Search Results (4,450)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that comprises amyloid-beta protein (Aβ) as a main component of neuritic plaques. Its deposition is considered a trigger for AD pathogenesis, progression, and the clinical symptoms of cognitive impairment. Some distinct pathological features of AD include phosphorylation of tau protein, oxidative stress, and mitochondrial dysfunction. These pathological consequences tend to produce reactive oxygen species (ROS), resulting in the dysregulation of various signaling pathways of neuroinflammation and neurodegeneration. The relationship between the Aβ cascade and oxidative stress in AD pathogenesis is like a “chicken and egg” story, with the etiology of the disease regarding these two factors remaining a question of “which comes first.” However, in this review, we have tried our best to clarify the interconnection between these two mechanisms and to show the precise cause-and-effect relationship. Based on the above hallmarks of AD, several therapeutic strategies using natural antioxidants, monoclonal antibodies, and vaccines are employed as anti-Aβ therapy to decrease ROS, Aβ burden, chronic neuroinflammation, and synaptic failure. These natural antioxidants and immunotherapeutics have demonstrated significant neuroprotective effects and symptomatic relief in various in vitro and in vivo models, as well as in clinical trials for AD. However, none of them have received final approval to enter the drug market for mitigating AD. In this review, we extensively elaborate on the pitfalls, assurances, and important crosstalk between oxidative stress and Aβ concerning current anti-Aβ therapy. Additionally, we discuss future strategies for the development of more Aβ-targeted approaches and the optimization of AD treatment and mitigation. Full article

Neurodegenerative disease is a major global health problem with 150 million people predicted to have dementia by 2050. Genetic factors, environmental factors, demographics, and some diseases have been associated with dementia. In addition to associations between diseases such as hypertension and cerebrovascular disease and dementia, emerging findings associate some psychiatric disorders with incident dementia. Because of the high and increasing global prevalence of dementia and the high worldwide prevalence of psychiatric disorders, the primary objective of this narrative review was to evaluate published findings that evaluate the association between bipolar disorder, depression, anxiety, post-traumatic stress disorder, obsessive–compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia and other psychosis syndromes, and personality disorders and personality traits and incident dementia. Here, we highlight findings indicating possible associations between these psychiatric disorders and subsequent dementia and suggest that some psychiatric disorders may be risk factors for incident dementia. Further research, including more large longitudinal studies and additional meta-analyses, however, is needed to better characterize the associations between psychiatric disorders and incident dementia, to identify possible mechanisms for these putative associations, and to identify risk factors within psychiatric disorders that predispose some people with a psychiatric disorder but not others to subsequent dementia. Additional important questions concern how the treatment of psychiatric disorders might affect the risk of incident dementia. Full article

Multiple studies have shown the importance of blood-based biomarkers indicating axonal damage (serum neurofilament light chains [sNfL]) or astroglia activation (serum glial fibrillary acidic protein [sGFAP]) for monitoring different neurological diseases. However, normal values of these variables remain to be clearly defined, partly due to the influence of different demographic factors. We investigated demographic differences in a cohort of healthy volunteers. A cross-sectional study was conducted including 116 healthy controls with ages between 18 and 69 years (67.5% females; n = 79). sNfL and sGFAP concentrations were measured using single-molecule arrays. Age and body mass index affected sNfL values, and age was found to be the most important factor. The normal values changed with age, and we established normal values for individuals younger than 45 years as <10 pg/mL and for controls older than 45 years as <15 pg/mL. We established normal values at <10 pg/mL for individuals younger than 45 years and <15 pg/mL for older individuals. Alternatively, a Z-score of 1.5 was relevant for all controls. sGFAP was only affected by age. Differences in normal values were evident by 55 years. The highest normality limit for sGFAP was 140 pg/mL for controls under 55 years and 280 for older controls. We defined normal levels for sNfL and sGFAP and their corresponding age-associated changes. These data may contribute to the application of such variables in clinical practice. Full article

