Iodine 131 Treatment in Graves’ Disease in a West African Country: Preliminary Study about 25 Cases in Senegal

Introduction: Graves’ disease is the most common cause of hyperthyroidism. Its treatment uses synthetic antithyroid drugs but the use of aggressive radical therapy such as surgery or non-aggressive therapy such as iodine-131 is not uncommon. Treatment of Graves’ disease with radioactive iodine or iratherapy is a simple, inexpensive, well-tolerated treatment. It was introduced in Senegal in 2016. We report through this work the preliminary assessment of the only nuclear medicine service in Senegal in the management of Graves’ disease by iodine-131. Patients and Methods: Retrospective study of the first cases of Graves’ disease treated with iratherapy in Senegal. Socio-demographic, clinical, paraclinical, therapeutic and evolutionary aspects were studied. Radiation protection rules have been implemented and contraception has been effective for six months in women of childbearing age. Results: 25 patients were collected with a mean age of 45 years, twenty women (80%), a family goiter in 24% and a psycho-affective context in 64% of cases. Thyrotoxicosis syndrome was associated with goiter in 68% of patients and exophthalmos in 64%. Thyroid ultrasound performed in 20 patients showed vascular goiter in 80% and thyroid scintigraphy in 3 patients, homogeneous and diffuse hyperfixation. TRAK dosed in 8 patients was still positive. All patients had received first-line medical treatment. The average duration of this treatment was more than 18 months in 92%. The empirically used iodine-131 activity averaged 15.35 mCi. Oral corticosteroid therapy was prescribed in 7 patients for the prevention of malignant orbitopathy. No early side effects were noted. The remission rate at 3 months was 52% and at 6 months was 88% to 92%. Conclusion: The effectiveness of radioactive iodine, in particular ablative doses in the treatment of hyperthyroidism, is no longer to be demonstrated. Taking into account our socioeconomic context, iratherapy should be a treatment of choice for hyperthyroidism with a good quality/price ratio and excellent tolerance.

Autoimmune thyroid diseases and Helicobacter pylori: The correlation is present only in Graves's disease

AIM: To investigate the correlation between autoimmune thyroid diseases (ATDs) and the prevalence of Cag-A positive strains of Helicobacter pylori (H. pylori) in stool samples. METHODS: We investigated 112 consecutive Caucasian patients (48 females and 4 males with Graves' disease and 54 females and 6 males with Hashimoto' s thyroiditis HT), at their first diagnosis of ATDs. We tested for H. pylori in stool samples using an amplified enzyme immunoassay and Cag-A in serum samples using an enzyme-linked immunoassay method (ELISA). The results were analyzed using the two-sided Fisher' s exact test and the respective odds ratio (OR) was calculated. RESULTS: A marked correlation was found between the presence of H. pylori (P ≤ 0.0001, OR 6.3) and, in particular, Cag-A positive strains (P ≤ 0.005, OR 5.3)in Graves' disease, but not in Hashimoto's thyroiditis, where we found only a correlation with Cag-A strains (P ≤ 0.005, OR 8.73) but not when H. pylori was present. CONCLUSION: The marked correlation between H. pylori and Cag-A, found in ATDs, could be dependent on the different expression of adhesion molecules in the gastric mucosa.

A comparative study of influential factors correlating with early and late hypothyroidism after ^131I therapy for Graves＇ disease

Background 131Ⅰ therapy is recognized as the simplest, safest, least expensive, and most effective treatment, and accepted by more and more patients. However its curative effect is influenced by many factors, therefore there are some difficulties for doctors to establish individual treatment strategy. The aims of this study were to determine the incidence of early and late hypothyroidism after 131Ⅰ treatment for Graves＇ disease （GD） and to compare their correlation, to observe and analyze the influential factors and to understand the predictabilities of them.Methods Five hundred GD patients （144 males, 356 females; age （41.2±12.3） years） received 131Ⅰ treatment for the first time. The therapeutic procedure was carried out as the following： undergoing 131Ⅰ uptake test to obtain maximum of thyroid uptake value and effective half-life （EHL） time; estimating the thyroid＇s weight by ultrasonography; determination of thyroid hormones and correlative antibodies; pre-therapy physical examination; thyroid imaging; calculating 131Ⅰtherapeutic dosage; per os uptake of the determined 131Ⅰ dosage; follow-up appraisal of curative effect. The observing parameters included age, gender, thyroid weight, GD duration, condition of onset, state of disease, course of treatment, EHL time, maximum of thyroid uptake value, 131Ⅰ dosage and titer of correlative antibodies. We sorted out the data and used both univariate and multivariate analysis to evaluate them statistically.Results The incidence rates of early and late hypothyroidism were 33.2% and 6.6% respectively after 131Ⅰ treatment and approximately 22.2% cases of late hypothyroidism developed from early hypothyroidism. The influential factors of early hypothyroidism included course of GD, the highest thyroid uptake ratio of 131Ⅰ, EHL time and thyroid microsome antibody （TMAb）, etc. A multivariate analysis on late hypothyroidism showed that female patients, with recurrence after anti-thyroid drug treatment and higher thyroid weight, had lower possibility of late hypothyroidism after 131Ⅰ therapy.Conclusions The incidence of early hypothyroidism is higher than that of late hypothyroidism. The highest thyroid uptake ratio of 131Ⅰ, EHL and TMAb will increase the possibility of early hypothyroidism, while GD course is the protective factor. Higher 131Ⅰ dosage, longer EHL and higher TMAb titer will also increase the possibility of late hypothyroidism. The multi-perspective and multi-factor analysis has the benefit to establish individualized treatment strategy.

