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Alzheimer's disease (AD) is a chronic neurodegenerative disorder with a global impact. The past few decades have witnessed significant strides in comprehending the underlying pathophysiological mechanisms and developing diagnostic methodologies for AD, such as neuroimaging approaches. Neuroimaging techniques, including positron emission tomography and magnetic resonance imaging, have revolutionized the field by providing valuable insights into the structural and functional alterations in the brains of individuals with AD. These imaging modalities enable the detection of early biomarkers such as amyloid-ß plaques and tau protein tangles, facilitating early and precise diagnosis. Furthermore, the emerging technologies encompassing blood-based biomarkers and neurochemical profiling exhibit promising results in the identification of specific molecular signatures for AD. The integration of machine learning algorithms and artificial intelligence has enhanced the predictive capacity of these diagnostic tools when analyzing complex datasets. In this review article, we will highlight not only some of the most used diagnostic imaging approaches in neurodegeneration research but focus much more on new tools like artificial intelligence, emphasizing their application in the realm of AD. These advancements hold immense potential for early detection and intervention, thereby paving the way for personalized therapeutic strategies and ultimately augmenting the quality of life for individuals affected by AD.
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Enfermedad de Alzheimer , Inteligencia Artificial , Diagnóstico Precoz , Neuroimagen , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Neuroimagen/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Tomografía de Emisión de Positrones/métodos , Biomarcadores/análisisRESUMEN
BACKGROUND: The phenotype of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients is determined by the type of DMD gene variation, its location, effect on reading frame, and its size. The primary objective of this investigation was to determine the frequency and distribution of DMD gene variants (deletions/duplications) in Sri Lanka through the utilization of a combined approach involving multiplex polymerase chain reaction (mPCR) followed by Multiplex Ligation Dependent Probe Amplification (MLPA) and compare to the international literature. The current consensus is that MLPA is a labor efficient yet expensive technique for identifying deletions and duplications in the DMD gene. METHODOLOGY: Genetic analysis was performed in a cohort of 236 clinically suspected pediatric and adult myopathy patients in Sri Lanka, using mPCR and MLPA. A comparative analysis was conducted between our findings and literature data. RESULTS: In the entire patient cohort (n = 236), mPCR solely was able to identify deletions in the DMD gene in 131/236 patients (DMD-120, BMD-11). In the same cohort, MLPA confirmed deletions in 149/236 patients [DMD-138, BMD -11]. These findings suggest that mPCR has a detection rate of 95% (131/138) among all patients who received a diagnosis. The distal and proximal deletion hotspots for DMD were exons 45-55 and 6-15. Exon 45-60 identified as a novel in-frame variation hotspot. Exon 45-59 was a hotspot for BMD deletions. Comparisons with the international literature show significant variations observed in deletion and duplication frequencies in DMD gene across different populations. CONCLUSION: DMD gene deletions and duplications are concentrated in exons 45-55 and 2-20 respectively, which match global variation hotspots. Disparities in deletion and duplication frequencies were observed when comparing our data to other Asian and Western populations. Identified a 95% deletion detection rate for mPCR, making it a viable initial molecular diagnostic approach for low-resource countries where MLPA could be used to evaluate negative mPCR cases and cases with ambiguous mutation borders. Our findings may have important implications in the early identification of DMD with limited resources in Sri Lanka and to develop tailored molecular diagnostic algorithms that are regional and population specific and easily implemented in resource limited settings.
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Patología Molecular , Configuración de Recursos Limitados , Adulto , Humanos , Niño , Sri Lanka , Algoritmos , FenotipoRESUMEN
The inherited disease community in Sri Lanka has been widely neglected. This article aimed to present accumulated knowledge in establishing a pro bono cost-effective national, island-wide, free-of-charge molecular diagnostic service, suggesting a model for other developing countries. The project provided 637 molecular diagnostic tests and reports free of charge to a nation with limited resources. We pioneered the implementation of mobile clinics and home visits, where the research team acted as barefoot doctors with the concept of the doctor and the researcher at the patient's doorstep. Establishing pro bono, cost-effective molecular diagnostics is feasible in developing countries with limited resources and state funding through the effort of dedicated postgraduate students. This service could provide an accurate molecular diagnosis of Duchenne muscular dystrophy, Huntington's disease, Spinocerebellar ataxia, and Spinal muscular atrophy, a diagnostic yield of 54% (343/637), of which 43% (147/343) of the patients identified as amenable for available gene therapies. Initiated human resource development by double doctoral degree opportunities with international collaborations. Established a neurobiobank and a national registry in Sri Lanka, a rich and unique repository, wealth creation for translational collaborative research and sharing of information in neurological diseases, as well as a lodestar for aspiring initiatives from other developing countries.
