for other neurodegenerative causes, 120/451 (26.6%) other. Of the 31.2% who had their gastrostomy removed within 3 years, head and neck cancer was the most common indication (58.3%) followed by stroke (10.2%), Motor Neuron Disease (7.1%) and other neurodegenerative diseases (3.1%). Gastrostomy removal was significantly influenced by age, place of residence, and having head and neck cancer ( p  < 0.05). There was the greatest likelihood of removal within the first year (24%). 70.5% had enteral feeding at home., Conclusion: This large cohort study demonstrates 31.2% of patients had their gastrostomy removed within 3 years. Head and neck cancer patients, younger age and residing at home can help positively predict removal. Most patients manage their feeding at home rather than a nursing home. This study provides new information on gastrostomy outcomes when counselling patients to provide realistic expectations.

Neurodegenerative disorders (NDs) are expected to pose a significant challenge for both medicine and public health in the upcoming years due to global demographic changes. NDs are mainly represented by degeneration/loss of neurons, which is primarily accountable for severe mental illness. This neuronal degeneration leads to many neuropsychiatric problems and permanent disability in an individual. Moreover, the tight junction of the brain, blood-brain barrier (BBB)has a protective feature, functioning as a biological barrier that can prevent medicines, toxins, and foreign substances from entering the brain. However, delivering any medicinal agent to the brain in NDs (i.e., Multiple sclerosis, Alzheimer's, Parkinson's, etc.) is enormously challenging. There are many approved therapies to address NDs, but most of them only help treat the associated manifestations. The available therapies have failed to control the progression of NDs due to certain factors, i.e., BBB and drug-associated undesirable effects. NDs have extremely complex pathology, with many pathogenic mechanisms involved in the initiation and progression; thereby, a limited survival rate has been observed in ND patients. Hence, understanding the exact mechanism behind NDs is crucial to developing alternative approaches for improving ND patients' survival rates. Thus, the present review sheds light on different cellular mechanisms involved in NDs and novel therapeutic approaches with their clinical relevance, which will assist researchers in developing alternate strategies to address the limitations of conventional ND therapies. The current work offers the scope into the near future to improve the therapeutic approach of NDs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Neurodegenerative diseases (NDs) are a group of heterogeneous disorders with a high socioeconomic burden. Although pharmacotherapy is currently the principal therapeutic approach for the management of NDs, mounting evidence supports the notion that the protracted application of available drugs would abate their dopaminergic outcomes in the long run. The therapeutic application of microbiome-based modalities has received escalating attention in biomedical works. In-depth investigations of the bidirectional communication between the microbiome in the gut and the brain offer a multitude of targets for the treatment of NDs or maximizing the patient's quality of life. Probiotic administration is a well-known microbial-oriented approach to modulate the gut microbiota and potentially influence the process of neurodegeneration. Of note, there is a strong need for further investigation to map out the mechanistic prospects for the gut-brain axis and the clinical efficacy of probiotics. In this review, we discuss the importance of microbiome modulation and hemostasis via probiotics, prebiotics, postbiotics and synbiotics in ameliorating pathological neurodegenerative events. Also, we meticulously describe the underlying mechanism of action of probiotics and their metabolites on the gut-brain axis in different NDs. We suppose that the present work will provide a functional direction for the use of probiotic-based modalities in promoting current practical treatments for the management of neurodegenerative-related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neuronal death is often observed in central nervous system injuries and neurodegenerative diseases. The mammalian central nervous system manifests limited neuronal regeneration capabilities, and traditional cell therapies are limited in their potential applications due to finite cell sources and immune rejection. Neuronal reprogramming has emerged as a novel technology, in which non-neuronal cells (e.g. glial cells) are transdifferentiated into mature neurons. This process results in relatively minimal immune rejection. The present review discuss the latest progress in this cutting-edge field, including starter cell selection, innovative technical strategies and methods of neuronal reprogramming for neurodegenerative diseases, as well as the potential problems and controversies. The further development of neuronal reprogramming technology may pave the way for novel therapeutic strategies in the treatment of neurodegenerative diseases., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The present case study reported a patient diagnosed with hypertrophic olivary degeneration, a rare condition characterized by a trans-neuronal degeneration and signal enhancement in T2-weighted images on magnetic resonance imaging, usually caused by cerebral hemorrhage, cerebral infarction, and trauma. Furthermore, the relevant literature review was performed. The existing pharmacological treatment has limited clinical benefits on the patient. Since spontaneous remission hardly occurs in the disease, there are no other effective treatments. In this case, the patient was a 55-year-old Chinese male who presented progressive gait difficulty for several months due to both-sided ataxia. Neurological examination revealed upper extremity and lower limb bilateral spasticity, ataxia, slurred speech, and dysmetria. Therefore, our study treated the patient through the inventive application of cerebello-spinal transcranial direct current stimulation and body weight-supported treadmill training. After a 4-week treatment, the patient could walk independently, without aid, speeding up by 7%, as well as the ataxia symptoms, and balance has improved significantly. It was demonstrated in this case report that the combination of cerebello-spinal tDCS and body weight-supported treadmill training can be an effective treatment for patients with Hypertrophic olivary degeneration., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Recent advancements in brain stimulation and nanomedicine have ushered in a new era of therapeutic interventions for psychiatric and neurodegenerative disorders. This review explores the cutting-edge innovations in brain stimulation techniques, including their applications in alleviating symptoms of main neurodegenerative disorders and addiction. Deep Brain Stimulation (DBS) is an FDA-approved treatment for specific neurodegenerative disorders, including Parkinson's Disease (PD), and is currently under evaluation for other conditions, such as Alzheimer's Disease. This technique has facilitated significant advancements in understanding brain electrical circuitry by enabling targeted brain stimulation and providing insights into neural network function and dysfunction. In reviewing DBS studies, this review places particular emphasis on the underlying main neurotransmitter modifications and their specific brain area location, particularly focusing on the dopaminergic system, which plays a critical role in these conditions. Furthermore, this review delves into the groundbreaking developments in nanomedicine, highlighting how nanotechnology can be utilized to target aberrant signaling in neurodegenerative diseases, with a specific focus on the dopaminergic system. The discussion extends to emerging technologies such as magnetoelectric nanoparticles (MENPs), which represent a novel intersection between nanoformulation and brain stimulation approaches. These innovative technologies offer promising avenues for enhancing the precision and effectiveness of treatments by enabling the non-invasive, targeted delivery of therapeutic agents as well as on-site, on-demand stimulation. By integrating insights from recent research and technological advances, this review aims to provide a comprehensive understanding of how brain stimulation and nanomedicine can be synergistically applied to address complex neuropsychiatric and neurodegenerative disorders, paving the way for future therapeutic strategies.

