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Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, characterised by the selective loss of retinal ganglion cells (RGCs). Over 60% of DOA cases are caused by pathogenic variants in the OPA1 gene, which encodes a dynamin-related GTPase protein. OPA1 plays a key role in the maintenance of the mitochondrial network, mitochondrial DNA integrity and bioenergetic function. However, our current understanding of how OPA1 dysfunction contributes to vision loss in DOA patients has been limited by access to patient-derived RGCs. Here, we used induced pluripotent stem cell (iPSC)-RGCs to study how OPA1 dysfunction affects cellular homeostasis in human RGCs. iPSCs derived from a DOA+ patient with the OPA1 R445H variant and isogenic CRISPR-Cas9-corrected iPSCs were differentiated to iPSC-RGCs. Defects in mitochondrial networks and increased levels of reactive oxygen species were observed in iPSC-RGCs carrying OPA1 R445H. Ultrastructural analyses also revealed changes in mitochondrial shape and cristae structure, with decreased endoplasmic reticulum (ER): mitochondrial contact length in DOA iPSC-RGCs. Mitochondrial membrane potential was reduced and its maintenance was also impaired following inhibition of the F1Fo-ATP synthase with oligomycin, suggesting that mitochondrial membrane potential is maintained in DOA iPSC-RGCs through reversal of the ATP synthase and ATP hydrolysis. These impairments in mitochondrial structure and function were associated with defects in cytosolic calcium buffering following ER calcium release and store-operated calcium entry, and following stimulation with the excitatory neurotransmitter glutamate. In response to mitochondrial calcium overload, DOA iPSC-RGCs exhibited increased sensitivity to opening of the mitochondrial permeability transition pore. These data reveal novel aspects of DOA pathogenesis in R445H patient-derived RGCs. The findings suggest a mechanism in which primary defects in mitochondrial network dynamics disrupt core mitochondrial functions, including bioenergetics, calcium homeostasis, and opening of the permeability transition pore, which may contribute to vision loss in DOA patients. [ABSTRACT FROM AUTHOR]

Inflammation plays a key role in the development of neurodegenerative disorders that are currently incurable. Licochalcone A (LCA) has been described as an emerging anti-inflammatory drug with multiple therapeutical properties that could potentially prevent neurodegeneration. However, its neuroprotective mechanism remains unclear. Here, we investigated if LCA prevents cognitive decline induced by Lipopolysaccharide (LPS) and elucidated its potential benefits. For that, 8-week-old C57BL6/J male mice were intraperitonially (i.p.) treated with saline solution or LCA (15 mg/kg/day, 3 times per week) for two weeks. The last day, a single i.p injection of LPS (1 mg/kg) or saline solution was administered 24 h before sacrifice. The results revealed a significant reduction in mRNA expression in genes involved in oxidative stress (Sod1, Cat, Pkm, Pdha1, Ndyfv1, Uqcrb1, Cycs and Cox4i1), metabolism (Slc2a1, Slc2a2, Prkaa1 and Gsk3b) and synapsis (Bdnf, Nrxn3 and Nlgn2) in LPS group compared to saline. These findings were linked to memory impairment and depressive-like behavior observed in this group. Interestingly, LCA protected against LPS alterations through its anti-inflammatory effect, reducing gliosis and regulating M1/M2 markers. Moreover, LCA-treated animals showed a significant improvement of antioxidant mechanisms, such as citrate synthase activity and SOD2. Additionally, LCA demonstrated protection against metabolic disturbances, downregulating GLUT4 and P-AKT, and enhanced the expression of synaptic-related proteins (P-CREB, BDNF, PSD95, DBN1 and NLG3), leading all together to dendritic spine preservation. In conclusion, our results demonstrate that LCA treatment prevents LPS-induced cognitive decline by reducing inflammation, enhancing the antioxidant response, protecting against metabolic disruptions and improving synapsis related mechanisms. [ABSTRACT FROM AUTHOR]

Neuronal autophagy is essential for maintaining protein and organelle turnover, thereby safeguarding neuronal health. LC3, a central autophagy protein, exists in lipidated (LC3-II) and non-lipidated (LC3-I) forms, both critical for neurons due to their sensitivity to metabolic and proteostatic stress. To elucidate the specific roles of membrane-anchored LC3A/B in post-mitotic neurons, we engineered deconjugases with enhanced selectivity for lipidated LC3. By modifying LC3-interacting regions (LIRs) at the deconjugase termini, we significantly improved targeting specificity toward LC3A/B. Deconjugases with N-terminal LIR modifications reduced LC3A/B-associated autophagosomes, highlighting the importance of LIR positioning for specificity. Sequential N-terminal LIR arrangements further refined LC3A/B targeting without affecting GABARAP-associated autophagosomes. Moreover, reducing the hydrophobicity of the α3 helix to limit membrane residence time further improved selectivity. These targeted modifications demonstrate the potential of customized deconjugases to dissect and modulate specific autophagic pathways in neurons, paving the way for novel therapeutic strategies against neurodegenerative diseases associated with autophagy dysregulation. [ABSTRACT FROM AUTHOR]

Repeat expansions in the C9ORF72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Considerable progress has been made in identifying C9ORF72-mediated disease and resolving its underlying etiopathogenesis. The contributions of intrinsic mitochondrial deficits as well as chronic endoplasmic reticulum stress to the development of the C9ORF72-linked pathology are well established. Nevertheless, to date, no cure or effective therapy is available, and thus attempts to find a potential drug target, have received increasing attention. Here, we investigated the mode of action and therapeutic effect of a naturally occurring dietary flavanol, kaempferol in preclinical rodent and human models of C9ORF72-ALS. Notably, kaempferol treatment of C9ORF72-ALS human patient-derived motor neurons/neurons, resolved mitochondrial deficits, promoted resiliency against severe ER stress, and conferred neuroprotection. Treatment of symptomatic C9ORF72 mice with kaempferol, normalized mitochondrial calcium uptake, restored mitochondria function, and diminished ER stress. Importantly, in vivo, chronic kaempferol administration ameliorated pathological motor dysfunction and inhibited motor neuron degeneration, highlighting the translational potential of kaempferol. Lastly, in silico modelling identified a novel kaempferol target and mechanistically the neuroprotective mechanism of kaempferol is through the iP3R-VDAC1 pathway via the modulation of GRP75 expression. Thus, kaempferol holds great promise for treating neurodegenerative diseases where both mitochondrial and ER dysfunction are causally linked to the pathophysiology. [ABSTRACT FROM AUTHOR]

Many diseases and disorders of the nervous system suffer from a lack of adequate therapeutics to halt or slow disease progression, and to this day, no cure exists for any of the fatal neurodegenerative diseases. In part this is due to the incredible diversity of cell types that comprise the brain, knowledge gaps in understanding basic mechanisms of disease, as well as a lack of reliable strategies for delivering new therapeutic modalities to affected areas. With the advent of single cell genomics, it is now possible to interrogate the molecular characteristics of diverse cell populations and their alterations in diseased states. More recently, much attention has been devoted to cell populations that have historically been difficult to profile with bulk single cell technologies. In particular, cell types that comprise the cerebrovasculature have become increasingly better characterized in normal and neurodegenerative disease contexts. In this review, we describe the current understanding of cerebrovasculature structure, function, and cell type diversity and its role in the mechanisms underlying various neurodegenerative diseases. We focus on human and mouse cerebrovasculature studies and discuss both origins and consequences of cerebrovascular dysfunction, emphasizing known cell type-specific vulnerabilities in neuronal and cerebrovascular cell populations. Lastly, we highlight how novel insights into cerebrovascular biology have impacted the development of modern therapeutic approaches and discuss outstanding questions in the field. [ABSTRACT FROM AUTHOR]

The generation of retinal models from human induced pluripotent stem cells holds significant potential for advancing our understanding of retinal development, neurodegeneration, and the in vitro modeling of neurodegenerative disorders. The retina, as an accessible part of the central nervous system, offers a unique window into these processes, making it invaluable for both study and early diagnosis. This study investigates the impact of the Frontotemporal Dementia-linked IVS 10 + 16 MAPT mutation on retinal development and function using 2D and 3D retinal models derived from human induced pluripotent stem cells. Our findings reveal that the MAPT mutation leads to delayed retinal cell differentiation and maturation, with tau-mutant disease models exhibiting sustained higher expression of retinal progenitor cell markers and a reduced presence of post-mitotic neurons. Both 2D and 3D tau-mutant retinal models demonstrated an imbalance in tau isoforms, favoring 4R tau, along with increased tau phosphorylation, altered neurite morphology, and impaired cytoskeletal maturation. These changes are associated with impaired synaptic development, reduced neuronal connectivity, and enhanced cellular stress responses, including the increased formation of stress granules, markers of apoptosis and autophagy, and the presence of intracellular toxic tau aggregates. This study highlights the value of retinal models derived from human induced pluripotent stem cells in exploring the mechanisms underlying retinal pathology associated with tau mutations. These models offer essential insights into the development of therapeutic strategies for neurodegenerative diseases characterized by tau aggregation. [ABSTRACT FROM AUTHOR]