Adult neurogenesis involves the generation of functional neurons from neural progenitor cells, which have the potential to complement and restore damaged neurons and neural circuits. Therefore, the development of drugs that stimulate neurogenesis represents a promising strategy in stem cell therapy and neural regeneration, greatly facilitating the reconstruction of neural circuits in cases of neurodegeneration and brain injury. Our study reveals that compound A5, previously designed and synthesized by our team, exhibits remarkable neuritogenic activities, effectively inducing neurogenesis in neural stem/progenitor cells (NSPCs). Subsequently, transcriptome analysis using high-throughput Illumina RNA-seq technology was performed to further elucidate the underlying molecular mechanisms by which Compound A5 promotes neurogenesis. Notably, comparative transcriptome analysis showed that the up-regulated genes were mainly associated with neurogenesis, and the down-regulated genes were mainly concerned with cell cycle progression. Furthermore, we confirmed that Compound A5 significantly affected the expression of transcription factors related to neurogenesis and cell cycle regulatory proteins. Collectively, these findings identify a new compound with neurogenic activity and may provide insights into drug discovery for neural repair and regeneration. Full article

Background: Over the last decade, studies have suggested that primary open-angle glaucoma (POAG) may be associated with cognitive impairment and dementia, as both pathologies are age-related neurodegenerative processes. It remains unclear to what extent neurodegeneration in POAG extends to other neurological functions beyond vision, such as cognition. This follow-up study examined the potential association between POAG and cognitive decline in an African ancestry population. Methods: The Telephone-Montreal Cognitive Assessment (T-MoCA) was administered to POAG cases and controls previously enrolled in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. Cases were assessed for retinal nerve fiber layer (RNFL) thickness and for the presence of dementia via chart review. Comparisons between POAG cases and controls were performed using two-sample t-tests for the T-MoCA total score and five subsection scores, and using chi-squared tests for incidence of dementia. Current scores were compared to scores from this same cohort from 7 years prior. Results: The T-MoCA was administered to 13 cases and 20 controls. The mean ± standard deviation (SD) T-MoCA total score was 15.5 ± 4.0 in cases and 16.7 ± 3.5 in controls (p = 0.36). However, there was a borderline significant difference in the delayed recall sub-score (2.3 ± 1.6 for cases vs. 3.4 ± 1.5 for controls, p = 0.052) and a significant difference in its sub-domain, the memory index score (MIS, 9.1 ± 4.3 for cases vs. 12.1 ± 3.0 for controls, p = 0.02). There were no significant differences between cases and controls for the remaining subsections. During 7 years of follow-up, a higher incidence of dementia was noted in POAG cases (7.1% for cases vs. 0% for controls, p = 0.058). Over 7 years, there was no significant deterioration in the cognitive performance of cases versus controls, and no association was seen between RNFL thinning and cognitive impairment. Conclusions: In this small-sample follow-up study of African ancestry individuals, POAG cases demonstrated worse short-term memory and higher incidence of dementia compared to controls. Future larger studies are needed to further investigate the presence and impact of neurodegeneration in POAG. Full article

Background: The regulation of divalent metal transporter-1 (DMT1) by insulin has been previously described in Langerhans cells and significant neuroprotection was found by insulin and insulin-like growth factor 1 treatment during experimental cerebral ischemia in acute ischemic stroke patients and in a rat 6-OHDA model of Parkinson’s disease, where DMT1 involvement is described. According to the regulation of DMT1, previously described as a target gene of NF-kB in the early phase of post-ischemic neurodegeneration, both in vitro and in vivo, and because insulin controls the NFkB signaling with protection from ischemic cell death in rat cardiomyocytes, we evaluated the role of insulin in relation to DMT1 expression and function during ischemic neurodegeneration. Methods: Insulin neuroprotection is evaluated in differentiated human neuroblastoma cells, SK-N-SH, and in primary mouse cortical neurons exposed to oxygen glucose deprivation (OGD) for 8 h or 3 h, respectively, with or without 300 nM insulin. The insulin neuroprotection during OGD was evaluated in both cellular models in terms of cell death, and in SK-N-SH for DMT1 protein expression and acute ferrous iron treatment, performed in acidic conditions, known to promote the maximum DMT1 uptake as a proton co-transporter; and the transactivation of 1B/DMT1 mouse promoter, already known to be responsive to NF-kB, was analyzed in primary mouse cortical neurons. Results: Insulin neuroprotection during OGD was concomitant to the down-regulation of both DMT1 protein expression and 1B/DMT1 mouse promoter transactivation. We also showed the insulin-dependent protection from cell death after acute ferrous iron treatment. In conclusion, although preliminary, this evaluation highlights the peculiar role of DMT1 as a possible pharmacological target, involved in neuroprotection by insulin during in vitro neuronal ischemia and acute ferrous iron uptake. Full article