Optogenetics, a revolutionary technique integrating optical and genetic methodologies, offers unparalleled precision in spatial targeting and temporal resolution for cellular control. This approach enables the selective manipulation of specific neuronal populations, inducing subtle electrical changes that significantly impact complex neural circuitry. As optogenetics precisely targets and modulates neuronal activity, it holds the potential for significant breakthroughs in understanding and potentially altering the course of neurodegenerative diseases, characterized by selective neuronal loss leading to functional deficits within the nervous system. The integration of optogenetics into neurodegenerative disease research has significantly advanced in the field, offering new insights and paving the way for innovative treatment strategies. Its application in clinical settings, although still in the nascent stages, suggests a promising future for addressing some of the most challenging aspects of neurodegenerative disorders. In this review, we provide a comprehensive overview of these research undertakings., (© 2024. The Author(s).)

Adult hippocampal neurogenesis (AHN) is affected by multiple factors, such as enriched environment, exercise, ageing, and neurodegenerative disorders. Neurodegenerative disorders can impair AHN, leading to progressive neuronal loss and cognitive decline. Compelling evidence suggests that individuals engaged in regular exercise exhibit higher production of proteins that are essential for AHN and memory. Interestingly, specific molecules that mediate the effects of exercise have shown effectiveness in promoting AHN and cognition in different transgenic animal models. Despite these advancements, the precise mechanisms by which exercise mimetics induce AHN remain partially understood. Recently, some novel exercise molecules have been tested and the underlying mechanisms have been proposed, involving intercommunications between multiple organs such as muscle-brain crosstalk, liver-brain crosstalk, and gut-brain crosstalk. In this review, we will discuss the current evidence regarding the effects and potential mechanisms of exercise mimetics on AHN and cognition in various neurological disorders. Opportunities, challenges, and future directions in this research field are also discussed., (© 2024. The Author(s).)

Exosomes emerge from endosomal invagination and range in size from 30 to 200 nm. Exosomes contain diverse proteins, lipids, and nucleic acids, which can indicate the state of various physiological and pathological processes. Studies have revealed the remarkable clinical potential of exosomes in diagnosing and prognosing multiple diseases, including cancer, cardiovascular disorders, and neurodegenerative conditions. Exosomes also have the potential to be engineered and deliver their cargo to a specific target. However, further advancements are imperative to optimize exosomes' diagnostic and therapeutic capabilities for practical implementation in clinical settings. This review highlights exosomes' diagnostic and therapeutic applications, emphasizing their engineering through simple incubation, biological, and click chemistry techniques. Additionally, the loading of therapeutic agents onto exosomes, utilizing passive and active strategies, and exploring hybrid and artificial exosomes are discussed., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Bahadorani et al.)