Association of Polymorphisms of rs179247 and rs12101255 in Thyroid Stimulating Hormone Receptor Intron 1 with an Increased Risk of Graves' Disease:A Meta-analysis

The polymorphisms of thyroid stimulating hormone receptor（TSHR） intron 1 rs179247 and rs12101255 have been found to be associated with Graves＇ disease（GD） in genetic studies. In the present study, we conducted a meta-analysis to examine this association. Two reviewers systematically searched eligible studies in Pub Med, Web of Science, Embase and China Biomedical Literature Database（CBM）. A meta-analysis on the association between GD and TSHR intron 1 rs179247 or rs12101255 was performed. The odd ratios（OR） were estimated with 95% confidence interval（CI）. Meta package in R was used for the analyses. Seven articles（13 studies） published between 2009 and 2014, involving 5754 GD patients and 5768 controls, were analyzed. The polymorphism of rs179247 was found to be associated with an increased GD risk in the allele analysis（A vs. G： OR=1.40, 95% CI=1.33–1.48） and all genetic models（AA vs. GG： OR=1.94, 95% CI=1.73–2.19; AA＋AG vs. GG： OR=1.57, 95% CI=1.41–1.74; AA vs. AG＋GG： OR=1.54, 95% CI=1.43–1.66）. The site rs12101255 also conferred a risk of GD in the allele analysis（T vs. C： OR=1.50, 95% CI=1.40–1.60） and all genetic models（TT vs. CC： OR=2.22, 95% CI=1.92–2.57; TT＋TC vs. CC： OR=1.66, 95% CI=1.50–1.83; TT vs. TC＋CC： OR=1.74, 95% CI=1.53–1.98）. Analysis of the relationship between rs179247 and Graves＇ ophthalmopathy（GO） showed no statistically significant correlation（A vs. G： OR=1.02, 95% CI=0.97–1.07）. Publication bias was not significant. In conclusion, GD is associated with polymorphisms of TSHR intron 1 rs179247 and rs12101255. There is no association between rs179247 SNPs and GO.

Changes of Regulatory T Cells in Graves' Disease

The immune mechanism of Graves＇ diseases （GD） and the roles of regulator T cells were investigated. In 32 patients with GD （GD group） and 20 healthy volunteers （control group）, flow cytometry was used to detect the proportion of CD4^＋CD25^＋ cells, MACS to isolate CD4^＋ CD25^＋ cells, RT-PCR to assay the expression of FOXP3, and ELISA to test the leyel of IL-10, respectively. It was found that there was no significant change in the proportion of CD4^＋CD25^＋ T cells between GD group and control group （P〉0.05）, while secretion of IL-10 and expression of FOXP3 in GD group were lower than control group （P〈0.01 and P〈0.05, respectively）. In conclusion, though the proportion of regulatory T cells of peripheral blood lymphocytes in the patients with GD, the functions of them were significantly weakened, which might be a pathogenic factor in GD.