Chronic innate immune activation in the central nervous system (CNS) significantly contributes to neurodegeneration in progressive multiple sclerosis (MS). Using multiple experimental autoimmune encephalomyelitis (EAE) models, we discovered that NLRX1 protects neurons in the anterior visual pathway from inflammatory neurodegeneration. We quantified retinal ganglion cell (RGC) density and optic nerve axonal degeneration, gliosis, and T-cell infiltration in Nlrx1−/− and wild-type (WT) EAE mice and found increased RGC loss and axonal injury in Nlrx1−/− mice compared to WT mice in both active immunization EAE and spontaneous opticospinal encephalomyelitis (OSE) models. To minimize the effects of Nlrx1−/− on peripheral lymphocyte priming during EAE, we performed adoptive transfer experiments, in which activated myelin-specific T cells were transferred into lymphocyte-deficient Rag−/− or Nlrx1−/−Rag−/− mice. In this model, we found more severe microgliosis and astrogliosis in the optic nerve of Nlrx1−/−Rag−/− mice compared to Rag−/− mice, suggesting a regulatory role of NLRX1 in innate immune cells. Transcriptome analysis in primary astrocytes activated with LPS and IFNγ demonstrated that NLRX1 suppresses NF-κB activation and regulates mitochondrial oxidative phosphorylation in inflammatory reactive astrocytes. The novel pharmacologic NLRX1 activators NX-13 and LABP-66 decreased LPS-mediated gene expression of inflammatory cytokines and chemokines in mixed glial cultures. Moreover, treating EAE mice with oral LABP-66, compared to vehicle, after the onset of paralysis resulted in less anterior visual pathway neurodegeneration. These data suggest that pharmacologic NLRX1 activators have the potential to limit inflammatory neurodegeneration. This study highlights that NLRX1 could serve as a promising target for neuroprotection in progressive MS and other neurodegenerative diseases. Further studies are needed to better understand the cell-specific mechanisms underlying the neuroprotective role of NLRX1 in response to inflammation in the CNS. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive age-related neurodegenerative disease whose annual incidence is increasing as populations continue to age. Although its pathogenesis has not been fully elucidated, oxidative stress has been shown to play an important role in promoting the occurrence and development of the disease. Long noncoding RNAs (lncRNAs), which are more than 200 nucleotides in length, are also involved in the pathogenesis of PD at the transcriptional level via epigenetic regulation, or at the post-transcriptional level by participating in physiological processes, including aggregation of the α-synuclein, mitochondrial dysfunction, oxidative stress, calcium stabilization, and neuroinflammation. LncRNAs and oxidative stress are correlated during neurodegenerative processes: oxidative stress affects the expression of multiple lncRNAs, while lncRNAs regulate many genes involved in oxidative stress responses. Oxidative stress and lncRNAs also affect other processes associated with neurodegeneration, including mitochondrial dysfunction and increased neuroinflammation that lead to neuronal death. Therefore, modulating the levels of specific lncRNAs may alleviate pathological oxidative damage and have neuroprotective effects. This review discusses the general mechanisms of oxidative stress, pathological mechanism underlying the role of oxidative stress in the pathogenesis of PD, and teases out the mechanisms through which lncRNAs regulate oxidative stress during PD pathogenesis, as well as identifies the possible neuroprotective mechanisms of lncRNAs. Reviewing published studies will help us further understand the mechanisms underlying the role of lncRNAs in the oxidative stress process in PD and to identify potential therapeutic strategies for PD. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation plays a major role in amyotrophic lateral sclerosis (ALS), and cumulative evidence suggests that systemic inflammation and the infiltration of immune cells into the brain contribute to this process. However, no study has investigated the role of peripheral blood immune cells in ALS pathophysiology using single-cell RNA sequencing (scRNAseq). Methods: We aimed to characterize immune cells from blood and identify ALS-related immune alterations at single-cell resolution. For this purpose, peripheral blood mononuclear cells (PBMC) were isolated from 14 ALS patients and 14 cognitively unimpaired healthy individuals (HC), matched by age and gender, and cryopreserved until library preparation and scRNAseq. We analyzed differences in the proportions of PBMC, gene expression, and cell-cell communication patterns between ALS patients and HC, as well as their association with plasma neurofilament light (NfL) concentrations, a surrogate biomarker for neurodegeneration. Flow cytometry was used to validate alterations in cell type proportions. Results: We identified the expansion of CD56dim natural killer (NK) cells in ALS (fold change = 2; adj. p-value = 0.0051), mainly driven by a specific subpopulation, NK_2 cells (fold change = 3.12; adj. p-value = 0.0001), which represent a mature and cytotoxic CD56dim NK subset. Our results revealed extensive gene expression alterations in NK_2 cells, pointing towards the activation of immune response (adj. p-value = 9.2 × 10− 11) and the regulation of lymphocyte proliferation (adj. p-value = 6.46 × 10− 6). We also identified gene expression changes in other immune cells, such as classical monocytes, and distinct CD8 + effector memory T cells which suggested enhanced antigen presentation via major histocompatibility class-II (adj. p-value = 1.23 × 10− 8) in ALS. The inference of cell-cell communication patterns demonstrated that the interaction between HLA-E and CD94:NKG2C from different lymphocytes to NK_2 cells is unique to ALS blood compared to HC. Finally, regression analysis revealed that the proportion of CD56bright NK cells along with the ALSFRS-r, disease duration, and gender, explained up to 76.4% of the variance in plasma NfL levels. Conclusion: Our results reveal a signature of relevant changes occurring in peripheral blood immune cells in ALS and underscore alterations in the proportion, gene expression, and signaling patterns of a cytotoxic and terminally differentiated CD56dim NK subpopulation (NK_2), as well as a possible role of CD56bright NK cells in neurodegeneration. [ABSTRACT FROM AUTHOR]

Inflammasomes represent a crucial component of the innate immune system, which respond to threats by recognizing different molecules. These are known as pathogen-associated molecular patterns (PAMPs) or host-derived damage-associated molecular patterns (DAMPs). In neurodegenerative diseases and neuroinflammation, the accumulation of misfolded proteins, such as beta-amyloid and alpha-synuclein, can lead to inflammasome activation, resulting in the release of interleukin (IL)-1β and IL-18. This activation also induces pyroptosis, the release of inflammatory mediators, and exacerbates neuroinflammation. Increasing evidence suggests that inflammasomes play a pivotal role in neurodegenerative diseases. Therefore, elucidating and investigating the activation and regulation of inflammasomes in these diseases is of paramount importance. This review is primarily focused on evidence indicating that inflammasomes are activated through the canonical pathway in these diseases. Inflammasomes as potential targets for treating neurodegenerative diseases are also discussed. [ABSTRACT FROM AUTHOR]

Enriched environment (EE), as a non-pharmacological intervention, has garnered considerable attention for its potential to ameliorate neurodegenerative diseases (NDs). This review delineated the impact of EE on the biological functions associated with NDs, emphasizing its role in enhancing neural plasticity, reducing inflammation, and bolstering cognitive performance. We discussed the molecular underpinnings of the effects of EE, including modulation of key signaling pathways such as extracellular regulated kinase 1/2 (ERK1/2), mitogen-activated protein kinases (MAPK), and AMPK/SIRT1, which were implicated in neuroprotection and synaptic plasticity. Additionally, we scrutinized the influence of EE on epigenetic modifications and autophagy, processes pivotal to ND pathogenesis. Animal models, encompassing both rodents and larger animals, offer insights into the disease-modifying effects of EE, underscoring its potential as a complementary approach to pharmacological interventions. In summary, EE emerges as a promising strategy to augment cognitive function and decelerate the progression of NDs. [ABSTRACT FROM AUTHOR]

Background: Deoxyribonuclease 2 (DNase II) is pivotal in the clearance of cytoplasmic double stranded DNA (dsDNA). Its deficiency incurs DNA accumulation in cytoplasm, which is a hallmark of multiple neurodegenerative diseases. Our previous study showed that neuronal DNase II deficiency drove tau hyperphosphorylation and neurodegeneration (Li et al., Transl Neurodegener 13:39, 2024). Although it has been verified that DNase II participates in type I interferons (IFN-I) mediated autoinflammation and senescence in peripheral systems, the role of microglial DNase II in neuroinflammation and neurodegenerative diseases such as Alzheimer's disease (AD) is still unknown. Methods: The levels of microglial DNase II in triple transgenic AD mice (3xTg-AD) were measured by immunohistochemistry. The cognitive performance of microglial DNase II deficient WT and AD mice was determined using the Morris water maze test, Y-maze test, novel object recognition test and open filed test. To investigate the impact of microglial DNase II deficiency on microglial morphology, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and IFN-I pathway, neuroinflammation, synapses loss, amyloid pathology and tauopathy, the levels of cGAS-STING and IFN-I pathway related protein, gliosis and proinflammatory cytokines, synaptic protein, complement protein, Aβ levels, phosphorylated tau in the brains of the microglial DNase II deficient WT and AD mice were evaluated by immunolabeling, immunoblotting, q-PCR or ELISA. Results: We found that the levels of DNase II were significantly decreased in the microglia of 3xTg-AD mice. Microglial DNase II deficiency altered microglial morphology and transcriptional signatures, activated the cGAS-STING and IFN-I pathway, initiated neuroinflammation, led to synapse loss via complement-dependent pathway, increased Aβ levels and tauopathy, and induced cognitive decline. Conclusions: Our study shows the effect of microglial DNase II deficiency and cytoplasmic accumulated dsDNA on neuroinflammation, and reveals the initiatory mechanism of AD pathology, suggesting that DNase II is a potential target for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are diverse in clinical presentation and are caused by complex and multiple factors, including genetic mutations and environmental factors. Numerous therapeutic approaches have been developed based on the genetic causes and potential mechanisms of ALS and HD. Currently, available treatments for various neurodegenerative diseases can alleviate symptoms but do not provide a definitive cure. Gene therapy, which aims to modify or express specific proteins for neuroprotection or correction, is considered a powerful tool in managing neurodegenerative conditions. To date, antisense oligonucleotide (ASO) drugs targeting the pathological genes associated with ALS and HD have shown promising results in numerous animal studies and several clinical trials. This review provides a comprehensive overview of the development, mechanisms of action, limitations, and clinical applications of ASO drugs in neurodegenerative diseases, with a specific focus on ALS and HD therapeutic strategies. [ABSTRACT FROM AUTHOR]