AIM2, a cytosolic innate immune receptor, has the capability to recognize double-stranded DNA (dsDNA). This paper delineates the structural features of AIM2 and its mechanisms of activation, emphasizing its capacity to detect cytosolic DNA and initiate inflammasome assembly. Additionally, we explore the diverse functions of AIM2 in different cells. Insights into AIM2-mediated neuroinflammation provide a foundation for investigating novel therapeutic strategies targeting AIM2 signaling pathways. Furthermore, we present a comprehensive review of the roles of AIM2 in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Finally, we discuss its therapeutic implications. In conclusion, a profound understanding of AIM2 in neurodegenerative diseases may facilitate the development of effective interventions to mitigate neuronal damage and slow disease progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Wang, Pan, Wang, Hu, Yao, Zhao and Sun.)

It has been widely established that the characterization of extracellular vesicles (EVs), particularly small EVs (sEVs), shed by different cell types into biofluids, helps to identify biomarkers and therapeutic targets in neurological and neurodegenerative diseases. Recent studies are also exploring the efficacy of mesenchymal stem cell-derived extracellular vesicles naturally enriched with therapeutic microRNAs and proteins for treating various diseases. In addition, EVs released by various neural cells play a crucial function in the modulation of signal transmission in the brain in physiological conditions. However, in pathological conditions, such EVs can facilitate the spread of pathological proteins from one brain region to the other. On the other hand, the analysis of EVs in biofluids can identify sensitive biomarkers for diagnosis, prognosis, and disease progression. This review discusses the potential therapeutic use of stem cell-derived EVs in several central nervous system diseases. It lists their differences and similarities and confers various studies exploring EVs as biomarkers. Further advances in EV research in the coming years will likely lead to the routine use of EVs in therapeutic settings.

Background: Within palliative care research, best practice guidelines to conduct scientifically rigorous clinical trials for neurodegenerative diseases are underexplored. This patient population experiences unique challenges, including fluctuations in cognitive capacity, care partner (CP) and proxy involvement, and high adverse events (AEs), that necessitate special consideration when designing clinical trials. Objective: The objective of this study was to describe and identify clinical trial design features that have been documented in studies involving a neuropalliative intervention for persons with neurodegenerative diseases, highlighting features that have been adapted for this unique patient population. Design: We conducted a scoping review of clinical trials with a neuropalliative intervention for persons with neurodegenerative disease. We searched Cochrane, Web of Science, EMBASE, Scopus, and PubMed (MEDLINE) databases for articles published in English between 1950 and 2023. Two reviewers screened, extracted, and synthesized data from the included articles. A third reviewer adjudicated instances of conflict. The data were analyzed using a thematic framework approach. Results: Of 1025 texts, 44 articles were included. Seven study design features were analyzed: (1) consent, (2) proxies and CPs, (3) recruitment strategies, (4) retention strategies, (5) choice of comparator, (6) AEs, and (7) internal validity. This scoping review found disparities in study design features around structured consent, proxies and CPs, comparators, and AEs. Conclusions: To date, neuropalliative care clinical trials have had varied study designs and the majority of research has focused on dementia. Research guideline development for high-quality neuropalliative care clinical trials is greatly needed across the range of neurodegenerative diseases. To increase the scientific rigor of clinical trials and neuropalliative care, we recommend a standardized capacity assessment for consent, defining conditions for the CP, proxy, and AEs, systematizing appropriate comparators, and outlining preemptive recruitment and retention strategies to address the broader unpredictable challenges of palliative care research.

Organelles, substructures in the cytoplasm with specific morphological structures and functions, interact with each other via membrane fusion, membrane transport, and protein interactions, collectively termed organelle interaction. Organelle interaction is a complex biological process involving the interaction and regulation of several organelles, including the interaction between mitochondria-endoplasmic reticulum, endoplasmic reticulum-Golgi, mitochondria-lysosomes, and endoplasmic reticulum-peroxisomes. This interaction enables intracellular substance transport, metabolism, and signal transmission, and is closely related to the occurrence, development, and treatment of many diseases, such as cancer, neurodegenerative diseases, and metabolic diseases. Herein, the mechanisms and regulation of organelle interactions are reviewed, which are critical for understanding basic principles of cell biology and disease development mechanisms. The findings will help to facilitate the development of novel strategies for disease prevention, diagnosis, and treatment opportunities., (© 2024 Wiley‐VCH GmbH.)

