Neurodegenerative Conditions Research Articles

How to Manage an Individual Living with Parkinson's Disease Who Acutely Cannot Swallow.

Parkinson's disease (PD) is a common neurodegenerative condition that can lead to problems swallowing. Individuals living with PD may be unable to take medications orally for various reasons including acute or chronic dysphagia, non-PD related causes and being placed nil-by-mouth for elective reasons. This article outlines a five-step approach to managing an individual living with PD who is unable to take oral medication acutely. This includes assessment for the appropriateness of nasogastric tube insertion and the conversion of an individual's usual medication regimen to either a dispersible one or to a topical patch if a nasogastric tube is not possible. A patient-centred multidisciplinary approach is important, with shared decision-making involving the individual and their next of kin with key members including the Speech and Language Therapy and dietetic teams. The patient should be reviewed daily with their medication titrated according to clinical response, aiming to restart their usual regimen as soon as possible.

Item-Level Analysis of Category Fluency Test Performance: A Systematic Review and Meta-Analysis of Studies of Normal and Neurologically Abnormal Ageing.

While Category Fluency (CF) is widely used to help profile semantic memory, item-level scoring (ILS) approaches to this test have been proposed to obtain indices that are less influenced by non-semantic supportive functions. We systematically reviewed the literature to test the hypotheses that (1) compared with healthy adults, individuals with a clinical diagnosis suggestive of neurodegeneration generate words of lower semantic complexity; (2) compared with young adults, older adults generate words of higher semantic complexity. We searched six databases (date of search: 8 December 2023) for studies that relied on CF and ILS methods, in normal ageing and in age-associated neurodegeneration. Thirty-four studies were shortlisted: 27 on neurodegenerative conditions; 7 on normal ageing. Risk of bias was evaluated via a published checklist. Data were presented via qualitative synthesis. Most studies reported words of lower semantic complexity in relation to at least one item-level feature in individuals with mild cognitive impairment (MCI), Alzheimer's dementia (AD), and other neurodegenerative diseases. Post-hoc meta-analyses focussing on the MCI/AD continuum confirmed an effect on words' frequency (385 MCI/AD individuals and 350 controls; Hedges's G = 0.59) and age-of-acquisition (193 MCI/AD individuals and 161 controls; Hedges's G = - 1.51). Studies on normal ageing, conversely, failed to demonstrate any overall effect. Most studies on MCI and AD have not relied on neurobiological diagnostic criteria. Moreover, only a small number of studies analysed ILS controlling for quantitative CF performance. Despite these two limitations, this study suggests that ILS can contribute to an in-depth characterisation of semantic memory in neurological ageing.

Transient upregulation of procaspase-3 during oligodendrocyte fate decisions.

Oligodendrocytes are generated throughout life and in neurodegenerative conditions from brain resident oligodendrocyte precursor cells (OPCs). The transition from OPC to oligodendrocyte involves a complex cascade of molecular and morphological states that position the cell to make a fate decision to integrate as a myelinating oligodendrocyte or die through apoptosis. Oligodendrocyte maturation impacts the cell death mechanisms that occur in degenerative conditions, but it is unclear if and how the cell death machinery changes as OPCs transition into oligodendrocytes. Here, we discovered that differentiating oligodendrocytes transiently upregulate the zymogen procaspase-3 in both female and male mice, equipping these cells to make a survival decision during differentiation. Pharmacological inhibition of caspase-3 decreases oligodendrocyte density, indicating that procaspase-3 upregulation is linked to successful oligodendrocyte generation. Moreover, using procaspase-3 as a marker, we show that oligodendrocyte differentiation continues in the aging cortex and white matter. Taken together, our data establish procaspase-3 as a differentiating oligodendrocyte marker and provide insight into the underlying mechanisms occurring during the decision to integrate or die.Significance statement Myelin dysfunction and oligodendrocyte death occur in several neurological disorders and with aging. While new oligodendrocytes can be generated from oligodendrocyte precursor cells throughout life and in neurodegenerative conditions, this process is inefficient with many differentiating oligodendrocytes failing to integrate and dying. Investigating the cellular checkpoints that regulate these fate decisions is complicated by a paucity of molecular markers precisely delineating differentiation stages. Here, we identify that oligodendrocytes transiently upregulate the zymogen procaspase-3 during differentiation, establishing procaspase-3 as a differentiating oligodendrocyte marker. Importantly, procaspase-3 upregulation equips differentiating oligodendrocytes for a fate decision between death or integration and promotes oligodendrocyte differentiation. Thus, our data uncover new insights into mechanisms guiding oligodendrocyte fate decisions.