Chitinase-3-like-1 (CHI3L1) is an evolutionarily conserved protein involved in key biological processes, including tissue remodeling, angiogenesis, and neuroinflammation. It has emerged as a significant player in various neurodegenerative diseases and brain disorders. Elevated CHI3L1 levels have been observed in neurological conditions such as traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD), multiple sclerosis (MS), Neuromyelitis optica (NMO), HIV-associated dementia (HAD), Cerebral ischemic stroke (CIS), and brain tumors. This review explores the role of CHI3L1 in the pathogenesis of these disorders, with a focus on its contributions to neuroinflammation, immune cell infiltration, and neuronal degeneration. As a key regulator of neuroinflammation, CHI3L1 modulates microglia and astrocyte activity, driving the release of proinflammatory cytokines that exacerbate disease progression. In addition to its role in disease pathology, CHI3L1 has emerged as a promising biomarker for the diagnosis and monitoring of brain disorders. Elevated cerebrospinal fluid (CSF) levels of CHI3L1 have been linked to disease severity and cognitive decline, particularly in AD and MS, highlighting its potential for clinical diagnostics. Furthermore, therapeutic strategies targeting CHI3L1, such as small-molecule inhibitors and neutralizing antibodies, have shown promise in preclinical studies, demonstrating reduced neuroinflammation, amyloid plaque accumulation, and improved neuronal survival. Despite its therapeutic potential, challenges remain in developing selective and safe CHI3L1-targeted therapies, particularly in ensuring effective delivery across the blood–brain barrier and mitigating off-target effects. This review addresses the complexities of targeting CHI3L1, highlights its potential in precision medicine, and outlines future research directions aimed at unlocking its full therapeutic potential in treating neurodegenerative diseases and brain pathologies. [ABSTRACT FROM AUTHOR]

Traumatic brain injury is a leading cause of chronic neurologic disability and a risk factor for development of neurodegenerative disease. However, little is known regarding the pathophysiology of human traumatic brain injury, especially in the window after acute injury and the later life development of progressive neurodegenerative disease. Given the proposed mechanisms of toxic protein production and neuroinflammation as possible initiators or contributors to progressive pathology, we examined phosphorylated tau accumulation, microgliosis and astrogliosis using immunostaining in the orbitofrontal cortex, a region often vulnerable across traumatic brain injury exposures, in an age and sex-matched cohort of community traumatic brain injury including both mild and severe cases in midlife. We found that microglial response is most prominent after chronic traumatic brain injury, and interactions with neurons in the form of satellite microglia are increased, even after mild traumatic brain injury. Taking our investigation into a mouse model, we identified that these satellite microglia suppress neuronal excitability in control conditions but lose this ability with chronic traumatic brain injury. At the same time, network hyperexcitability is present in both mouse and human orbitofrontal cortex. Our findings support a role for loss of homeostatic control by satellite microglia in the maladaptive circuit changes that occur after traumatic brain injury. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (NDDs) cause a progressive loss of neurons. Since NDDs are multifactorial, the precise etiology varies on the basis of the type of disease and patient history. Cohort studies and case studies have demonstrated a potential link between viral infections and the onset or progression of NDDs. Recent findings concerning the mechanisms by which neuropathic infections occur have provided more insights into the importance of such connections. In this review, we aim to elaborate on the occurrence of the neuropathic effects of viruses from epidemiological, clinical, and biological perspectives while highlighting potential treatments and challenges. One of the key players in viral neuropathogenesis is neuroinflammation caused by the immune response to the virus; this can occur due to both neurotropic and nonneurotropic viruses. The COVID-19 pandemic has raised concerns about whether vaccines are essential for preventing viruses or whether vaccines may play a part in exacerbating or accelerating NDDs. By classifying viruses and the common NDDs associated with them and further delving into their cellular pathways, this review provides insights to advance the development of potential treatments and diagnostic methods. [ABSTRACT FROM AUTHOR]

Purpose: X-linked adrenoleukodystrophy (XALD) can affect the eyes. Existing therapies are hampered by early quantitative examination methods. This study used an optical coherence tomography angiography system (OCTA) to investigate retinal microvascular density and perfusion in XALD patients. Methods: Fifty-two patients and 47 age-matched controls were included in this cross-sectional study. The patients were divided into three groups (symptomatic, less symptomatic, and controls). We compared the foveal avascular zone area, vascular density and perfusion area at the superficial vascular complex (SVC) and deep vascular complex (DVC) of the peripapillary and macular between the groups. We correlated these measurements with scale scores. Results: Compared with the controls, the symptomatic group had significantly lower vascular density in the superior nasal sector of the peripapillary SVC (MD − 4.940884; 95% CI − 9.655061 to − 0.226707; p = 0.036), lower vascular density (MD − 4.259225; 95% CI − 8.248627 to − 0.269823; p = 0.032) and lower perfusion area (MD − 0.180304; 95% CI − 0.337135 to − 0.023472; p = 0.018) in the peripheral ring superior quadrant of the macular SVC. Compared with the less symptomatic group, the symptomatic group exhibited a significantly lower vascular density (MD − 5.635483; 95% CI − 10.450009 to − 0.820957; p = 0.015) and perfusion area (MD − 0.063351; 95% CI − 0.116611 to − 0.010091; p = 0.013) in the superior nasal sector of the peripapillary SVC; lower vascular density (MD − 4.817846; 95% CI − 8.924294 to − 0.711399; p = 0.015) and perfusion area (MD − 0.202707; 95% CI − 0.369499 to − 0.035915; p = 0.011) in the peripheral ring superior quadrant of the macular SVC; and greater vascular density (MD 7.209401; 95% CI 0.818716–13.600086; p = 0.021) and perfusion area (MD 0.047320; 95% CI 0.001685–0.092956; p = 0.039) in the inferior nasal sector of the peripapillary DVC. Among the 52 patients, the expanded disability status score (EDSS) was moderately negatively correlated with the vascular density (p = 0.001) and perfusion area (p = 0.002) in the peripheral ring superior quadrant of the macular SVC. Conclusion: Changes in retinal vascular density and perfusion exist in XALD patients and are correlated with disease severity. OCTA has the potential to monitor the progression of XALD. [ABSTRACT FROM AUTHOR]

Background: Neurodegenerative tauopathies may progress based on seeding by pathological tau assemblies, whereby an aggregate is released from one cell, gains entry to an adjacent or connected cell, and serves as a specific template for its own replication in the cytoplasm. Seeding into the complex cytoplasmic milieu happens within hours, implying the existence of unknown factors that regulate this process. Methods: We used proximity labeling to identify proteins that control seed amplification within 5 h of seed exposure. We fused split-APEX2 to the C-terminus of tau repeat domain (RD) to reconstitute peroxidase activity 5 h after seeded intracellular tau aggregation. Valosin containing protein (VCP/p97) was the top hit. VCP harbors dominant mutations that underlie two neurodegenerative diseases, multisystem proteinopathy and vacuolar tauopathy, but its mechanistic role is unclear. We used immortalized cells and human neurons to study the effects of VCP on tau seeding. We exposed cells to fibrils or brain homogenates in cell culture media and measured effects on uptake and induction of intracellular tau aggregation following various genetic and pharmacological manipulations of VCP. Results: VCP knockdown reduced tau seeding. Chemical inhibitors had opposing effects on seeding in HEK293T tau biosensor cells and human neurons: ML-240 increased seeding efficiency, whereas NMS-873 decreased it. The inhibitors only functioned when administered within 8 h of seed exposure, indicating a role for VCP early in seed processing. We screened 30 VCP co-factors in HEK293T biosensor cells by genetic knockout or knockdown. Reduction of ATXN3, NSFL1C, UBE4B, NGLY1, and OTUB1 decreased tau seeding, as did NPLOC4, which also uniquely increased soluble tau levels. By contrast, reduction of FAF2 increased tau seeding. Conclusions: Divergent effects on tau seeding of chemical inhibitors and cofactor reduction indicate that VCP regulates this process. This is consistent with a cytoplasmic processing complex centered on VCP that directs seeds acutely towards degradation vs. amplification. [ABSTRACT FROM AUTHOR]