Objective: This systematic review aimed to evaluate the effects of Tai Chi on the health-related quality of life (HRQoL) of people with neurodegenerative diseases., Data Source: This review followed the guidelines of the updated PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020. A systematic search in five electronic databases (Medline via PubMed, Web of Science, Scopus, PEDro, and OTseeker) was performed., Study Inclusion and Exclusion Criteria: Randomized control trials (RCTs) examining Tai Chi interventions to improve HRQoL in patients with neurodegenerative diseases published through March 2023 were included., Data Extraction: Data were extracted from each study by two independent researchers into a data extraction form based on the Cochrane recommendations. Methodological quality and risk of bias were assessed., Data Synthesis: A meta-analysis was performed using Review Manager 5.3 software., Results: Of the 439 records that were screened, eight RCTs met the eligibility criteria. They assessed cognitive decline (n = 2) or Parkinson's disease (n = 6). RCT comparison groups included active interventions or usual care. The duration of Tai Chi therapy ranged from 8 to 24 weeks. A sensitivity analysis using a fixed effect model indicated that Tai Chi therapy significantly increased HRQoL [ P < 001, SMD (95% CI) = .41 [.21, .60], I 2 = 4%]., Conclusion: Tai Chi can effectively improve the HRQoL of people with neurodegenerative diseases, but the heterogeneity across intervention was relatively high. Further studies are needed as research into the benefits of Tai Chi in neurodegenerative disease rehabilitation is still limited., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Over the past few decades, there has been a notable increase in the global burden of central nervous system (CNS) diseases. Despite advances in technology and therapeutic options, neurological and neurodegenerative disorders persist as significant challenges in treatment and cure. Recently, there has been a remarkable surge of interest in extracellular vesicles (EVs) as pivotal mediators of intercellular communication. As carriers of molecular cargo, EVs demonstrate the ability to traverse the blood-brain barrier, enabling bidirectional communication. As a result, they have garnered attention as potential biomarkers and therapeutic agents, whether in their natural form or after being engineered for use in the CNS. This review article aims to provide a comprehensive introduction to EVs, encompassing various aspects such as their diverse isolation methods, characterization, handling, storage, and different routes for EV administration. Additionally, it underscores the recent advances in their potential applications in neurodegenerative disorder therapeutics. By exploring their unique capabilities, this study sheds light on the promising future of EVs in clinical research. It considers the inherent challenges and limitations of these emerging applications while incorporating the most recent updates in the field., (© 2024 The Authors. Medicinal Research Reviews published by Wiley Periodicals LLC.)

Over the last three decades, neurodegenerative diseases (NDs) have increased in frequency. About 15% of the world's population suffers from NDs in some capacity, which causes cognitive and physical impairment. Neurodegenerative diseases, including Amyotrophic Lateral Sclerosis, Parkinson's disease, Alzheimer's disease, and others represent a significant and growing global health challenge. Neuroinflammation is recognized to be related to all NDs, even though NDs are caused by a complex mix of genetic, environmental, and lifestyle factors. Numerous genes and pathways such as NFκB, p38 MAPK, Akt/mTOR, caspase, nitric oxide, and COX are involved in triggering brain immune cells like astrocytes and microglia to secrete inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. In AD, the binding of Aβ with CD36, TLR4, and TLR6 receptors results in activation of microglia which start to produce proinflammatory cytokines and chemokines. Consequently, the pro-inflammatory cytokines worsen and spread neuroinflammation, causing the deterioration of healthy neurons and the impairment of brain functions. Gene therapy has emerged as a promising therapeutic approach to modulate the inflammatory response