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Objectives: Pain is common after craniotomy. Its incidence and predictors in developing nations are not adequately studied. We aimed to assess the incidence, predictors, and impact of acute post-operative pain after intracranial neurosurgeries. Materials and Methods: This prospective observational study was conducted in adult patients undergoing intracranial neurosurgeries. After patient consent, ethics committee approval, and study registration, we assessed the incidence of post-operative pain using numerical rating scale (NRS) score. Predictors and impact of pain on patient outcomes were also evaluated. Results: A total of 497 patients were recruited during 10-month study period. Significant (4-10 NRS score) post-operative pain at any time-point during the first 3 days after intracranial neurosurgery was reported by 65.5% (307/469) of patients. Incidence of significant pain during the 1st post-operative h, on the 1st, 2nd, and 3rd post-operative days was 20% (78/391), 50% (209/418), 38% (152/401), and 24% (86/360), respectively. Higher pre-operative NRS score and pain during the 1st h post-operatively, predicted the occurrence of pain during the first 3 days after surgery, P = 0.003 and P < 0.001, respectively. Pain was significantly associated with poor sleep quality on the first 2 post-operative nights (P < 0.001). Patient satisfaction score was higher in patients with post-operative pain, P = 0.002. Conclusion: Every two in three patients undergoing elective intracranial neurosurgery report significant pain at some point during the first 3 postoperative days. Pre-operative pain and pain during 1st post-operative h predict the occurrence of significant post-operative pain.
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Brain function and its effect on motor performance in Duchenne muscular dystrophy (DMD) is an emerging concept. The present study explored how cumulative dystrophin isoform loss, age, and a corticosteroid treatment affect DMD motor outcomes. A total of 133 genetically confirmed DMD patients from Sri Lanka were divided into two groups based on whether their shorter dystrophin isoforms (Dp140, Dp116, and Dp71) were affected: Group 1, containing patients with Dp140, Dp116, and Dp71 affected (n = 98), and Group 2, containing unaffected patients (n = 35). A subset of 52 patients (Group 1, n = 38; Group 2, n = 14) was followed for up to three follow-ups performed in an average of 28-month intervals. The effect of the cumulative loss of shorter dystrophin isoforms on the natural history of DMD was analyzed. A total of 74/133 (56%) patients encountered developmental delays, with 66/74 (89%) being in Group 1 and 8/74 (11%) being in Group 2 (p < 0.001). Motor developmental delays were predominant. The hip and knee muscular strength, according to the Medical Research Council (MRC) scale and the North Star Ambulatory Assessment (NSAA) activities, "standing on one leg R", "standing on one leg L", and "walk", declined rapidly in Group 1 (p < 0.001 In the follow-up analysis, Group 1 patients became wheelchair-bound at a younger age than those of Group 2 (p = 0.004). DMD motor dysfunction is linked to DMD mutations that affect shorter dystrophin isoforms. When stratifying individuals for clinical trials, considering the DMD mutation site and its impact on a shorter dystrophin isoform is crucial.