Neurodegeneration in glaucoma patients is clinically identified through longitudinal assessment of structure–function changes, including intraocular pressure, cup-to-disc ratios from fundus images, and optical coherence tomography imaging of the retinal nerve fiber layer. Use of human post-mortem ocular tissue for basic research is rising in the glaucoma field, yet there are challenges in assessing disease stage and severity, since tissue donations with informed consent are often unaccompanied by detailed pre-mortem clinical information. Further, the interpretation of disease severity based solely on anatomical and morphological assessments by histology can be affected by differences in death-to-preservation time and tissue processing. These are difficult confounders that cannot be easily controlled. As pathogenesis and molecular mechanisms can vary depending on the stage and severity of glaucoma, there is a need for the field to maximize use of donated tissue to better understand the molecular mechanisms of glaucoma and develop new therapeutic hypotheses. Further, there is a lack of consensus around the molecular RNA and protein markers that can be used to classify glaucoma severity. Here, we describe a multiparametric grading system that combines structural measurements of the retinal nerve fiber layer with linear regression and principal component analyses of molecular markers of retinal ganglion cells and glia (RBPMS, NEFL, IBA1 and GFAP) to stratify post-mortem glaucoma eyes by the severity of disease. Our findings show that a quantitative grading approach can stratify post-mortem glaucoma samples with minimal clinical histories into at least three severity groups and suggest that this type of approach may be useful for researchers aiming to maximize insights derived from eye bank donor tissue. [ABSTRACT FROM AUTHOR]

Oxidative stress and neuroinflammation are recognized as key factors in the development of neurodegenerative diseases, yet effective interventions and biomarkers to address oxidative stress and neuroinflammation in these conditions are limited. Uric acid (UA), traditionally associated with gout, is now gaining prominence as a potential target in neurodegenerative diseases. Soluble UA stands out as one of the most vital antioxidant compounds produced by the human body, accounting for up to 55% of the extracellular capacity to neutralize free radicals. While there is increasing evidence supporting the neuroprotective properties of UA in Parkinson's disease and Alzheimer's disease, gaps in knowledge still exist regarding the underlying mechanisms and how to effectively translate these benefits into clinical practice. Moreover, the current UA elevation therapy exhibits unstable antioxidant properties, individual variability, and even adverse effects, limiting its potential clinical applications. This review consolidates recent advancements in understanding how UA exerts neuroprotective effects on neurodegenerative diseases and emphasizes the dual roles of UA in managing oxidative stress and neuroinflammation. Additionally, the review elucidates the mechanisms through which UA confers neuroprotection. Based on this, the review underscores the significance of UA as a potential biomarker and aims to provide a comprehensive understanding of its potential as a therapeutic target, while also addressing possible challenges to clinical implementation. [ABSTRACT FROM AUTHOR]

TAR DNA-binding protein 43 (TDP-43) has emerged as a critical player in neurodegenerative disorders, with its dysfunction implicated in a wide spectrum of diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer's disease (AD). This comprehensive review explores the multifaceted roles of TDP-43 in both physiological and pathological contexts. We delve into TDP-43's crucial functions in RNA metabolism, including splicing regulation, mRNA stability, and miRNA biogenesis. Particular emphasis is placed on recent discoveries regarding TDP-43's involvement in DNA interactions and chromatin dynamics, highlighting its broader impact on gene expression and genome stability. The review also examines the complex pathogenesis of TDP-43-related disorders, discussing the protein's propensity for aggregation, its effects on mitochondrial function, and its non-cell autonomous impacts on glial cells. We provide an in-depth analysis of TDP-43 pathology across various neurodegenerative conditions, from well-established associations in ALS and FTLD to emerging roles in diseases such as Huntington's disease and Niemann-Pick C disease. The potential of TDP-43 as a therapeutic target is explored, with a focus on recent developments in targeting cryptic exon inclusion and other TDP-43-mediated processes. This review synthesizes current knowledge on TDP-43 biology and pathology, offering insights into the protein's central role in neurodegeneration and highlighting promising avenues for future research and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: The prion-like spreading of Tau pathology is the leading cause of disease progression in various tauopathies. A critical step in propagating pathologic Tau in the brain is the transport from the extracellular environment and accumulation inside naïve neurons. Current research indicates that human neurons internalize both the physiological extracellular Tau (eTau) monomers and the pathological eTau aggregates. However, similarities or differences in neuronal transport mechanisms between Tau species remain elusive. Method: Monomers, oligomers, and fibrils of recombinant 2N4R Tau were produced and characterized by biochemical and biophysical methods. A neuronal eTau uptake and accumulation assay was developed for human induced pluripotent stem cell-derived neurons (iPSCNs) and Lund human mesencephalic cells (LUHMES)-derived neurons. Mechanisms of uptake and cellular accumulation of eTau species were studied by using small molecule inhibitors of endocytic mechanisms and siRNAs targeting Tau uptake mediators. Results: Extracellular Tau aggregates accumulated more than monomers in human neurons, mainly due to the higher efficiency of small fibrillar and soluble oligomeric aggregates in intraneuronal accumulation. A competition assay revealed a distinction in the neuronal accumulation between physiological eTau Monomers and pathology-relevant aggregates, suggesting differential transport mechanisms. Blocking heparan sulfate proteoglycans (HSPGs) with heparin only inhibited the accumulation of eTau aggregates, whereas monomers' uptake remained unaltered. At the molecular level, the downregulation of genes involved in HSPG synthesis exclusively blocked neuronal accumulation of eTau aggregates but not monomers, suggesting its role in the transport of pathologic Tau. Moreover, the knockdown of LRP1, as a receptor of Tau, mainly reduced the accumulation of monomeric form, confirming its involvement in Tau's physiological transport. Conclusion: These data propose that despite the similarity in the cellular mechanism, the uptake and accumulation of eTau Monomers and aggregates in human neurons are regulated by different molecular mediators. Thus, they address the possibility of targeting the pathological spreading of Tau aggregates without disturbing the probable physiological or non-pathogenic transport of Tau Monomers. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of people worldwide. Mobile technologies enable Parkinson's patients to improve their quality of life, manage symptoms, and enhance overall well-being through various applications (apps). There is no integrated list of specific capabilities available to cater to the unique needs of Parkinson's patient-focused mobile apps. Objective: This study aimed to identify the key features and capabilities prioritized in developing mobile apps for patients with Parkinson's disease (PWP) and rank the related apps in this field. Methods: We searched iTunes and Google Play for PWP apps with "Parkinson" or "Parkinson's" in their title or description. We evaluated existing mobile apps through a four-step process: identification, screening, eligibility, and feature analysis. We installed apps on Android and iOS devices, categorized their features/capabilities by the "use case model" and other additional identified features. We scored them using a tool called FARM (Feature-based Application Rating Method) and ranked PWP-related apps. Results: Thirty-three apps related to the PWP were included and evaluated. Almost half of the apps were available on both the Android and iOS platforms. Seventy-five percent of the genres were associated with health and fitness. Although the included apps utilized certain features, none of the capabilities were used simultaneously. According to the experts' opinions, 'large font' was the most important feature and was utilized in 70% of the mobile applications. Additionally, the average score for all Parkinson's disease-related applications was 17.71 (SD = 7.92). The app titled 'Swiss Parkinson' had the highest score. Conclusions: Integrating a relevant list of features used for Parkinson's patients' applications yielded valuable insights for the design of mobile applications tailored to patients' needs. These features are highly efficient in dealing with the specific obstacles related to this disease. [ABSTRACT FROM AUTHOR]

In recent years, a growing body of research has unveiled the involvement of the necroptosis pathway in the pathogenesis of Alzheimer's disease (AD). This evidence has shed light on the mechanisms underlying neuronal death in AD, positioning necroptosis at the forefront as a potential target for therapeutic intervention. This review provides an update on the current knowledge on this emerging, yet rapidly advancing topic, encompassing all published studies that present supporting proof of the role of the necroptosis pathway in the neurodegenerative processes of AD. The implication of misfolded tau and amyloid-β (Aβ) aggregates is highlighted, with evidence suggesting their direct or indirect involvement in necroptosis activation. In summary, the review underscores the significance of understanding the complex interplay between necroptosis, protein aggregates, and neurodegeneration in AD. The findings advocate for a comprehensive approach, combining therapeutic and early diagnostic strategies, to intervene in the disease process before irreversible damage occurs. [ABSTRACT FROM AUTHOR]