Association between TSHR gene polymorphism and the risk of Graves' disease:a meta-analysis

Thyroid stimulating hormone receptor（TSHR） is thought to be a significant candidate for genetic susceptibility to Graves＇ disease（GD）.However,the association between TSHR gene polymorphism and the risk of GD remains controversial.In this study,we investigated the relationship between the two conditions by meta-analysis.We searched all relevant case-control studies in PubMed,Web of Science,CNKI and Wanfang for literature available until May2015,and chose studies on two single nucleotide polymorphisms（SNPs）：rs 179247 and rsl2101255,within TSHR intron-1.Bias of heterogeneity test among studies was determined by the fixed or random effect pooled measure,and publication bias was examined by modified Begg＇s and Egger＇s test.Eight eligible studies with 15 outcomes were involved in this meta-analysis,including 6,976 GD cases and 7,089 controls from China,Japan,Poland,UK and Brazil.Pooled odds ratios（ORs） for allelic comparisons showed that both TSHR rsl79247A/G and rsl2101255T/C polymorphism had significant association with GD（OR=1.422,95%CI=1.353—1.495,P〈0.001,P_（heterogeneity）=0.448;OR= 1.502,95%CI：1.410-1.600,P〈0.001,P_（heterogeneity）=0.642）,and the associations were the same under dominant,recessive and co-dominant models.In subgroup analyses,the conclusions are also consistent with all those in Asian,European and South America subgroups（P〈0.001）.Our meta-analysis revealed a significant association between TSHR rsl79247A/G and rsl2101255T/C polymorphism with GD in five different populations from Asia,Europe and South America.Further studies are needed in other ethnic backgrounds to independently confirm our findings.

Copper homeostasis and neurodegenerative diseases

Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and COX17.Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue.Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative disorders.However,the exact mechanisms underlying these processes are not known.Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress.Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction.Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory pathways.Additionally,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell death.This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis.By synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders,such as Wilson's disease,Menkes'disease,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,Huntington's disease,and multiple sclerosis.Potential clinically significant therapeutic targets,including superoxide dismutase 1,D-penicillamine,and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline,along with their associated therapeutic agents,are further discussed.Ultimately,we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.

Toward understanding the role of genomic repeat elements in neurodegenerative diseases

Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage sequencing technology, researchers have started to notice that genomic repeat regions, previously neglected in search of disease culprits, are active contributors to multiple neurodegenerative diseases. In this review, we describe the association between repeat element variants and multiple degenerative diseases through genome-wide association studies and targeted sequencing. We discuss the identification of disease-relevant repeat element variants, further powered by the advancement of long-read sequencing technologies and their related tools, and summarize recent findings in the molecular mechanisms of repeat element variants in brain degeneration, such as those causing transcriptional silencing or RNA-mediated gain of toxic function. Furthermore, we describe how in silico predictions using innovative computational models, such as deep learning language models, could enhance and accelerate our understanding of the functional impact of repeat element variants. Finally, we discuss future directions to advance current findings for a better understanding of neurodegenerative diseases and the clinical applications of genomic repeat elements.

Pyrroloquinoline quinone:a potential neuroprotective compound for neurodegenerative diseases targeting metabolism

Pyrroloquinoline quinone is a quinone described as a cofactor for many bacterial dehydrogenases and is reported to exert an effect on metabolism in mammalian cells/tissues.Pyrroloquinoline quinone is present in the diet being available in foodstuffs,conferring the potential of this compound to be supplemented by dietary administration.Pyrroloquinoline quinone’s nutritional role in mammalian health is supported by the extensive deficits in reproduction,growth,and immunity resulting from the dietary absence of pyrroloquinoline quinone,and as such,pyrroloquinoline quinone has been considered as a“new vitamin.”Although the classification of pyrroloquinoline quinone as a vitamin needs to be properly established,the wide range of benefits for health provided has been reported in many studies.In this respect,pyrroloquinoline quinone seems to be particularly involved in regulating cell signaling pathways that promote metabolic and mitochondrial processes in many experimental contexts,thus dictating the rationale to consider pyrroloquinoline quinone as a vital compound for mammalian life.Through the regulation of different metabolic mechanisms,pyrroloquinoline quinone may improve clinical deficits where dysfunctional metabolism and mitochondrial activity contribute to induce cell damage and death.Pyrroloquinoline quinone has been demonstrated to have neuroprotective properties in different experimental models of neurodegeneration,although the link between pyrroloquinoline quinone-promoted metabolism and improved neuronal viability in some of such contexts is still to be fully elucidated.Here,we review the general properties of pyrroloquinoline quinone and its capacity to modulate metabolic and mitochondrial mechanisms in physiological contexts.In addition,we analyze the neuroprotective properties of pyrroloquinoline quinone in different neurodegenerative conditions and consider future perspectives for pyrroloquinoline quinone’s potential in health and disease.