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Introduction: Documented Duchenne Muscular Dystrophy (DMD) biomarkers are confined to Caucasians and are poor indicators of cognitive difficulties and neuropsychological alterations. Materials and methods: This study correlates serum protein signatures with cognitive performance in DMD patients of South Asian origin. Study included 25 DMD patients aged 6-16 years. Cognitive profiles were assessed by Wechsler Intelligence Scale for Children. Serum proteome profiling of 1317 proteins was performed in eight DMD patients and eight age-matched healthy volunteers. Results: Among the several novel observations we report, better cognitive performance in DMD was associated with increased serum levels of MMP9 and FN1 but decreased Siglec-3, C4b, and C3b. Worse cognitive performance was associated with increased serum levels of LDH-H1 and PDGF-BB but reduced GDF-11, MMP12, TPSB2, and G1B. Secondly, better cognitive performance in Processing Speed (PSI) and Perceptual Reasoning (PRI) domains was associated with intact Dp116, Dp140, and Dp71 dystrophin isoforms while better performance in Verbal Comprehension (VCI) and Working Memory (WMI) domains was associated with intact Dp116 and Dp140 isoforms. Finally, functional pathways shared with Alzheimer's Disease (AD) point towards an astrocyte-centric model for DMD. Conclusion: Astrocytic dysfunction leading to synaptic dysfunction reported previously in AD may be a common pathogenic mechanism underlying both AD and DMD, linking protein alterations to cognitive impairment. This new insight may pave the path towards novel therapeutic approaches targeting reactive astrocytes.
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High-frequency stimulation (HFS) is a promising therapy for patients with depression. However, the mechanisms underlying the HFS-induced antidepressant-like effects on susceptibility and resilience to depressive-like behaviors remain obscure. Given that dopaminergic neurotransmission has been found to be disrupted in depression, we investigated the dopamine(DA)-dependent mechanism of the antidepressant-like effects of HFS of the prelimbic cortex (HFS PrL). We performed HFS PrL in a rat model of mild chronic unpredictable stress (CUS) together with 6-hydroxydopamine lesioning in the dorsal raphe nucleus (DRN) and ventral tegmental area (VTA). Animals were assessed for anxiety, anhedonia, and behavioral despair. We also examined levels of corticosterone, hippocampal neurotransmitters, neuroplasticity-related proteins, and morphological changes in dopaminergic neurons. We found 54.3% of CUS animals exhibited decreased sucrose consumption and were designated as CUS-susceptible, while the others were designated CUS-resilient. HFS PrL in both the CUS-susceptible and CUS-resilient animals significantly increased hedonia, reduced anxiety, decreased forced swim immobility, enhanced hippocampal DA and serotonin levels, and reduced corticosterone levels when compared with the respective sham groups. The hedonic-like effects were abolished in both DRN- and VTA-lesioned groups, suggesting the effects of HFS PrL are DA-dependent. Interestingly, VTA-lesioned sham animals had increased anxiety and forced swim immobility, which was reversed by HFS PrL. The VTA-lesioned HFS PrL animals also had elevated DA levels, and reduced p-p38 MAPK and NF-κB levels when compared to VTA-lesioned sham animals. These findings suggest that HFS PrL in stressed animals leads to profound antidepressant-like responses possibly through both DA-dependent and -independent mechanisms.
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Corticosterona , Dopamina , Ratas , Animales , Ratas Sprague-Dawley , Dopamina/metabolismo , Antidepresivos/farmacología , Corteza Cerebral/metabolismoRESUMEN
A promising direction in the research on Alzheimer's Disease (AD) is the identification of biomarkers that better inform the disease progression of AD. However, the performance of amyloid-based biomarkers in predicting cognitive performance has been shown to be suboptimal. We hypothesise that neuronal loss could better inform cognitive impairment. We have utilised the 5xFAD transgenic mouse model that displays AD pathology at an early phase, already fully manifested after 6 months. We have evaluated the relationships between cognitive impairment, amyloid deposition, and neuronal loss in the hippocampus in both male and female mice. We observed the onset of disease characterized by the emergence of cognitive impairment in 6-month-old 5xFAD mice coinciding with the emergence of neuronal loss in the subiculum, but not amyloid pathology. We also showed that female mice exhibited significantly increased amyloid deposition in the hippocampus and entorhinal cortex, highlighting sex-related differences in the amyloid pathology of this model. Therefore, parameters based on neuronal loss might more accurately reflect disease onset and progression compared to amyloid-based biomarkers in AD patients. Moreover, sex-related differences should be considered in studies involving 5xFAD mouse models.