in NDs, offering potential neuroprotective effects and disease-modifying benefits. This review article focuses on recent advances in gene therapy strategies targeting neuroinflammation pathways in NDs. We discussed the molecular pathways involved in neuroinflammation, highlighted key genes and proteins implicated in these processes, and reviewed the latest preclinical and clinical studies utilizing gene therapy to modulate neuroinflammatory responses. Additionally, this review addressed the prospects and challenges in translating gene therapy approaches into effective treatments for NDs., Competing Interests: Declaration of Competing Interest None, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Aims: Microbiota plays an essential role in maintaining body health, through positive influences on metabolic, defensive, and trophic processes and on intercellular communication. Imbalance in intestinal flora, with the proliferation of harmful bacterial species (dysbiosis) is consistently reported in chronic illnesses, including neurodegenerative diseases (ND). Correcting dysbiosis can have a beneficial impact on the symptoms and evolution of ND. This review examines the effects of microbiota modulation through administration of probiotics, prebiotics, symbiotics, or prebiotics' metabolites (postbiotics) in patients with ND like multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS)., Methods: PubMed, Web of Science, Medline databases and ClinicalTrials.gov registry searches were performed using pre-/pro-/postbiotics and ND-related terms. Further references were obtained by checking relevant articles., Results: Although few compared to animal studies, the human studies generally show positive effects on disease-specific symptoms, overall health, metabolic parameters, on oxidative stress and immunological markers. Therapy with probiotics in various forms (mixtures of bacterial strains, fecal microbiota transplant, diets rich in fermented foods) exert favorable effects on patients' mental health, cognition, and quality of life, targeting pathogenetic ND mechanisms and inducing reparatory mechanisms at the cellular level. More encouraging results have been observed in prebiotic/postbiotic therapy in some ND., Conclusions: The effects of probiotic-related interventions depend on the patients' ND stage and pre-existing allopathic medication. Further studies on larger cohorts and long term comprehensive neuropsychiatric, metabolic, biochemical testing, and neuroimaging monitoring are necessary to optimize therapeutic protocols in ND., Competing Interests: Conflict of interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Neurodegenerative disorders, including Dementia, Parkinson's disease, various Vision disorders, Multiple sclerosis, and transsynaptic degenerative changes represent a significant challenge in aging populations. This editorial synthesizes and discusses recent advancements in understanding the genetic and environmental factors contributing to these diseases. Central to these advancements is the role of neuroinflammation and oxidative stress, which exacerbate neuronal damage and accelerate disease progression. Emerging research underscores the significance of mitochondrial dysfunction and protein aggregation in neurodegenerative pathology, highlighting shared mechanisms across various disorders. Innovative therapeutic strategies, including gene therapy, CRISPR-Cas technology, and the use of naturally occurring antioxidant molecules, are being investigated to target and manage these conditions. Additionally, lifestyle interventions such as exercise and healthy diet have shown promise in enhancing brain plasticity and reducing neuroinflammation. Advances in neuroimaging and biomarker discovery are necessary to improve early diagnosis, while clinical and preclinical studies are essential for the translation of these novel treatments. This edition aims to bridge the gap between molecular mechanisms and therapeutic applications, offering insights into potential interventions to mitigate the impact of neurodegenerative diseases. By establishing a deeper understanding of these complex processes, we aim to move closer to effective prevention and treatment strategies, ultimately improving the quality of life for those affected by neurodegenerative disorders.