Potential role of tanycyte-derived neurogenesis in Alzheimer's disease

Tanycytes, specialized ependymal cells located in the hypothalamus, play a crucial role in the generation of new neurons that contribute to the neural circuits responsible for regulating the systemic energy balance. The precise coordination of the gene networks controlling neurogenesis in naive and mature tanycytes is essential for maintaining homeostasis in adulthood. However, our understanding of the molecular mechanisms and signaling pathways that govern the proliferation and differentiation of tanycytes into neurons remains limited. This article aims to review the recent advancements in research into the mechanisms and functions of tanycyte-derived neurogenesis. Studies employing lineage-tracing techniques have revealed that the neurogenesis specifically originating from tanycytes in the hypothalamus has a compensatory role in neuronal loss and helps maintain energy homeostasis during metabolic diseases. Intriguingly,metabolic disorders are considered early biomarkers of Alzheimer's disease. Furthermore,the neurogenic potential of tanycytes and the state of newborn neurons derived from tanycytes heavily depend on the maintenance of mild microenvironments, which may be disrupted in Alzheimer's disease due to the impaired blood–brain barrier function.However, the specific alterations and regulatory mechanisms governing tanycyte-derived neurogenesis in Alzheimer's disease remain unclear. Accumulating evidence suggests that tanycyte-derived neurogenesis might be impaired in Alzheimer's disease, exacerbating neurodegeneration. Confirming this hypothesis, however, poses a challenge because of the lack of long-term tracing and nucleus-specific analyses of newborn neurons in the hypothalamus of patients with Alzheimer's disease. Further research into the molecular mechanisms underlying tanycyte-derived neurogenesis holds promise for identifying small molecules capable of restoring tanycyte proliferation in neurodegenerative diseases. This line of investigation could provide valuable insights into potential therapeutic strategies for Alzheimer's disease and related conditions.

Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases

Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.

Neuronal regulated cell death in aging-related neurodegenerative diseases:key pathways and therapeutic potentials

Regulated cell death(such as apoptosis,necroptosis,pyroptosis,autophagy,cuproptosis,ferroptosis,disulfidptosis)involves complex signaling pathways and molecular effectors,and has been proven to be an important regulatory mechanism for regulating neuronal aging and death.However,excessive activation of regulated cell death may lead to the progression of aging-related diseases.This review summarizes recent advances in the understanding of seven forms of regulated cell death in age-related diseases.Notably,the newly identified ferroptosis and cuproptosis have been implicated in the risk of cognitive impairment and neurodegenerative diseases.These forms of cell death exacerbate disease progression by promoting inflammation,oxidative stress,and pathological protein aggregation.The review also provides an overview of key signaling pathways and crosstalk mechanisms among these regulated cell death forms,with a focus on ferroptosis,cuproptosis,and disulfidptosis.For instance,FDX1 directly induces cuproptosis by regulating copper ion valency and dihydrolipoamide S-acetyltransferase aggregation,while copper mediates glutathione peroxidase 4 degradation,enhancing ferroptosis sensitivity.Additionally,inhibiting the Xc-transport system to prevent ferroptosis can increase disulfide formation and shift the NADP^(+)/NADPH ratio,transitioning ferroptosis to disulfidptosis.These insights help to uncover the potential connections among these novel regulated cell death forms and differentiate them from traditional regulated cell death mechanisms.In conclusion,identifying key targets and their crosstalk points among various regulated cell death pathways may aid in developing specific biomarkers to reverse the aging clock and treat age-related neurodegenerative conditions.

Nanomaterials-mediated lysosomal regulation:a robust protein-clearance approach for the treatment of Alzheimer’s disease

Alzheimer’s disease is a debilitating,progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins,including amyloid plaques and intracellular tau tangles,primarily within the brain.Lysosomes,crucial intracellular organelles responsible for protein degradation,play a key role in maintaining cellular homeostasis.Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases,including Alzheimer’s disease.Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer’s disease.Currently,the efficacy of drugs in treating Alzheimer’s disease is limited,with major challenges in drug delivery efficiency and targeting.Recently,nanomaterials have gained widespread use in Alzheimer’s disease drug research owing to their favorable physical and chemical properties.This review aims to provide a comprehensive overview of recent advances in using nanomaterials(polymeric nanomaterials,nanoemulsions,and carbon-based nanomaterials)to enhance lysosomal function in treating Alzheimer’s disease.This review also explores new concepts and potential therapeutic strategies for Alzheimer’s disease through the integration of nanomaterials and modulation of lysosomal function.In conclusion,this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer’s disease.The application of nanotechnology to the development of Alzheimer’s disease drugs brings new ideas and approaches for future treatment of this disease.