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Enfermedad de Alzheimer , Femenino , Ratones , Masculino , Animales , Enfermedad de Alzheimer/patología , Ratones Transgénicos , Precursor de Proteína beta-Amiloide , Péptidos beta-Amiloides , Placa Amiloide/patología , Caracteres Sexuales , AmiloideRESUMEN
Background: In this article, the authors discuss how they utilized the genetic mutation data in Sri Lankan Duchenne muscular dystrophy (DMD), Spinal muscular atrophy (SMA), Spinocerebellar ataxia (SCA) and Huntington's disease (HD) patients and compare the available literature from South Asian countries to identifying potential candidates for available gene therapy for DMD, SMA, SCA and HD patients. Methods: Rare disease patients (n = 623) with the characteristic clinical findings suspected of HD, SCA, SMA and Muscular Dystrophy were genetically confirmed using Multiplex Ligation Dependent Probe Amplification (MLPA), and single plex PCR. A survey was conducted in the "Wiley database on Gene Therapy Trials Worldwide" to identify DMD, SMA, SCA, and HD gene therapy clinical trials performed worldwide up to April 2021. In order to identify candidates for gene therapy in other neighboring countries we compared our findings with available literature from India and Pakistan which has utilized the same molecular diagnostic protocol to our study. Results: From the overall cohort of 623 rare disease patients with the characteristic clinical findings suspected of HD, SCA, SMA and Muscular Dystrophy, n = 343 (55%) [Muscular Dystrophy- 65%; (DMD-139, Becker Muscular Dystrophy -BMD-11), SCA type 1-3-53% (SCA1-61,SCA2- 23, SCA3- 39), HD- 52% (45) and SMA- 34% (22)] patients were positive for molecular diagnostics by MLPA and single plex PCR. A total of 147 patients in Sri Lanka amenable to available gene therapy; [DMD-83, SMA-15 and HD-49] were identified. A comparison of Sri Lankan finding with available literature from India and Pakistan identified a total of 1257 patients [DMD-1076, SMA- 57, and HD-124] from these three South Asian Countries as amenable for existing gene therapy trials. DMD, SMA, and HD gene therapy clinical trials (113 studies) performed worldwide up to April 2021 were concentrated mostly (99%) in High Income Countries (HIC) and Upper Middle-Income Countries (UMIC). However, studies on the potential use of anti-sense oligonucleotides (ASO) for treatment of SCAs have yet to reach clinical trials. Conclusion: Most genetic therapies for neurodegenerative and neuromuscular disorders have been evaluated for efficacy primarily in Western populations. No multicenter gene therapy clinical trial sites for DMD, SMA and HD in the South Asian region, leading to lack of knowledge on the safety and efficacy of such personalized therapies in other populations, including South Asians. By fostering collaboration between researchers, clinicians, patient advocacy groups, government and industry in gene therapy initiatives for the inherited-diseases community in the developing world would link the Global North and Global South and breathe life into the motto "Together we can make a difference".
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Excessively released proinflammatory mediators from activated macrophages and lymphocytes may contribute to the etiology of depression. However, the relationship between lymphocytes and depression is not fully understood. Although women have higher depression risk than men, sex/gender differences in psychoneuroimmunological mechanisms are still unclear. To explore these two questions, chronic unpredictable mild stress (CUMS) was used to evaluate the changes in behaviors, inflammation and lymphocyte subtypes in adult male and female Wistar rats. Results show that CUMS increased anhedonia and anxiety-like behaviors, along with increased serum corticosterone, hippocampal pro-inflammatory factors, CD11b, IFN-γ, IL-6 and IL-17, but decreased CD4, CD25, CD4/CD8 ratio, GFAP, 5-hydroxytryptamine (5-HT) and NE concentrations, regardless of sex. There was no positive correlation between sucrose preference and blood CD4/CD8 ratio, but a positive correlation between sucrose preference and spleen CD25, sucrose preference and neurotransmitters (NE and 5-HT), spleen CD25 and serum TGF-ß1/IL-6 ratio were found, regardless of sex. Females presented higher basal locomotion, blood CD4, CD4/CD8 ratio, serum corticosteroid and IL-6 concentrations, but lower hippocampal norepinephrine (NE) than males. Although CUMS didn't induce significant sex differences, females presented more changes in CD4 and CD8 lymphocytes than male rats. CUMS caused abnormalities in corticosteroid, lymphocytes, cytokines and neurotransmitters, which might be the precursors for inducing depression-like behaviors in both sexes.