Alzheimer’s disease (AD) brains are histologically marked by the presence of intracellular and extracellular amyloid deposits, which characterize the onset of the disease pathogenesis. Increasing evidence suggests that certain nutrients exert a direct or indirect effect on amyloid β (Aβ)-peptide production and accumulation and, consequently, on AD pathogenesis. We exploited the fruit fly Drosophila melanogaster model of AD to evaluate in vivo the beneficial properties of Lisosan G, a fermented powder obtained from organic whole grains, on the intracellular Aβ-42 peptide accumulation and related pathological phenotypes of AD. Our data showed that the Lisosan G-enriched diet attenuates the production of neurotoxic Aβ peptides in fly brains and reduces neuronal apoptosis. Notably, Lisosan G exerted anti-oxidant effects, lowering brain levels of reactive oxygen species and enhancing mitochondrial activity. These aspects paralleled the increase in autophagy turnover and the inhibition of nucleolar stress. Our results give support to the use of the Drosophila model not only to investigate the molecular genetic bases of neurodegenerative disease but also to rapidly and reliably test the efficiency of potential therapeutic agents and diet regimens. Full article

Neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are severe age-related disorders with complex and multifactorial causes. Recent research suggests a critical link between neurodegeneration and the gut microbiome, via the gut–brain communication pathway. This review examines the role of trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, in the development of AD and PD, and investigates its interaction with microRNAs (miRNAs) along this bidirectional pathway. TMAO, which is produced from dietary metabolites like choline and carnitine, has been linked to increased neuroinflammation, protein misfolding, and cognitive decline. In AD, elevated TMAO levels are associated with amyloid-beta and tau pathologies, blood–brain barrier disruption, and neuronal death. TMAO can cross the blood–brain barrier and promote the aggregation of amyloid and tau proteins. Similarly, TMAO affects alpha-synuclein conformation and aggregation, a hallmark of PD. TMAO also activates pro-inflammatory pathways such as NF-kB signaling, exacerbating neuroinflammation further. Moreover, TMAO modulates the expression of various miRNAs that are involved in neurodegenerative processes. Thus, the gut microbiome–miRNA–brain axis represents a newly discovered mechanistic link between gut dysbiosis and neurodegeneration. MiRNAs regulate the key pathways involved in neuroinflammation, oxidative stress, and neuronal death, contributing to disease progression. As a direct consequence, specific miRNA signatures may serve as potential biomarkers for the early detection and monitoring of AD and PD progression. This review aims to elucidate the complex interrelationships between the gut microbiota, trimethylamine-N-oxide (TMAO), microRNAs (miRNAs), and the central nervous system, and the implications of these connections in neurodegenerative diseases. In this context, an overview of the current neuroradiology techniques available for studying neuroinflammation and of the animal models used to investigate these intricate pathologies will also be provided. In summary, a bulk of evidence supports the concept that modulating the gut–brain communication pathway through dietary changes, the manipulation of the microbiome, and/or miRNA-based therapies may offer novel approaches for implementing the treatment of debilitating neurological disorders. Full article

Parkinson’s disease (PD) is characterized by a long prodromal period, during which patients often have sleep disturbances. The histaminergic system and circadian rhythms play an important role in the regulation of the sleep–wake cycle. Changes in the functioning of these systems may be involved in the pathogenesis of early stages of PD and may be age-dependent. Here, we have analyzed changes in the expression of genes associated with the regulation of the sleep–wake cycle (Hnmt, Hrh1, Hrh3, Per1, Per2, and Chrm3) in the substantia nigra (SN) and striatum of normal male mice of different ages, as well as in young and adult male mice with an MPTP-induced model of the early symptomatic stage (ESS) of PD. Age-dependent expression analysis in normal mouse brain tissue revealed changes in Hrh3, Per1, Per2, and Chrm3 genes in adult mice relative to young mice. When gene expression was examined in mice with the MPTP-induced model of the ESS of PD, changes in the expression of all studied genes were found only in the SN of adult mice with the ESS model of PD. These data suggest that age is a significant factor influencing changes in the expression of genes associated with sleep–wake cycle regulation in the development of PD. Full article