Background: The global incidence of type 2 diabetes (T2D) is rapidly increasing, with retinopathy being its most common complication and a leading cause of preventable blindness. Although the precise mechanisms involved in the development of diabetic retinopathy (DR) are not fully understood, defective immunomodulation is a recognized key factor in its pathophysiology. Regulatory T cells (Treg) regulate inflammation and promote regeneration, and while they are known to have important anti-inflammatory and neuroprotective roles in other tissues, including central nervous system, their role in the diabetic retina remains largely unknown. The aim of the present study is to examine the effect of Treg expansion of retinal neurodegeneration, an early event in the pathogenesis of DR. Methods: Treg expansion was achieved by co-injecting recombinant mouse IL-2 with anti-IL-2 monoclonal antibody or its isotype in db/db mice as an established model of T2D. Treg expansion was confirmed via flow cytometry in blood, spleen, and retina. Fundus angiography was performed in the days prior to animal sacrifice at 18 weeks. To study the effect of Tregs on retinal neurons, glia and vascular permeability, immunohistochemistry against Cone-Arrestin, PKCα, synaptophysin, ChAT, TH, GFAP, Iba-1, calbindin, Brn3a, RBPMS, isolectin B4, and albumin was used. Retinal VEGF levels were measured with a magnetic bead-based immunoassay, and NLRP3, Casp1, p20 and IL-18 were analyzed by Western Blot in retinal homogenates. Results: There was a significant decrease in Treg in db/db mice blood. When this deficiency was corrected in db/db mice by systemic Treg expansion, there was an effective protection against retinal neurodegenerative, gliotic, inflammatory changes and vascular leakage associated with T2D. Importantly, Treg expansion did not impact the T2D phenotype in db/db mice as evaluated by blood glucose, HbA1c and circulating insulin. Conclusion: Treg modulation in T2D offers a promising therapeutic approach to prevent early stages of DR. This strategy focuses on reducing neuroinflammation and mitigating the associated neuronal, glial, and vascular degenerative changes characteristic of DR. [ABSTRACT FROM AUTHOR]

Endosomes are crucial sites for intracellular material sorting and transportation. Endosomal transport is a critical process involved in the selective uptake, processing, and intracellular transport of substances. The equilibrium between endocytosis and circulation mediated by the endosome-centered transport pathway plays a significant role in cell homeostasis, signal transduction, and immune response. In recent years, there have been hints linking endosomal transport abnormalities to neurodegenerative diseases, including Alzheimer's disease. Nonetheless, the related mechanisms remain unclear. Here, we provide an overview of endosomal-centered transport pathways and highlight potential physiological processes regulated by these pathways, with a particular focus on the correlation of endosomal trafficking disorders with common pathological features of neurodegenerative diseases. Additionally, we summarize potential therapeutic agents targeting endosomal trafficking for the treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Inflammasomes represent a crucial component of the innate immune system, which respond to threats by recognizing different molecules. These are known as pathogen-associated molecular patterns (PAMPs) or host-derived damage-associated molecular patterns (DAMPs). In neurodegenerative diseases and neuroinflammation, the accumulation of misfolded proteins, such as beta-amyloid and alpha-synuclein, can lead to inflammasome activation, resulting in the release of interleukin (IL)-1β and IL-18. This activation also induces pyroptosis, the release of inflammatory mediators, and exacerbates neuroinflammation. Increasing evidence suggests that inflammasomes play a pivotal role in neurodegenerative diseases. Therefore, elucidating and investigating the activation and regulation of inflammasomes in these diseases is of paramount importance. This review is primarily focused on evidence indicating that inflammasomes are activated through the canonical pathway in these diseases. Inflammasomes as potential targets for treating neurodegenerative diseases are also discussed. [ABSTRACT FROM AUTHOR]

Background: Age-related macular degeneration (AMD), is a neurodegenerative ocular disease. This study investigated the role of ferroptosis-related genes and their interaction with immune cell infiltration in AMD. Methods: We screened differential expression genes (DEGs) of AMD from data sets in Gene Expression Omnibus. We identified ferroptosis-related differentially expressed genes (ferroDEGs) by intersecting DEGs with ferroptosis-related genes. Protein–protein interactions network and Cytoscape were used for screening hub genes. Next, we analyzed immune cell infiltration using CIBERSORT and examined the crosstalk between hub ferroDEGs and immune cell infiltration. Hub genes expression in each cell cluster and the proportions of different cell clusters between AMD and normal samples were examined using single-cell data. The hub ferroDEG expressions were verified in cell and mouse models using RT–qPCR, western blot, and immunofluorescence assay. The roles of ANXA1 in ferroptosis and its crosstalk with microglia were investigated. Results: We identified hub ferroDEGs that include six genes (ANXA1, DKK1, CD44, VIM, TGFB2, DUSP1). Functional analysis of those hub ferroDEGs was found to be correlated with leukocyte migration and chemotaxis, macrophage migration, and gliogenesis. The high-risk ferroptosis group exhibited elevated levels of CD8+ T cells, activated NK cells, and M2 macrophages. Single-cell sequencing data revealed a high degree of cell heterogeneity in macular degeneration and the monocytes proportion in the macular area was higher in AMD samples. Moreover, we observed elevated mRNA and protein levels of CD44, ANXA1 (P < 0.01), while ANXA1 knockdown reduced GPX4 expression in the cell model. Finally, we validated increased ANXA1 expression and observed its colocalization with microglia in mouse models using immunofluorescence assays. Conclusions: This study offers insights into the AMD pathogenesis and identifies ANXA1 as a potential target related to protecting from ferroptosis and immune response for future research. [ABSTRACT FROM AUTHOR]

Alterations to the composition and function of neuronal nuclear pore complexes (NPCs) have been documented in multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Moreover, recent work has suggested that injury to the NPC can at least in part contribute to TDP-43 loss of function and mislocalization, a pathological hallmark of ALS and related neurodegenerative diseases. Collectively, these studies highlight a role for disruptions in NPC homeostasis and surveillance as a significant pathophysiologic event in neurodegeneration. The ESCRT-III nuclear surveillance pathway plays a critical role in the surveillance and maintenance of NPCs and the surrounding nuclear environment. Importantly, pathologic alterations to this pathway and its protein constituents have been implicated in neurodegenerative diseases such as ALS. However, the mechanism by which this pathway contributes to disease associated alterations in the NPC remains unknown. Here we use an induced pluripotent stem cell (iPSC) derived neuron (iPSN) model of sALS to demonstrate that CHMP7/ESCRT-III nuclear maintenance/surveillance is overactivated in sALS neurons. This overactivation is dependent upon the ESCRT-III protein CHMP2B and sustained CHMP2B dependent "activation" is sufficient to contribute to pathologic CHMP7 nuclear accumulation and POM121 reduction. Importantly, partial knockdown of CHMP2B was sufficient to alleviate NPC injury and downstream TDP-43 dysfunction in sALS neurons thereby highlighting CHMP2B as a potential therapeutic target in disease. [ABSTRACT FROM AUTHOR]

The identification of ferroptosis represents a pivotal advancement in the field of cell death research, revealing an entirely novel mechanism of cellular demise and offering new insights into the initiation, progression, and therapeutic management of various diseases. Ferroptosis is predominantly induced by intracellular iron accumulation, lipid peroxidation, or impairments in the antioxidant defense system, culminating in membrane rupture and consequent cell death. Studies have associated ferroptosis with a wide range of diseases, and by enhancing our comprehension of its underlying mechanisms, we can formulate innovative therapeutic strategies, thereby providing renewed hope for patients. [ABSTRACT FROM AUTHOR]

Misfolding of normal prion protein (PrPC) to pathological isoforms (prions) causes prion diseases (PrDs) with clinical manifestations including cognitive decline and mood-related behavioral changes. Cognition and mood are linked to the neurophysiology of the limbic system. Little is known about how the disease affects the synaptic activity in brain parts associated with this system. We hypothesize that the dysfunction of synaptic transmission in the limbic regions correlates with the onset of reduced cognition and behavioral deficits. Here, we studied how prion infection in mice disrupts the synaptic function in three limbic regions, the hippocampus, hypothalamus, and amygdala, at a pre-clinical stage (mid-incubation period) and early clinical onset. PrD caused calcium flux dysregulation associated with lesser spontaneous synchronous neuronal firing and slowing neural oscillation at the pre-clinical stage in the hippocampal CA1, ventral medial hypothalamus, and basolateral amygdala (BLA). At clinical onset, synaptic transmission and synaptic plasticity became significantly disrupted. This correlated with a substantial depletion of the soluble prion protein, loss of total synapses, abnormal neurotransmitter levels and synaptic release, decline in synaptic vesicle recycling, and cytoskeletal damage. Further, the amygdala exhibited distinct disease-related changes in synaptic morphology and physiology compared with the other regions, but generally to a lesser degree, demonstrating how different rates of damage in the limbic system influence the evolution of clinical disease. Overall, PrD causes synaptic damage in three essential limbic regions starting at a preclinical stage and resulting in synaptic plasticity dysfunction correlated with early disease signs. Therapeutic drugs that alleviate these early neuronal dysfunctions may significantly delay clinical onset. [ABSTRACT FROM AUTHOR]

Background: Posterior Cortical Atrophy (PCA) is a clinical syndrome characterized by progressive visuospatial and visuoperceptual impairment. As the neurodegenerative disease progresses, patients lose independent functioning due to the worsening of initial symptoms and development of symptoms in other cognitive domains. The timeline of clinical progression is variable across patients, and the field currently lacks robust methods for prognostication. Here, evaluated the utility of MRI-based cortical atrophy as a predictor of longitudinal clinical decline in a sample of PCA patients. Methods: PCA patients were recruited through the Massachusetts General Hospital Frontotemporal Disorders Unit PCA Program. All patients had cortical thickness estimates from baseline MRI scans, which were used to predict longitudinal change in clinical impairment assessed by the CDR Sum-of-Boxes (CDR-SB) score. Multivariable linear regression was used to estimate the magnitude of cortical atrophy in PCA patients relative to a group of amyloid-negative cognitively unimpaired participants. Linear mixed-effects models were used to test hypotheses about the utility of baseline cortical atrophy for predicting longitudinal clinical decline. Results: Data acquired from 34 PCA patients (mean age = 65.41 ± 7.90, 71% females) and 24 controls (mean age = 67.34 ± 4.93, 50% females) were analyzed. 62% of the PCA patients were classified as having mild cognitive impairment (CDR 0.5) at baseline, with the rest having mild dementia (CDR 1). Each patient had at least one clinical follow-up, with the mean duration of 2.78 ± 1.62 years. Relative to controls, PCA patients showed prominent baseline atrophy in the posterior cortical regions, with the largest effect size observed in the visual network of the cerebral cortex. Cortical atrophy localized to the dorsal attention network, which supports higher-order visuospatial function, selectively predicted the rate of subsequent clinical decline. Conclusions: These results demonstrate the utility of a snapshot measure of cortical atrophy of the dorsal attention network for predicting the rate of subsequent clinical decline in PCA. If replicated, this topographically-specific MRI-based biomarker could be useful as a clinical prognostication tool that facilitates personalized care planning. [ABSTRACT FROM AUTHOR]