Neurodegenerative diseases (NDDs) are a class of neurological disorders marked by the progressive loss of neurons that afflict millions of people worldwide. These illnesses affect brain connection, impairing memory, cognition, behavior, sensory perception, and motor function. Alzheimer's, Parkinson's, and Huntington's diseases are examples of common NDDs, which frequently include the buildup of misfolded proteins. Cognitive-behavioral impairments are early markers of neurodevelopmental disorders, emphasizing the importance of early detection and intervention. Neurotrophins such as brain-derived neurotrophic factor (BDNF) are critical for neuron survival and synaptic plasticity, which is required for learning and memory. NDDs have been associated with decreased BDNF levels. Physical exercise, a non-pharmacological intervention, benefits brain health by increasing BDNF levels, lowering cognitive deficits, and slowing brain degradation. Exercise advantages include increased well-being, reduced depression, improved cognitive skills, and neuroprotection by lowering amyloid accumulation, oxidative stress, and neuroinflammation. This study examines the effects of physical exercise on cognitive-behavioral deficits and BDNF levels in the limbic system impacted by neurodegeneration. The findings highlight the necessity of including exercise into NDD treatment to improve brain structure, function, and total BDNF levels. As research advances, exercise is becoming increasingly acknowledged as an important technique for treating cognitive decline and neurodegenerative disorders., Competing Interests: Conflict of interest The authors of this work declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Neurodegeneration, known as the progressive loss of neurons in terms of their structure and function, is the principal pathophysiological change found in the majority of brain-related disorders. Ageing has been considered the most well-established risk factor in most common neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). There is currently no effective treatment or cure for these diseases; the approved therapeutic options to date are only for palliative care. Ageing and neurodegenerative diseases are closely intertwined; reversing the aspects of brain ageing could theoretically mitigate age-related neurodegeneration. Ever since the regenerative properties of young blood on aged tissues came to light, substantial efforts have been focused on identifying and characterizing the circulating factors in the young and old systemic milieu that may attenuate or accentuate brain ageing and neurodegeneration. Later studies discovered the superiority of old plasma dilution in tissue rejuvenation, which is achieved through a molecular reset of the systemic proteome. These findings supported the use of therapeutic blood exchange for the treatment of degenerative diseases in older individuals. The first objective of this article is to explore the rejuvenating properties of blood-based therapies in the ageing brains and their therapeutic effects on AD. Then, we also look into the clinical applications, various limitations, and challenges associated with blood-based therapies for AD patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Extracellular vesicles (EVs) are minute lipid-bilayer sacs discharged by cells, encompassing a diverse array of proteins, nucleic acids, and lipids. The identification of EVs as pivotal agents in intercellular communication has sparked compelling research pathways in the realms of cell biology and neurodegenerative diseases. Utilizing EVs for medicinal reasons has garnered interest due to the adaptability of EV-mediated communication. EVs can be classified based on their physical characteristics, biochemical composition, or cell of origin following purification. This review delves into the primary sub-types of EVs, providing an overview of the biogenesis of each type. Additionally, it explores the diverse environmental conditions triggering EV release and the originating cells, including stem cells and those from the Central Nervous System. Within the brain, EVs play a pivotal role as essential mediators of intercellular communication, significantly impacting synaptic plasticity, brain development, and the etiology of neurological diseases. Their potential diagnostic and therapeutic applications in various brain-related conditions are underscored, given their ability to carry specific cargo. Specially engineered EVs hold promise for treating diverse diseases, including neurodegenerative disorders. This study primarily emphasizes the diagnostic and potential therapeutic uses of EVs in neurological disorders such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Prions disease. It also summarizes innovative techniques for detecting EVs in the brain, suggesting that EVs could serve as non-invasive biomarkers for early detection, disease monitoring, and prognosis in neurological disorders., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: Neurodegenerative diseases are still challenging clinical issues, with no curative interventions available and early, accurate diagnosis remaining difficult. Finding solutions to them is of great importance. In this review, we discuss possible exosomal diagnostic biomarkers and explore current explorations in exosome-targeted therapy for some common neurodegenerative diseases, offering insights into the clinical transformation of exosomes in this field., Recent Findings: The burgeoning research on exosomes has shed light on their potential applications in disease diagnosis and treatment. As a type of extracellular vesicles, exosomes are capable of crossing the blood - brain barrier and exist in various body fluids, whose components can reflect pathophysiological changes in the brain. In addition, they can deliver specific drugs to brain tissue, and even possess certain therapeutic effects themselves. And the recent advancements in engineering modification technology have further enabled exosomes to selectively target specific sites, facilitating the possibility of targeted therapy for neurodegenerative diseases. The unique properties of exosomes give them great potential in the diagnosis and treatment of neurodegenerative diseases, and provide novel ideas for dealing with such diseases., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Our limited understanding of complex neurodegenerative disorders has held us back on the development of efficient therapies. While several approaches are currently being considered, it is still unclear what will be most successful. Among the latest and more novel ideas, the concept of blood or plasma transfusion from young healthy donors to diseased patients is gaining momentum and attracting attention beyond the scientific arena. While young or healthy blood is enriched with protective and restorative components, blood from older subjects may accumulate neurotoxic agents or be impoverished of beneficial factors. In this commentary, we present an overview of the compelling evidence collected in various animal models of brain diseases (e.g., Alzheimer, Parkinson, Huntington) to the actual clinical trials that have been conducted to test the validity of blood-related treatments in neurodegenerative diseases and argue in favor of such approach., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Obesity is a major global health concern because of its strong association with metabolic and neurodegenerative diseases such as diabetes, dementia, and Alzheimer's disease. Unfortunately, brain insulin resistance in obesity is likely to lead to neuroplasticity deficits. Since the evidence shows that insulin resistance in brain regions abundant in insulin receptors significantly alters mitochondrial efficiency and function, strategies targeting the mitochondrial quality control system may be of therapeutic and practical value in obesity-induced cognitive decline. Exercise is considered as a powerful stimulant of mitochondria that improves insulin sensitivity and enhances neuroplasticity. It has great potential as a non-pharmacological intervention against the onset and progression of obesity associated neurodegeneration. Here, we integrate the current knowledge of the mechanisms of neurodegenration in obesity and focus on brain insulin resistance to explain the relationship between the impairment of neuronal plasticity and mitochondrial dysfunction. This knowledge was synthesised to explore the exercise paradigm as a feasible intervention for obese neurodegenration in terms of improving brain insulin signals and regulating the mitochondrial quality control system., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identified in many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, and cancer. However, the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among the most important therapeutic targets. In recent years, strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials. Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria, has shown promise in preclinical trials of various diseases. Mitochondrial components, including mtDNA, mitochondria-located microRNA, and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries. Here, we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases. We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies, as well as the clinical translational situation of related pharmacology agents. Finally, this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment., (© 2024. The Author(s).)