Background: The announcement of Parkinson’s disease (PD) diagnosis may provoke negative feelings that impact the ability to cope with the disease and all life changes related to this new condition. There are scarce data on how to improve communication about PD diagnosis and which factors may influence this outcome. Methods: We performed a national French survey, investigating the diagnosis announcement impact on a large population of people living with PD (PwPD), who recently received the diagnosis (≤1 year since PD diagnosis), and on related caregivers and health care professionals (HCPs), from tertiary and community-based hospitals. Results: A total of 397 PwPD (45% female and 82% > 50 years old), 192 caregivers and 120 HCPs (69% neurologists) completed the questionnaire. The diagnosis was not expected by about 60% of PwPD and induced negative feelings in the majority (82%) of them. Negative feelings that PwPD experience in the moment of the diagnosis announcement were related with male gender [OR = 2.034, CI 95% 1.09–3.78; p = 0.025] and older age [OR = 1.05, CI 95% 1.01–1.08; p = 0.004], while tremor as the first symptom had a threshold significance [OR = 1.78, CI 95% 0.994–3.187; p = 0.052]. Half of the PwPD and caregivers considered that they did not receive enough information and one third had a short-term appointment to rediscuss the diagnosis. A total of 82% of PwPD expressed the willingness to have a multidisciplinary follow-up (PD nurse, psychologists). Only 24% of the HCPs had been trained for PD announcement. Conclusions: The way a PD diagnosis is delivered represents a pivotal moment in the journey of PwPD and caregivers. This process requires improvement in addressing the gaps expressed by PwPD, caregivers, and HCPs through a participatory approach. Full article

Gastrodin (GAS) is the main chemical component of the traditional Chinese herb Gastrodia elata (called “Tianma” in Chinese), which has been used to treat neurological conditions, including headaches, epilepsy, stroke, and memory loss. To our knowledge, it is unclear whether GAS has a therapeutic effect on Huntington’s disease (HD). In the present study, we evaluated the effect of GAS on the degradation of mutant huntingtin protein (mHtt) by using PC12 cells transfected with N-terminal mHtt Q74. We found that 0.1–100 μM GAS had no effect on the survival rate of Q23 and Q74 PC12 cells after 24–48 h of incubation. The ubiquitin–proteasome system (UPS) is the main system that clears misfolded proteins in eukaryotic cells. Mutated Htt significantly upregulated total ubiquitinated protein (Ub) expression, decreased chymotrypsin-like, trypsin-like and caspase-like peptidase activity, and reduced the colocalization of the 20S proteasome with mHtt. GAS (25 μM) attenuated all of the abovementioned pathological changes, and the regulatory effect of GAS on mHtt was found to be abolished by MG132, a proteasome inhibitor. The autophagy–lysosome pathway (ALP) is another system for misfolded protein degradation. Although GAS downregulated the expression of autophagy markers (LC3II and P62), it increased the colocalization of LC3II with lysosomal associated membrane protein 1 (LAMP1), which indicates that ALP was activated. Moreover, GAS prevented mHtt-induced neuronal damage in PC12 cells. GAS has a selective effect on mHtt in Q74 PC12 cells and has no effect on Q23 and proteins encoded by other genes containing long CAGs, such as Rbm33 (10 CAG repeats) and Hcn1 (>30 CAG repeats). Furthermore, oral administration of 100 mg/kg GAS increased grip strength and attenuated mHtt aggregates in B6-hHTT130-N transgenic mice. This is a high dose (100 mg/kg GAS) when compared with experiments on HD mice with other small molecules. We will design more doses to evaluate the dose–response relationship of the inhibition effect of GAS on mHtt in our next study. In summary, GAS can promote the degradation of mHtt by activating the UPS and ALP, making it a potential therapeutic agent for HD. Full article

Pathological mutations in the LRRK2 gene are the major genetic cause of Parkinson’s disease (PD). Although several animal models with either LRRK2 down- or over-expression have been developed, the physiological function of LRRK2 remains elusive. LRRK2 is constitutively expressed in various tissues including neurons and glial cells, but importantly, it is expressed at low levels in dopaminergic neurons, further contributing to the cryptic function of LRRK2. Significant levels of LRRK2 protein and mRNA have been detected in peripheral blood mononuclear cells, lymph nodes, the spleen, and primary microglia, strongly suggesting the contribution of inflammatory cells to neuronal degeneration. In this research article, using Drosophila LRRK2 models, we were able to demonstrate a significant contribution of glial cells to the LRRK2 pathological phenotype. Furthermore, in Drosophila, neurodegeneration is associated with a significant and important increase in specific inflammatory peptides. Finally, levetiracetam, a compound widely used in human therapy to treat epilepsy, was able to rescue both neuronal degeneration and neuroinflammation. Full article