Background: Clinical studies have long observed that neurodegenerative disorders display a range of symptoms and pathological features and, in some cases, overlap, suggesting that these diseases exist on a spectrum. Dementia with Lewy Bodies (DLB), a synucleinopathy, is a prominent example, where symptomatic similarities with tauopathy, Alzheimer's disease, are observed. Although tau pathology has been observed in DLB, the interplay between tau and α-synuclein is poorly understood at a molecular level. Methods: Quantitative mass spectrometry analysis was used to measure protein abundance in the insoluble fraction from cortical brain tissue from pathologically diagnosed DLB subjects (n = 30) and age-matched controls (n = 29). Using tau abundance, we stratified the DLB subjects into two subgroups termed DLBTau+ (higher abundance) and DLBTau− (lower abundance). We conducted proteomic analysis to characterize and compare the cortical proteome of DLB subjects exhibiting elevated tau, as well as the molecular modifications of tau and α-synuclein to explore the dynamic between tau and α-synuclein pathology in these patients. Results: Proteomic analyses revealed distinct global protein dysregulations in DLBTau+ and DLBTau− subjects when compared to controls. Notably, DLBTau+ patients exhibited increased levels of tau, along with ubiquitin, and APOE, indicative of cortical proteome alterations associated with elevated tau. Comparing DLBTau+ and DLBTau− groups, we observed significant upregulation of cytokine signaling and metabolic pathways in DLBTau− patients, while DLBTau+ subjects showed increases in protein ubiquitination processes and regulation of vesicle-mediated transport. Additionally, we examined the post-translational modification patterns of tau and α-synuclein. Our analysis revealed distinct phosphorylation and ubiquitination sites on α-synuclein between groups. Moreover, we observed increased modifications on tau specifically within the DLBTau+ subgroup. Conclusion: This molecular-level data supports the idea of neurodegenerative disease as a continuum of diseases with distinct PTM profiles DLBTau+ and DLBTau− patients in comparison to AD. These findings further emphasize the importance of identifying specific and tailored therapeutic approaches targeting the involved proteopathies in the neurodegenerative disease spectrum. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) and stroke pose major health challenges, impacting millions of individuals globally. Once considered solely acute events, these neurological conditions are now recognized as enduring pathological processes with long-term consequences, including an increased susceptibility to neurodegeneration. However, effective strategies to counteract their devastating consequences are still lacking. Cellular senescence, marked by irreversible cell-cycle arrest, is emerging as a crucial factor in various neurodegenerative diseases. Recent research further reveals that cellular senescence may be a potential driver for secondary neurodegeneration following brain injury. Herein, we synthesize emerging evidence that TBI and stroke drive the accumulation of senescent cells in the brain. The rationale for targeting senescent cells as a therapeutic approach to combat neurodegeneration following TBI/stroke is outlined. From a translational perspective, we emphasize current knowledge and future directions of senolytic therapy for these neurological conditions. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are membrane vesicles originating from different cells within the brain. The pathophysiological role of EVs in neurodegenerative diseases is progressively acknowledged. This field has advanced from basic biological research to essential clinical significance. The capacity to selectively enrich specific subsets of EVs from biofluids via distinctive surface markers has opened new avenues for molecular understandings across various tissues and organs, notably in the brain. In recent years, brain-derived EVs have been extensively investigated as biomarkers, therapeutic targets, and drug-delivery vehicles for neurodegenerative diseases. This review provides a brief overview of the characteristics and physiological functions of the various classes of EVs, focusing on the biological mechanisms by which various types of brain-derived EVs mediate the occurrence and development of neurodegenerative diseases. Concurrently, novel therapeutic approaches and challenges for the use of EVs as delivery vehicles are delineated. [ABSTRACT FROM AUTHOR]

Background: The expansion of CAG/CTG repeats in functionally unrelated genes is a causative factor in many inherited neurodegenerative disorders, including Huntington's disease (HD), spinocerebellar ataxias (SCAs), and myotonic dystrophy type 1 (DM1). Despite many years of research, the mechanism responsible for repeat instability is unknown, and recent findings indicate the key role of DNA repair in this process. The repair of DSBs induced by genome editing tools results in the shortening of long CAG/CTG repeats in yeast models. Understanding this mechanism is the first step in developing a therapeutic strategy based on the controlled shortening of repeats. The aim of this study was to characterize Cas9-induced DSB repair products at the endogenous HTT locus in human cells and to identify factors affecting the formation of specific types of sequences. Results: The location of the cleavage site and the surrounding sequence influence the outcome of DNA repair. DSBs within CAG repeats result in shortening of the repeats in frame in ~ 90% of products. The mechanism of this contraction involves MRE11-CTIP and RAD51 activity and DNA end resection. We demonstrated that a DSB located upstream of CAG repeats induces polymerase theta-mediated end joining, resulting in deletion of the entire CAG tract. Furthermore, using proteomic analysis, we identified novel factors that may be involved in CAG sequence repair. Conclusions: Our study provides new insights into the complex mechanisms of CRISPR/Cas9-induced shortening of CAG repeats in human cells. [ABSTRACT FROM AUTHOR]

Multisensory decline is common as people age, and aging is the primary risk of Alzheimer's Disease (AD). Recent studies have begun to shed light on the possibility that age-related sensory decline could accelerate AD pathogenesis, or be a prodromal indicator of AD. Sensory impairments, specifically in taste and smell, often emerge before cognitive symptoms in AD, indicating their potential as early biomarkers. Olfactory dysfunction has been frequently associated with AD and may offer valuable insights into early detection. Hearing impairment is significantly associated with AD, but its causal impact on AD progression remains unclear. The review also discusses visual and tactile deficits in AD, including retinal thinning and changes in tactile perception, highlighting their links to disease progression. Focusing on molecular mechanisms, the review explores the roles of amyloid-β (Aβ) accumulation and tau protein pathology in sensory decline and their bidirectional relationship with AD. In summary, the evidence presented conclusively supports advocating for an integrated approach to understanding AD and sensory decline, to enhance early detection, implementing preventive strategies, and developing therapeutic interventions for AD. This approach underscores the significance of sensory health in addressing neurodegenerative diseases, particularly AD. [ABSTRACT FROM AUTHOR]

Background: Understanding quality of life (QoL) is important in diseases for which there is no cure to date, such as Huntington's disease (HD). A deeper level of understanding is, however, compromised by the lack of studies examining QoL from the perspectives of HD gene expansion carriers (HDGECs). Only a few qualitative studies on QoL in HD have been performed, yet none investigated how QoL is defined by HDGECs themselves. Objective: This qualitative study explores how premanifest and manifest HDGECs define their QoL. Methods: Online semi-structured interviews were conducted with 6 premanifest and 6 manifest HDGECs in the Netherlands. Qualitative content analysis was used to explore participants' QoL definitions via inductive coding and the subsequent formulation of (sub)categories and (sub)themes. Results: Premanifest and manifest HDGECs had a different focus when defining QoL. Two subthemes were identified for premanifest HDGECs: Thoughts about a meaningful life regardless of HD and Concerns about the future progression and impact of HD. For manifest HDGECs, two other subthemes were identified: Coming to terms with HD and Shifting perspectives due to the impact of HD. One overall theme was generated, reflecting the difference and adaptive shift in focus between premanifest and manifest HDGECs: Shifting focus from ideality to reality. Conclusions: In providing optimal care, HDGECs should be considered as part of a complex, continuously changing environment, thereby taking into account their individual QoL experiences and tailoring care accordingly. HDGECs might benefit from forming helpful beliefs about future adaptability and resilience and developing adaptive coping strategies. [ABSTRACT FROM AUTHOR]