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Depresión , Interleucina-6 , Ratas , Femenino , Masculino , Animales , Depresión/etiología , Ratas Wistar , Serotonina/farmacología , Inflamación , Hipocampo , Norepinefrina/farmacología , Sacarosa/farmacología , Linfocitos , Estrés Psicológico , Modelos Animales de EnfermedadRESUMEN
Alzheimer's disease (AD) is the most prevalent form of dementia. Key AD symptoms include memory and cognitive decline; however, comorbid symptoms such as depression and sensory-perceptual dysfunction are often reported. Among these, a deterioration of olfactory sensation is observed in approximately 90% of AD patients. However, the precise pathophysiological basis underlying olfactory deficits because of AD remains elusive. The olfactory glomeruli in the olfactory bulb (OB) receive sensory information in the olfactory processing pathway. Maintaining the structural and functional integrity of the olfactory glomerulus is critical to olfactory signalling. Herein, we conducted an in-depth histopathological assessment to reveal detailed structural alterations in the olfactory glomeruli in AD patients. Fresh frozen post-mortem OB specimens obtained from six AD patients and seven healthy age-matched individuals were examined. We used combined immunohistochemistry and stereology to assess the gross morphology and histological alterations, such as those in the expression of Aß protein, microglia, and neurotransmitters in the OB. Electron microscopy was employed to study the ultrastructural features in the glomeruli. Significant accumulation of Aß, morphologic damage, altered neurotransmitter levels, and microgliosis in the olfactory glomeruli of AD patients suggests that glomerular damage could affect olfactory function. Moreover, greater neurodegeneration was observed in the ventral olfactory glomeruli of AD patients. The synaptic ultrastructure revealed distorted postsynaptic densities and a decline in presynaptic vesicles in AD specimens. These findings show that the primary olfactory pathway is affected by the pathogenesis of AD, and may provide clues to identifying the mechanism involved in olfactory dysfunction in AD.
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Enfermedad de Alzheimer , Bulbo Olfatorio , Enfermedad de Alzheimer/patología , Autopsia , Humanos , Bulbo Olfatorio/metabolismo , OlfatoRESUMEN
Acquiring the recommended daily allowance of vitamins is crucial for maintaining homeostatic balance in humans and other animals. A deficiency in or dysregulation of vitamins adversely affects the neuronal metabolism, which may lead to neurodegenerative diseases. In this article, we discuss how novel vitamin-based approaches aid in attenuating abnormal neuronal functioning in neurodegeneration-based brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Prion disease. Vitamins show their therapeutic activity in Parkinson's disease by antioxidative and anti-inflammatory activity. In addition, different water- and lipid-soluble vitamins have also prevented amyloid beta and tau pathology. On the other hand, some results also show no correlation between vitamin action and the prevention of neurodegenerative diseases. Some vitamins also exhibit toxic activity too. This review discusses both the beneficial and null effects of vitamin supplementation for neurological disorders. The detailed mechanism of action of both water- and lipid-soluble vitamins is addressed in the manuscript. Hormesis is also an essential factor that is very helpful to determine the effective dose of vitamins. PubMed, Google Scholar, Web of Science, and Scopus were employed to conduct the literature search of original articles, review articles, and meta-analyses.
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Olfactory neuropathology is a cause of olfactory loss in Alzheimer's disease (AD). Olfactory dysfunction is also associated with memory and cognitive dysfunction and is an incidental finding of AD dementia. Here we review neuropathological research on the olfactory system in AD, considering both structural and functional evidence. Experimental and clinical findings identify olfactory dysfunction as an early indicator of AD. In keeping with this, amyloid-ß production and neuroinflammation are related to underlying causes of impaired olfaction. Notably, physiological features of the spatial map in the olfactory system suggest the evidence of ongoing neurodegeneration. Our aim in this review is to examine olfactory pathology findings essential to identifying mechanisms of olfactory dysfunction in the development of AD in hopes of supporting investigations leading towards revealing potential diagnostic methods and causes of early pathogenesis in the olfactory system. [BMB Reports 2021; 54(6): 295-304].