The complex roles of m^(6)A modifications in neural stem cell proliferation, differentiation, and self-renewal and implications for memory and neurodegenerative diseases

N6-methyladenosine(m^(6)A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis and neural regeneration, where it is highly concentrated and actively involved in these processes. Changes in m^(6)A modification levels and the expression levels of related enzymatic proteins can lead to neurological dysfunction and contribute to the development of neurological diseases. Furthermore, the proliferation and differentiation of neural stem cells, as well as nerve regeneration, are intimately linked to memory function and neurodegenerative diseases. This paper presents a comprehensive review of the roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m^(6)A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m^(6)A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m^(6)A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m^(6)A levels across different models of neurodegenerative disease, particularly Alzheimer's disease and Parkinson's disease, suggest that these disparities are linked to variations in the affected brain regions. Notably, the opposing changes in m^(6)A levels observed in Parkinson's disease models exposed to manganese compared to normal Parkinson's disease models further underscore the complexity of m^(6)A's role in neurodegenerative processes. The roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, and its implications in memory and neurodegenerative diseases, appear contradictory. These inconsistencies may be attributed to the timespecific nature of m^(6)A and its varying effects on distinct brain regions and in different environments.

Role of resident memory T cells in neuroinflammatory and neurodegenerative diseases in the central nervous system

The immune system has been attracting increasing attention in the field of chronic neurological disorders in the central nervous system(CNS).Autoreactive T cells targeting CNS antigens play a crucial role in the development of various autoimmune diseases,such as multiple sclerosis(MS)and neuromyelitis optica spectrum disorder(NMOSD).Moreover,T cells are now recognized as a pivotal contributor to the pathology of neurodegenerative disorders,including Alzheimer's disease(AD),Parkinson's disease(PD),and multiple system atrophy.

Mitochondrial therapeutics and mitochondrial transfer for neurodegenerative diseases and aging

Mitochondrial dysfunction and neurodegeneration:Progressive neurodegenerative diseases affect a significant proportion of the population;in a single year,there are as many as 276 million disabilities and 9 million deaths as a result of neurological diseases.

Amyloid-β-induced disruption of axon-initial-segment mitochondria localization:consequences for TAU missorting in Alzheimer's disease pathology

TAU is a neuronal microtubule-associated protein preferentially located in axons.In a battery of neurodegenerative diseases termed"tauopathies,"including Alzheimer's disease (AD),TAU is missorted and abnormally phosphorylated,leading to filamentous accumulations of hyperphosphorylated TAU,a pathological hallmark and potential disease driver of AD and related tauopathies (Zempel,2024).

Brain-penetrating neurotrophic factor mimetics: HER-096 as a disease-modifying therapy for Parkinson’s disease

Neurotrophic factors as a therapeutic approach in neurodegenerative diseases:A major unmet need in the field of central nervous system diseases is disease-modifying treatments.While for decades there have been various symptomatic treatments available to alleviate the symptoms of the disease,disease-modification,i.e.treatments that stop,significantly delay,or reverse the progression of the disease,has been turned out to a difficult goal to achieve.

Netrin-1 signaling pathway mechanisms in neurodegenerative diseases

Netrin-1 and its receptors play crucial roles in inducing axonal growth and neuronal migration during neuronal development.Their profound impacts then extend into adulthood to encompass the maintenance of neuronal survival and synaptic function.Increasing amounts of evidence highlight several key points:(1)Diminished Netrin-1 levels exacerbate pathological progression in animal models of Alzheimer’s disease and Parkinson’s disease,and potentially,similar alterations occur in humans.(2)Genetic mutations of Netrin-1 receptors increase an individuals’susceptibility to neurodegenerative disorders.(3)Therapeutic approaches targeting Netrin-1 and its receptors offer the benefits of enhancing memory and motor function.(4)Netrin-1 and its receptors show genetic and epigenetic alterations in a variety of cancers.These findings provide compelling evidence that Netrin-1 and its receptors are crucial targets in neurodegenerative diseases.Through a comprehensive review of Netrin-1 signaling pathways,our objective is to uncover potential therapeutic avenues for neurodegenerative disorders.

Microglial dysfunction and genetic risk for neurodegenerative disease

Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases a re increasing in prevalence as world populations age.While tremendous progress has been made,our understanding of the mechanisms that underlie the development of these diseases remains far from com plete.More troubling,despite the growing emotional and financial toll being to ken by neurodegenerative disorders,existing treatment options are limited almost exclusively to those that help manage symptoms but that lack the ability to alter the progression of the disease(Liu et al.,2022).