Parkinson’s disease (PD) is a neurodegenerative disorder which affects dopaminergic neurons of the midbrain. Accumulation of α-synuclein or exposure to neurotoxins like 6-hydroxydopamine (6-OHDA) induces endoplasmic reticulum (ER) stress along with the unfolded protein response (UPR), which executes apoptosis via activation of PERK/CHOP or IRE1/JNK signaling. The present study aimed to determine which of these pathways is a major contributor to neurodegeneration in an 6-OHDA-induced in vitro model of PD. For this purpose, we have applied pharmacological PERK and JNK inhibitors (AMG44 and JNK V) in differentiated SH-SY5Y cells exposed to 6-OHDA. Inhibition of PERK and JNK significantly decreased genotoxicity and improved mitochondrial respiration, but only JNK inhibition significantly increased cell viability. Gene expression analysis revealed that the effect of JNK inhibition was dependent on a decrease in MAPK10 and XBP1 mRNA levels, whereas inhibition of either PERK or JNK significantly reduced the expression of DDIT3 mRNA. Western blot has shown that JNK inhibition strongly induced the XBP1s protein, and inhibition of each pathway attenuated the phosphorylation of eIF2α and JNK, as well as the expression of CHOP. Collectively, our data suggests that targeting the IRE1/JNK pathway of the UPR is a more effective option for PD treatment as it simultaneously affects more than one pro-apoptotic pathway. Full article

Over the past three decades, substantial advancements have occurred in non-invasive brain stimulation (NIBS). These developments encompass various non-invasive techniques aimed at modulating brain function. Among the most widely utilized methods today are transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES), which include direct- or alternating-current transcranial stimulation (tDCS/tACS). In addition to these established techniques, newer modalities have emerged, broadening the scope of non-invasive neuromodulation approaches available for research and clinical applications in movement disorders, particularly for Parkinson’s disease (PD) and, to a lesser extent, atypical Parkinsonism (AP). All NIBS techniques offer the opportunity to explore a wide range of neurophysiological mechanisms and exert influence over distinct brain regions implicated in the pathophysiology of Parkinsonism. This paper’s first aim is to provide a brief overview of the historical background and underlying physiological principles of primary NIBS techniques, focusing on their translational relevance. It aims to shed light on the potential identification of biomarkers for diagnostic and therapeutic purposes, by summarising available experimental data on individuals with Parkinsonism. To date, despite promising findings indicating the potential utility of NIBS techniques in Parkinsonism, their integration into clinical routine for diagnostic or therapeutic protocols remains a subject of ongoing investigation and scientific debate. In this context, this paper addresses current unsolved issues and methodological challenges concerning the use of NIBS, focusing on the importance of future research endeavours for maximizing the efficacy and relevance of NIBS strategies for individuals with Parkinsonism. Full article

Aging is the most prominent risk factor for neurodegeneration occurrence. The most common neurodegenerative diseases (NDs), Alzheimer’s (AD) and Parkinson’s (PD) diseases, are characterized by the incidence of proteinopathy, abnormal activation of glial cells, oxidative stress, neuroinflammation, impaired autophagy and cellular senescence excessive for the patient’s age. Moreover, mitochondrial disfunction, epigenetic alterations and neurogenesis inhibition, together with increased blood–brain barrier permeability and gut dysbiosis, have been linked to ND pathogenesis. Since NDs still lack curative treatment, recent research has sought therapeutic options in restoring gut microbiota and supplementing probiotic bacteria-derived metabolites with beneficial action to the host—so called postbiotics. The current review focuses on literature explaining cellular mechanisms involved in ND pathogenesis and research addressing the impact that postbiotics as a whole mixture and particular metabolites, such as short-chain fatty acids (SCFAs), lactate, polyamines, polyphenols, tryptophan metabolites, exopolysaccharides and bacterial extracellular vesicles, have on the ageing-associated processes underlying ND occurrence. The review also discusses the issue of implementing postbiotics into ND prophylaxis and therapy, depicting them as compounds addressing senescence-triggered dysfunctions that are worth translating from bench to pharmaceutical market in response to “silver consumers” demands. Full article