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Enfermedad de Alzheimer/complicaciones , Vías Nerviosas/patología , Enfermedades Neurodegenerativas/patología , Trastornos del Olfato/patología , Vías Olfatorias/patología , Animales , Humanos , Enfermedades Neurodegenerativas/etiología , Trastornos del Olfato/etiologíaRESUMEN
Mutations in RNA binding proteins (RBPs) and in genes regulating autophagy are frequent causes of familial amyotrophic lateral sclerosis (fALS). The P56S mutation in vesicle-associated membrane protein-associated protein B (VAPB) leads to fALS (ALS8) and spinal muscular atrophy (SMA). While VAPB is primarily involved in the unfolded protein response (UPR), vesicular trafficking and in initial steps of the autophagy pathway, the effect of mutant P56S-VAPB on autophagy regulation in connection with RBP homeostasis has not been explored yet. Examining the muscle biopsy of our index ALS8 patient of European origin revealed globular accumulations of VAPB aggregates co-localised with autophagy markers LC3 and p62 in partially atrophic and atrophic muscle fibres. In line with this skin fibroblasts obtained from the same patient showed accumulation of P56S-VAPB aggregates together with LC3 and p62. Detailed investigations of autophagic flux in cell culture models revealed that P56S-VAPB alters both initial and late steps of the autophagy pathway. Accordingly, electron microscopy complemented with live cell imaging highlighted the impaired fusion of accumulated autophagosomes with lysosomes in cells expressing P56S-VAPB. Consistent with these observations, neuropathological studies of brain and spinal cord of P56S-VAPB transgenic mice revealed signs of neurodegeneration associated with altered protein quality control and defective autophagy. Autophagy and RBP homeostasis are interdependent, as demonstrated by the cytoplasmic mis-localisation of several RBPs including pTDP-43, FUS, Matrin 3 which often sequestered with P56S-VAPB aggregates both in cell culture and in the muscle biopsy of the ALS8 patient. Further confirming the notion that aggregation of the RBPs proceeds through the stress granule (SG) pathway, we found persistent G3BP- and TIAR1-positive SGs in P56S-VAPB expressing cells as well as in the ALS8 patient muscle biopsy. We conclude that P56S-VAPB-ALS8 involves a cohesive pathomechanism of aberrant RBP homeostasis together with dysfunctional autophagy.
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Esclerosis Amiotrófica Lateral/patología , Proteínas de Unión al ARN/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Autofagia , Homeostasis , Humanos , MutaciónRESUMEN
The brainstem is a neglected brain area in neurodegenerative diseases, including Alzheimer's and Parkinson's disease, frontotemporal lobar degeneration and autonomic dysfunction. In Depression, several observations have been made in relation to changes in one particular the Dorsal Raphe Nucleus (DRN) which also points toward as key area in various age-related and neurodevelopmental diseases. The DRN is further thought to be related to stress regulated processes and cognitive events. It is involved in neurodegeneration, e.g., amyloid plaques, neurofibrillary tangles, and impaired synaptic transmission in Alzheimer's disease as shown in our autopsy findings. The DRN is a phylogenetically old brain area, with projections that reach out to a large number of regions and nuclei of the central nervous system, particularly in the forebrain. These ascending projections contain multiple neurotransmitters. One of the main reasons for the past and current interest in the DRN is its involvement in depression, and its main transmitter serotonin. The DRN also points toward the increased importance and focus of the brainstem as key area in various age-related and neurodevelopmental diseases. This review describes the morphology, ascending projections and the complex neurotransmitter nature of the DRN, stressing its role as a key research target into the neural bases of depression.