Background: Tauopathies are a group of age-related neurodegenerative diseases characterized by the accumulation of pathologically hyperphosphorylated tau protein in the brain, leading to prion-like aggregation and propagation. They include Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). Currently, reliable diagnostic biomarkers that directly reflect the capability of propagation and spreading of misfolded tau aggregates in peripheral tissues and body fluids are lacking. Methods: We utilized the seed-amplification assay (SAA) employing ultrasensitive real-time quaking-induced conversion (RT-QuIC) to assess the prion-like seeding activity of pathological tau in the skin of cadavers with neuropathologically confirmed tauopathies, including AD, PSP, CBD, and PiD, compared to normal controls. Results: We found that the skin tau-SAA demonstrated a significantly higher sensitivity (75–80%) and specificity (95–100%) for detecting tauopathy, depending on the tau substrates used. Moreover, the increased tau-seeding activity was also observed in biopsy skin samples from living AD and PSP patients examined. Analysis of the end products of skin-tau SAA confirmed that the increased seeding activity was accompanied by the formation of tau aggregates with different physicochemical properties related to two different tau substrates used. Conclusions: Overall, our study provides proof-of-concept that the skin tau-SAA can differentiate tauopathies from normal controls, suggesting that the seeding activity of misfolded tau in the skin could serve as a diagnostic biomarker for tauopathies. [ABSTRACT FROM AUTHOR]

The Nuclear factor erythroid 2–related factor (Nrf2)/ Heme oxygenase-1 (HO-1) pathway, known for its significant role in regulating innate antioxidant defense mechanisms, is increasingly being recognized for its potential in neuroprotection studies. Derived from bee venom, melittin's neuroprotective effects have raised interest. This study confirmed that melittin specificity upregulated the weakened Nrf2/HO-1 signaling in mice brain. Interestingly, we also revealed melittin's efficient tactic, as it was suggested to first restore redox balance and then gradually stabilized other regulations of the mouse hippocampus. Using a neuro-stress-induced scopolamine model, chromatography and mass spectrometry analysis revealed that melittin crossed the compromised blood–brain barrier and accumulated in the hippocampus, which provided the chance to interact directly to weakened neurons. A wide range of improvements of melittin action were observed from various tests from behavior Morris water maze, Y maze test to immune florescent staining, western blots. As we need to find out what is the focus of melittin action, we conducted a careful observation in mice which showed that: the first signs of changes, in the hippocampus, within 5 h after melittin administration were the restoration of the Nrf2/HO-1 system and suppression of oxidative stress. After this event, from 7 to 12.5 h after administration, a diversity of conditions was all ameliorated: inflammation, apoptosis, neurotrophic factors, cholinergic function, and tissue ATP level. This chain reaction underscores that melittin focus was on redox balance's role, which revived multiple neuronal functions. Evidence of enhancement in the mouse hippocampus led to further exploration with hippocampal cell line HT22 model. Immunofluorescence analysis showed melittin-induced Nrf2 translocation to the nucleus, which would initiating the translation of antioxidant genes like HO-1. Pathway inhibitors pinpointed melittin's direct influence on the Nrf2/HO-1 pathway. 3D docking models and pull-down assays suggested melittin's direct interaction with Keap1, the regulator of the Nrf2/HO-1 pathway. Overall, this study not only highlighted melittin specifically effect on Nrf2/HO-1, thus rebalancing cellular redox, and also showed that this is an effective multi-faceted therapeutic strategy against neurodegeneration. [ABSTRACT FROM AUTHOR]

Neuroinflammation is a significant contributor to the pathology of glaucoma. Targeting key-mediators in this process is a realistic option to slow disease progression. Galectin-3 is a β-galactoside binding lectin that has been associated with inflammation in both systemic and central nervous system diseases. Elevated Galectin-3 has recently been detected in multiple animal models of glaucoma and inhibiting Galectin-3 using an intravitreal injection of TD139 (a Galectin-3 small molecule inhibitor) is neuroprotective. We queried whether this neuroprotective effect was translatable to another animal model and species. TD139 was intravitreally injected, in a rat ocular hypertensive model of glaucoma, 3 days after the induction of ocular hypertension (at peak intraocular pressure). Retinal ganglion cell survival and glial morphological markers were quantified. The degeneration of retinal ganglion cells was prevented by TD139 injection, but gross glial markers remained unaffected. These data confirm that the intravitreal injection of TD139 is neuroprotective in a rat ocular hypertensive model of glaucoma, while suggesting that the inhibition of Galectin-3 is not sufficient to alter the gross inflammatory outcome. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) is known for its potent prosurvival effect. Despite successfully replicating this effect in various clinical and pre-clinical models, the complete characterization of the molecular mechanisms underlying its neuroprotective action remains incomplete. Emerging research suggests a vital role for A-kinase anchoring proteins (AKAPs) as central nodal points orchestrating BDNF-dependent signaling. Among the over 50 identified AKAPs, AKAP6 has recently gained special attention due to its involvement in the neurotrophin-mediated survival of injured retinal ganglion cells (RGCs). However, the mechanisms by which AKAP6 responds to pro-survival BDNF signaling remain unknown. In this study, we shown that AKAP6 plays a crucial role in regulating BDNF-mediated NFAT transcriptional activity in neuronal survival by anchoring protein phosphatase calcineurin (CaN) and nuclear factor of activated T cells (NFATc4). Furthermore, we demonstrate that disrupting the anchoring of CaN diminishes the pro-survival effect of BDNF. Lastly, through experiments with NFATc4−/− mice, we provide evidence that NFATc4 acts downstream to BDNF's neuroprotection in vivo. These findings could offer valuable insights for developing neuroprotective strategies aimed at preserving injured neurons from degeneration and promoting their regeneration. [ABSTRACT FROM AUTHOR]

Nuclear pore complexes (NPCs) are embedded in the nuclear envelope and facilitate the exchange of macromolecules between the nucleus and cytoplasm in eukaryotic cells. The dysfunction of the NPC and nuclear transport plays a significant role in aging and the pathogenesis of various neurodegenerative diseases. Common features among these neurodegenerative diseases, including Parkinson's disease (PD), encompass mitochondrial dysfunction, oxidative stress and the accumulation of insoluble protein aggregates in specific brain regions. The susceptibility of dopaminergic neurons to mitochondrial stress underscores the pivotal role of mitochondria in PD progression. Disruptions in mitochondrial-nuclear communication are exacerbated by aging and α-synuclein-induced oxidative stress in PD. The precise mechanisms underlying mitochondrial impairment-induced neurodegeneration in PD are still unclear. Evidence suggests that perturbations in dopaminergic neuronal nuclei are linked to PD-related neurodegeneration. These perturbations involve structural damage to the nuclear envelope and mislocalization of pivotal transcription factors, potentially driven by oxidative stress or α-synuclein pathology. The presence of protein aggregates, pathogenic mutations, and ongoing oxidative stress can exacerbate the dysfunction of NPCs, yet this mechanism remains understudied in the context of oxidative stress-induced PD. This review summarizes the link between mitochondrial dysfunction and dopaminergic neurodegeneration and outlines the current evidence for nuclear envelope and nuclear transport abnormalities in PD, particularly in oxidative stress. We highlight the potential role of nuclear pore and nucleocytoplasmic transport dysfunction in PD and stress the importance of systematically investigating NPC components in PD. [ABSTRACT FROM AUTHOR]

The spectrum of synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), is characterized by α-synuclein (αSyn) pathology, which serves as the definitive diagnostic marker. However, current diagnostic methods primarily rely on motor symptoms that manifest years after the initial neuropathological changes, thereby delaying potential treatment. The symptomatic overlap between PD and MSA further complicates the diagnosis, highlighting the need for precise and differential diagnostic methods for these overlapping neurodegenerative diseases. αSyn misfolding and aggregation occur before clinical symptoms appear, suggesting that detection of pathological αSyn could enable early molecular diagnosis of synucleinopathies. Recent advances in seed amplification assay (SAA) offer a tool for detecting neurodegenerative diseases by identifying αSyn misfolding in fluid and tissue samples, even at preclinical stages. Extensive research has validated the effectiveness and reproducibility of SAAs for diagnosing synucleinopathies, with ongoing efforts focusing on optimizing conditions for detecting pathological αSyn in more accessible samples and identifying specific αSyn species to differentiate between various synucleinopathies. This review offers a thorough overview of SAA technology, exploring its applications for diagnosing synucleinopathies, addressing the current challenges, and outlining future directions for its clinical use. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, characterized by the accumulation of Aβ and abnormal tau hyperphosphorylation. Despite substantial efforts in development of drugs targeting Aβ and tau pathologies, effective therapeutic strategies for AD remain elusive. Recent attention has been paid to the significant role of cellular senescence in AD progression. Mounting evidence suggests that interventions targeting cellular senescence hold promise in improving cognitive function and ameliorating hallmark pathologies in AD. This narrative review provides a comprehensive summary and discussion of the physiological roles, characteristics, biomarkers, and commonly employed in vivo and in vitro models of cellular senescence, with a particular focus on various cell types in the brain, including astrocytes, microglia, oligodendrocyte precursor cells, neurons, and endothelial cells. The review further delves into factors influencing cellular senescence in AD and emphasizes the significance of targeting cellular senescence as a promising approach for AD treatment, which includes the utilization of senolytics and senomorphics. [ABSTRACT FROM AUTHOR]