Emerging from several decades of extensive research, key genetic elements and biochemical mechanisms implicated in neuroinflammation have been delineated, contributing substantially to our understanding of neurodegenerative diseases (NDDs). In this minireview, we discuss data predominantly from the past three years, highlighting the pivotal roles and mechanisms of the two principal cell types implicated in neuroinflammation. The review also underscores the extended process of peripheral inflammation that predates symptomatic onset, the critical influence of neuroinflammation, and their dynamic interplay in the pathogenesis of NDDs. Confronting these complex challenges, we introduce compelling evidence supporting the use of mesenchymal stem cell-based cell-free therapy. This therapeutic strategy includes the regulation of microglia and astrocytes, modulation of peripheral nerve cell inflammation, and targeted anti-inflammatory interventions specifically designed for NDDs, while also discussing engineering and safety considerations. This innovative therapeutic approach intricately modulates the immune system across the peripheral and nervous systems, with an emphasis on achieving superior penetration and targeted delivery. The insights offered by this review have significant implications for the better understanding and management of neuroinflammation.

Mesenchymal stem cells (MSCs) have garnered significant interest in the field of regenerative medicine for their ability to potentially treat various diseases, especially neurodegenerative disorders [...].

Radiation therapy targeting the central nervous system is widely utilized for the management of various brain tumors, significantly prolonging patient survival. Presently, investigations are assessing both clinical and preclinical applications of low-dose radiation (LDR) for the treatment of neuropathological conditions beyond tumor therapy. Special focus is given to refractory neurodegenerative diseases linked to neuroinflammation, such as Alzheimer's and Parkinson's diseases, where LDR has shown promising results. This comprehensive review examines the existing experimental data regarding the utilization of LDR in neurological disorders. It covers potential advantages in reducing neurodegenerative alterations and inflammation, as well as possible adverse effects, including neurological impairments. The review underscores the importance of the exposure protocol and the age at which LDR is administered in the context of the nervous system's pathological and physiological states, as these elements are crucial in determining LDR's therapeutic and toxic outcomes. The article concludes with a discussion on the future directions and challenges in optimizing LDR use, aiming to reduce toxicity while effectively managing neurological disorders.

Neurodegenerative disorders present major challenges to global health, exacerbated by an aging population and the absence of therapies. Despite diverse pathological manifestations, they share a common hallmark, loosely termed 'neuroinflammation'. The prevailing dogma is that the immune system is an active contributor to neurodegeneration; however, recent evidence challenges this. By analogy with road construction, which causes temporary closures and disruptions, the immune system's actions in the central nervous system (CNS) might initially appear destructive, and might even cause harm, while aiming to combat neurodegeneration. We propose that the application of cellular immunotherapies to coordinate the immune response towards remodeling might pave the way for new modes of tackling the roadblocks of neurodegenerative diseases., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aromatic l-amino acid decarboxylase deficiency (AADC-DY) is caused by one or more mutations in the DDC gene, resulting in the deficit in catecholamines and serotonin neurotransmitters. The disease has limited therapeutic options with relatively poor clinical outcomes. Accumulated evidence suggests the involvement of neurodegenerative mechanisms in the etiology of AADC-DY. In the absence of neurotransmitters' neuroprotective effects, the accumulation and the chronic presence of several neurotoxic metabolites including 4-dihydroxy-L-phenylalanine, 3-methyldopa, and homocysteine, in the brain of subjects with AADC-DY, promote oxidative stress and reduce the cellular antioxidant and methylation capacities, leading to glial activation and mitochondrial dysfunction, culminating to neuronal injury and death. These pathophysiological processes have the potential to hinder the clinical efficacy of treatments aimed at increasing neurotransmitters' synthesis and or function. This review describes in detail the mechanisms involved in AADC-DY neurodegenerative etiology, highlighting the close similarities with those involved in other neurodegenerative diseases. We then offer novel strategies for the treatment of the disease with the objective to either reduce the level of the metabolites or counteract their prooxidant and neurotoxic effects. These treatment modalities used singly or in combination, early in the course of the disease, will minimize neuronal injury, preserving the functional integrity of neurons, hence improving the clinical outcomes of both conventional and unconventional interventions in AADC-DY. These modalities may not be limited to AADC-DY but also to other metabolic disorders where a specific mutation leads to the accumulation of prooxidant and neurotoxic metabolites., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Glaucoma is the leading cause of irreversible blindness globally. The disease causes vision loss due to neurodegeneration of the retinal ganglion cell (RGC) projection to the brain through the optic nerve. Glaucoma is associated with sensitivity to intraocular pressure (IOP). Thus, mainstay treatments seek to manage IOP, though many patients continue to lose vision. To address neurodegeneration directly, numerous preclinical studies seek to develop protective or reparative therapies that act independently of IOP. These include growth factors, compounds targeting metabolism, anti-inflammatory and antioxidant agents, and neuromodulators. Despite success in experimental models, many of these approaches fail to translate into clinical benefits. Several factors contribute to this challenge. Firstly, the anatomic structure of the optic nerve head differs between rodents, nonhuman primates, and humans. Additionally, animal models do not replicate the complex glaucoma pathophysiology in humans. Therefore, to enhance the success of translating these findings, we propose two approaches. First, thorough evaluation of experimental targets in multiple animal models, including nonhuman primates, should precede clinical trials. Second, we advocate for combination therapy, which involves using multiple agents simultaneously, especially in the early and potentially reversible stages of the disease. These strategies aim to increase the chances of successful neuroprotective treatment for glaucoma., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