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Núcleo Dorsal del Rafe , Enfermedad de Alzheimer , Animales , Tronco Encefálico , Humanos , Mamíferos , Neurotransmisores , SerotoninaRESUMEN
BACKGROUND: Hyposmia in Alzheimer's disease (AD) is a typical early symptom according to numerous previous clinical studies. Although amyloid-ß (Aß), which is one of the toxic factors upregulated early in AD, has been identified in many studies, even in the peripheral areas of the olfactory system, the pathology involving olfactory sensory neurons (OSNs) remains poorly understood. METHODS: Here, we focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also confirmed histologically the pathological changes in 3-month-old 5xFAD mouse models, which recapitulates AD pathology. We introduced a numeric scale histologically to compare physiological phenomenon and local tissue lesions regardless of the anatomical plane. RESULTS: We observed the odorant group that the 5xFAD mice showed reduced responses to odorants. These also did not physiologically activate OSNs that propagate their axons to the ventral olfactory bulb. Interestingly, the amount of accumulated amyloid-ß (Aß) was high in the OSNs located in the olfactory epithelial ectoturbinate and the ventral olfactory bulb glomeruli. We also observed irreversible damage to the ectoturbinate of the olfactory epithelium by measuring the impaired neuronal turnover ratio from the basal cells to the matured OSNs. CONCLUSIONS: Our results showed that partial and asymmetrical accumulation of Aß coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely associated with peripheral OSN's loss could be a leading cause of AD-related hyposmia, a characteristic of early AD.
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Neuronas Receptoras Olfatorias , Péptidos beta-Amiloides/metabolismo , Animales , Axones/metabolismo , Ratones , Ratones Transgénicos , Bulbo Olfatorio/metabolismo , Neuronas Receptoras Olfatorias/metabolismo , OlfatoRESUMEN
Hypoxic-ischemic neonatal encephalopathy due to perinatal asphyxia is the leading cause of brain injury in newborns. Clinical data suggest that brain inflammation induced by perinatal insults can persist for years. We previously showed that signaling through the receptor for complement peptide C3a (C3aR) protects against cognitive impairment induced by experimental perinatal asphyxia. To investigate the long-term neuropathological effects of hypoxic-ischemic injury to the developing brain and the role of C3aR signaling therein, we subjected wildtype mice, C3aR deficient mice, and mice expressing biologically active C3a in the CNS to mild hypoxic-ischemic brain injury on postnatal day 9. We found that such injury triggers neurodegeneration and pronounced reactive gliosis in the ipsilesional hippocampus both of which persist long into adulthood. Transgenic expression of C3a in reactive astrocytes reduced hippocampal neurodegeneration and reactive gliosis. In contrast, neurodegeneration and microglial cell density increased in mice lacking C3aR. Intranasal administration of C3a for 3 days starting 1 h after induction of hypoxia-ischemia reduced neurodegeneration and reactive gliosis in the hippocampus of wildtype mice. We conclude that neonatal hypoxic-ischemic brain injury leads to long-lasting neurodegeneration. This neurodegeneration is substantially reduced by treatment with C3aR agonists, conceivably through modulation of reactive gliosis.
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Complemento C3a/fisiología , Hipoxia-Isquemia Encefálica/complicaciones , Enfermedades Neurodegenerativas/prevención & control , Receptores de Complemento/fisiología , Animales , Animales Recién Nacidos , Gliosis/etiología , Ratones , Ratones Endogámicos C57BL , Enfermedades Neurodegenerativas/etiología , Transducción de Señal/fisiologíaRESUMEN
The dual-specificity phosphatase (DUSP) family includes a heterogeneous group of protein phosphatases that dephosphorylate both phospho-tyrosine and phospho-serine/phospho-threonine residues within a single substrate. These protein phosphatases have many substrates and modulate diverse neural functions, such as neurogenesis, differentiation, and apoptosis. DUSP genes have furthermore been associated with mental disorders such as depression and neurological disorders such as Alzheimer's disease. Herein, we review the current literature on the DUSP family of genes concerning mental and neurological disorders. This review i) outlines the structure and general functions of DUSP genes, and ii) overviews the literature on DUSP genes concerning mental and neurological disorders, including model systems, while furthermore providing perspectives for future research.