Background: The resident astrocyte-retinal ganglion cell (RGC) lipoxin circuit is impaired during retinal stress, which includes ocular hypertension-induced neuropathy. Lipoxin B4 produced by homeostatic astrocytes directly acts on RGCs to increase survival and function in ocular hypertension-induced neuropathy. RGC death in the retina and axonal degeneration in the optic nerve are driven by the complex interactions between microglia and macroglia. Whether LXB4 neuroprotective actions include regulation of other cell types in the retina and/or optic nerve is an important knowledge gap. Methods: Cellular targets and signaling of LXB4 in the retina were defined by single-cell RNA sequencing. Retinal neurodegeneration was induced by injecting silicone oil into the anterior chamber of mouse eyes, which induced sustained and stable ocular hypertension. Morphological characterization of microglia populations in the retina and optic nerve was established by MorphOMICs and pseudotime trajectory analyses. The pathways and mechanisms of action of LXB4 in the optic nerve were investigated using bulk RNA sequencing. Transcriptomics data was validated by qPCR and immunohistochemistry. Differences between experimental groups were assessed by Student's t-test and one-way ANOVA. Results: Single-cell transcriptomics identified microglia as a primary target for LXB4 in the healthy retina. LXB4 downregulated genes that drive microglia environmental sensing and reactivity responses. Analysis of microglial function revealed that ocular hypertension induced distinct, temporally defined, and dynamic phenotypes in the retina and, unexpectedly, in the distal myelinated optic nerve. Microglial expression of CD74, a marker of disease-associated microglia in the brain, was only induced in a unique population of optic nerve microglia, but not in the retina. Genetic deletion of lipoxin formation correlated with the presence of a CD74 optic nerve microglia population in normotensive eyes, while LXB4 treatment during ocular hypertension shifted optic nerve microglia toward a homeostatic morphology and non-reactive state and downregulated the expression of CD74. Furthermore, we identified a correlation between CD74 and phospho-phosphoinositide 3-kinases (p-PI3K) expression levels in the optic nerve, which was reduced by LXB4 treatment. Conclusion: We identified early and dynamic changes in the microglia functional phenotype, reactivity, and induction of a unique CD74 microglia population in the distal optic nerve as key features of ocular hypertension-induced neurodegeneration. Our findings establish microglia regulation as a novel LXB4 target in the retina and optic nerve. LXB4 maintenance of a homeostatic optic nerve microglia phenotype and inhibition of a disease-associated phenotype are potential neuroprotective mechanisms for the resident LXB4 pathway. [ABSTRACT FROM AUTHOR]

Background: Circular RNAs (circRNAs) are highly stable regulators, often accumulated in mammalian brains and thought to serve as "memory molecules" that govern the long process of aging. Mounting evidence demonstrated circRNA dysregulation in the brains of Alzheimer's disease (AD) patients. However, whether and how circRNA dysregulation underlies AD progression remains unexplored. Methods: We combined Poly(A)-tailing/RNase R digestion experimental approach with CARP, our published computational framework using pseudo-reference alignment for more sensitive and accurate circRNA detection to identify genome-wide circRNA dysregulation and their downstream pathways in the 5xFAD mouse cerebral cortex between 5 and 7 months of age, a critical window marks the transition from reversible to irreversible pathogenic progression. Dysregulated circRNAs and pathways associated with disease progression in 5xFAD cortex were systematically compared with circRNAs affected in postmortem subcortical areas of a large human AD cohort. A top-ranked circRNA conserved and commonly affected in AD patients and 5xFAD mice was depleted in cultured cells to examine AD-relevant molecular and cellular changes. Results: We discovered genome-wide circRNA alterations specifically in 5xFAD cortex associated with AD progression, many of which are commonly dysregulated in the subcortical areas of AD patients. Among these circRNAs, circGigyf2 is highly conserved and showed the highest net reduction specifically in the 7-month 5xFAD cortex. CircGIGYF2 level in AD patients' cortices negatively correlated with dementia severity. Mechanistically, we found multiple AD-affected splicing factors that are essential for circGigyf2 biogenesis. Functionally, we identified and experimentally validated the conserved roles of circGigyf2 in sponging AD-relevant miRNAs and AD-associated RNA binding proteins (RBPs), including the cleavage and polyadenylation factor 6 (CPSF6). Moreover, circGigyf2 downregulation in AD promoted silencing activities of its sponged miRNAs and enhanced polyadenylation site processing efficiency of CPSF6 targets. Furthermore, circGigyf2 depletion in a mouse neuronal cell line dysregulated circGigyf2-miRNA and circGigyf2-CPSF6 axes and potentiated apoptotic responses upon insults, which strongly support the causative roles of circGigyf2 deficiency in AD neurodegeneration. Conclusions: Together, our results unveiled brain circRNAs associated with irreversible disease progression in an AD mouse model that is also affected in AD patients and identified novel molecular mechanisms underlying the dysregulation of conserved circRNA pathways contributing to AD pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common human neurodegenerative disorder worldwide. Owing to its chronic nature, our limited understanding of its pathophysiological mechanisms, and because of the lack of effective anti-AD drugs, AD represents a significant socio-economic challenge for all industrialized countries. Neuronal cell death is a key factor in AD pathogenesis and recent studies have suggested that neuronal ferroptosis may play a major patho-physiological role. Since ferroptosis involves free radical-mediated lipid peroxidation, we hypothesized that enteral administration of the radical scavenger butylated hydroxytoluene (BHT) might slow down or even prevent the development of AD-related symptoms in an in vivo animal AD model. Material and methods: To test this hypothesis, we employed the rat model of streptozotocin-induced AD and administered butylated hydroxytoluene orally at a dose of 120 mg/kg body weight. Following BHT treatment, neuronal cell death was induced by bilateral stereotactic intraventricular injection of streptozotocin at a dose of 3.0 mg/kg body weight. Three weeks after surgery, we assessed the learning capabilities and the short-term memory of three experimental groups using the conventional y-maze test: (i) streptozotocin-treated rats (BHT pre-treatment), (ii) streptozotocin-treated rats (no BHT pre-treatment), (iii) sham-operated rats (BHT pre-treatment but no streptozotocin administration). After the y-maze test, the animals were sacrificed, hippocampal tissue was prepared and several biochemical (malonyl dialdehyde formation, glutathione homeostasis, gene expression patterns) and histochemical (Congo-red staining, Nissl staining, Perls staining) readout parameters were quantified. Results: Intraventricular streptozotocin injection induced the development of AD-related symptoms, elevated the degree of lipid peroxidation and upregulated the expression of ferroptosis-related genes. Histochemical analysis indicated neuronal cell death and neuroinflammation, which were paralleled by aberrant intraneuronal iron deposition. The streptozotocin-induced alterations were significantly reduced and sometimes even abolished by oral BHT treatment. Conclusion: Our data indicate that oral BHT treatment attenuated the development of AD-related symptoms in an in vivo rat model, most probably via inhibiting neuronal ferroptosis. These findings suggest that BHT might constitute a promising candidate as anti-AD drug. However, more work is needed to explore the potential applicability of BHT in other models of neurodegeneration and in additional ferroptosis-related disorders. [ABSTRACT FROM AUTHOR]

Background: In mucopolysaccharidosis type III (MPS III, also known as Sanfilippo syndrome), a pediatric neurodegenerative disorder, accumulation of abnormal glycosaminoglycans (GAGs) induces severe neuroinflammation by triggering the microglial pro-inflammatory cytokines production via a TLR4-dependent pathway. But the extent of the microglia contribution to the MPS III neuropathology remains unclear. Extracellular vesicles (EVs) mediate intercellular communication and are known to participate in the pathogenesis of adult neurodegenerative diseases. However, characterization of the molecular profiles of EVs released by MPS III microglia and their effects on neuronal functions have not been described. Methods: Here, we isolated EVs secreted by the microglial cells after treatment with GAGs purified from urines of Sanfilippo patients (sfGAGs-EVs) or from age-matched healthy subjects (nGAGs-EVs) to explore the EVs' proteins and small RNA profiles using LC–MS/MS and RNA sequencing. We next performed a functional assay by immunofluorescence following nGAGs- or sfGAGs-EVs uptake by WT primary cortical neurons and analyzed their extensions metrics after staining of βIII-tubulin and MAP2 by confocal microscopy. Results: Functional enrichment analysis for both proteomics and RNA sequencing data from sfGAGs-EVs revealed a specific content involved in neuroinflammation and neurodevelopment pathways. Treatment of cortical neurons with sfGAGs-EVs induced a disease-associated phenotype demonstrated by a lower total neurite surface area, an impaired somatodendritic compartment, and a higher number of immature dendritic spines. Conclusions: This study shows, for the first time, that GAGs from patients with Sanfilippo syndrome can induce microglial secretion of EVs that deliver a specific molecular message to recipient naive neurons, while promoting the neuroinflammation, and depriving neurons of neurodevelopmental factors. This work provides a framework for further studies of biomarkers to evaluate efficiency of emerging therapies. [ABSTRACT FROM AUTHOR]

Creative movement, in the form of music- and dance-based exercise and rehabilitation, can serve as a model for learning and memory, visuospatial orientation, mental imagery, and multimodal sensory-motor integration. This review summarizes the advancement in cognitive neuroscience aimed at determining cognitive processes and brain structural and functional correlates involved in dance or creative movement, as well as the cognitive processes which accompany such activities. We synthesize the evidence for the use of cognitive, motor, and cognitive-motor function in dance as well as dance's potential application in neurological therapy and neurorehabilitation. Finally, we discuss how partnered interaction and sensorimotor integration in dance, and "dancing robots" could shed light on future application of dance as rehabilitation, of dance used in technology and potential mechanisms of benefit from dance-based activities. [ABSTRACT FROM AUTHOR]