After decades of being overlooked, a recent wave of studies have explored the roles of microglia in brain health and disease. Microglia perform important physiological functions to set up and maintain proper neural network functions, as well as orchestrate responses to toxic stimuli to limit harm. Many microglial transcriptional programs, extracellular sensing molecules, and functional outputs are seen throughout life. A stark example is the similarity of microglial responses to stressors during neurodevelopment and neurodegeneration. The same themes often match that of other tissue-resident macrophages, presenting an opportunity to apply known concepts as therapeutics develop. We argue that microglial signaling during development and neurologic disease overlap with one another and with other tissue-resident macrophage pathways, in part due to similar sensed stimuli and a conserved sensome of receptors and signaling molecules, akin to a toolkit., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Accumulation of misfolded proteins and protein aggregates leading to degeneration of neurons is a hallmark of several neurodegenerative diseases. Therapy mostly relies on symptomatic relief. Immunotherapy offers a promising approach for the development of disease-modifying routes. Such strategies have shown remarkable results in oncology, and this promise is increasingly being realized for neurodegenerative diseases in advanced preclinical and clinical studies. This review highlights cases of passive and active immunotherapies in Parkinson's and Alzheimer's diseases. The reasons for success and failure, wherever available, and strategies to cross the blood-brain barrier, are discussed. The need for conditional modulation of the immune response is also reflected on., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Neurodegenerative diseases (NDDs) are characterized by neuronal damage and progressive loss of neuron function. Microbiome-based interventions, such as dietary interventions, biotics, and fecal microbiome transplant, have been proposed as a novel approach to managing symptoms and modulating disease progression. Emerging clinical trials have investigated the efficacy of interventions modulating the GM in alleviating or reversing disease progression, yet no comprehensive synthesis have been done. A systematic review of the literature was therefore conducted to investigate the efficacy of microbiome-modulating methods. The search yielded 4051 articles, with 15 clinical trials included. The overall risk of bias was moderate in most studies. Most microbiome-modulating interventions changed the GM composition. Despite inconsistent changes in GM composition, the meta-analysis showed that microbiome-modulating interventions improved disease burden (SMD, - 0.57; 95% CI - 0.93 to - 0.21; I 2  = 42%; P = 0.002) with a qualitative trend of improvement in constipation. However, current studies have high methodological heterogeneity and small sample sizes, requiring more well-designed and controlled studies to elucidate the complex linkage between microbiome, microbiome-modulating interventions, and NDDs., (© 2024. The Author(s).)

Neurodegenerative disorders (NDs) and the development of various therapeutic strategies to combat them have received increased attention in recent decades [...].

With the increasing proportion of the aging population, neurodegenerative diseases have become one of the major health issues in society. Neurodegenerative diseases (NDs), including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neurodegeneration associated with aging, leading to a gradual decline in cognitive, emotional, and motor functions in patients. The process of aging is a normal physiological process in human life and is accompanied by the aging of the immune system, which is known as immunosenescence. T-cells are an important part of the immune system, and their senescence is the main feature of immunosenescence. The appearance of senescent T-cells has been shown to potentially lead to chronic inflammation and tissue damage, with some studies indicating a direct link between T-cell senescence, inflammation, and neuronal damage. The role of these subsets with different functions in NDs is still under debate. A growing body of evidence suggests that in people with a ND, there is a prevalence of CD4 + T-cell subsets exhibiting characteristics that are linked to senescence. This underscores the significance of CD4 + T-cells in NDs. In this review, we summarize the classification and function of CD4 + T-cell subpopulations, the characteristics of CD4 + T-cell senescence, the potential roles of these cells in animal models and human studies of NDs, and therapeutic strategies targeting CD4 + T-cell senescence.

This review delves into the groundbreaking impact of induced pluripotent stem cells (iPSCs) and three-dimensional organoid models in propelling forward neuropathology research. With a focus on neurodegenerative diseases, neuromotor disorders, and related conditions, iPSCs provide a platform for personalized disease modeling, holding significant potential for regenerative therapy and drug discovery. The adaptability of iPSCs, along with associated methodologies, enables the generation of various types of neural cell differentiations and their integration into three-dimensional organoid models, effectively replicating complex tissue structures in vitro. Key advancements in organoid and iPSC generation protocols, alongside the careful selection of donor cell types, are emphasized as critical steps in harnessing these technologies to mitigate tumorigenic risks and other hurdles. Encouragingly, iPSCs show promising outcomes in regenerative therapies, as evidenced by their successful application in animal models.

The genetic landscape of neurodegenerative diseases encompasses genes affecting multiple cellular pathways which exert effects in an array of neuronal and glial cell-types. Deconvolution of the roles of genes implicated in disease and the effects of disease-associated variants remains a vital step in the understanding of neurodegeneration and the development of therapeutics. Disease modelling using patient induced pluripotent stem cells (iPSCs) has enabled the generation of key cell-types associated with disease whilst maintaining the genomic variants that predispose to neurodegeneration. The use of CRISPR interference (CRISPRi), alongside other CRISPR-perturbations, allows the modelling of the effects of these disease-associated variants or identifying genes which modify disease phenotypes. This review summarises the current applications of CRISPRi in iPSC-derived neuronal models, such as fluorescence-activated cell sorting (FACS)-based screens, and discusses the future opportunities for disease modelling, identification of disease risk modifiers and target/drug discovery in neurodegeneration., (© 2024 The Author(s).)