Charge Modification of Lysine Mitigates Amyloid-β Aggregation.

Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by the deposition of amyloid-β (Aβ) peptides, which aggregate into toxic structures such as oligomers, fibrils, and plaques. The presence of these Aβ aggregates in the brain plays a crucial role in the pathophysiology, leading to synaptic dysfunction and cognitive impairment. Understanding how physiological factors affect Aβ aggregation is essential, and therefore, exploring their influence in vitro will likely provide insights into their role in AD pathology. In this study, we investigated the effects of physiological, free amino acids on Aβ aggregation dynamics. We focused on positively charged amino acids, particularly lysine, and employed a chemical modification, methylation, to neutralize its charge. Our analyses revealed that modified lysine significantly reduced Aβ aggregation, indicating that charge distribution of amino acids plays a crucial role in modulating Aβ aggregation behavior. These findings enhance our understanding of the regulatory factors influencing Aβ aggregation and highlight important considerations for future research on Aβ.

Exploring the impact of exercise-induced BDNF on neuroplasticity in neurodegenerative and neuropsychiatric conditions.

This review investigates the intricate relationship between exercise, brain-derived neurotrophic factor (BDNF), neuroplasticity, and cognitive function, with a focus on implications for neuropsychiatric and neurodegenerative disorders. A systematic review was conducted by searching various databases for relevant studies that explored the connections between exercise, BDNF, neuroplasticity, and cognitive health. The analysis of eligible studies revealed that exercise increases BDNF levels in the brain, promoting neuroplasticity and enhancing cognitive functions. Furthermore, we discuss the protective effects of exercise against cognitive decline and neurological disorders, suggesting that BDNF plays a critical role in mediating these effects. Regular physical activity not only elevates BDNF levels but also fosters memory and learning, offering important implications for the prevention and treatment of neuropsychiatric and neurodegenerative conditions. Our findings underscore the necessity of incorporating exercise into a healthy lifestyle to optimize brain health. Future research is essential to elucidate the underlying mechanisms of this relationship and to refine exercise interventions for improved cognitive outcomes.

Rural Environment as a Risk Factor for the Age at Onset of Machado-Joseph Disease.

Machado-Joseph disease (SCA3/MJD) is a neurodegenerative condition caused by a dominant expansion of a CAG repeat (CAGexp). Most of the variability in the age at onset of symptoms (AO) remains unexplained, and environmental influences were scarcely studied. The objective was to test if AO of SCA3/MJD carriers can be associated with markers of the rural environment, such as demographic density (DeD), proportion of rural population (PRP), and the consumption of untreated well water (CWW). Symptomatic subjects from Rio Grande do Sul, Brazil, diagnosed between 1999 and 2017, and living in the same municipalities where they were born, were included, provided their CAGexp and AO were available, and the residual AO (RAO) could be estimated. DeD, PRP, and CWW were obtained from the Brazilian Census of 2010. Participants were stratified in high versus low DeD, PRP, and CWW groups, and their RAOs were compared for a P < 0.05. A total of 188 subjects were studied. The mean (SD) RAOs of subjects from low and high DeD groups were -1.90 (6.98) and -0.11 (6.20) (P = 0.046); from low and high PRP groups were -0.12 (6.20) and -1.90 (6.99) (P = 0.046); and from low and high CWW groups were -0.11 (6.04) and -1.89 (7.11) (P = 0.034). AO of SCA3/MJD carriers was earlier in groups related to rural life. Our evidence suggests the presence of a risk factor in the rural environment, for earlier onset of symptoms in SCA3/MJD.

Nimodipine ameliorates subarachnoid hemorrhage-induced neuroinflammation and injury by protecting mitochondrial function and regulating autophagy.

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke, and the neuroprotective effects of nimodipine following SAH have been well-documented. Sirtuin 3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, plays a significant role in mitigating oxidative stress in various neurodegenerative conditions. However, the role of SIRT3 in the neuroprotective mechanisms of nimodipine after SAH remains unclear. In this study, the in vitro cytotoxicity of neurons exposed to 2% ethanol (to stimulate oxidative stress) was assessed. An in vivo experimental SAH model was established in adult mice through internal carotid perforation. A series of in vitro and in vivo experiments were conducted to investigate the function of SIRT3 and its potential mechanisms in nimodipine-treated SAH. Nimodipine, at a concentration of 10μM within 48h of incubation, exerted significant neuroprotective effects, enhancing SIRT3 protein expression under oxidative stress. Functional in vitro studies revealed that elevated SIRT3 expression improved mitochondrial function and promoted neuronal autophagy. Additional studies unveiled that SIRT3 knockdown or inhibition of autophagosome formation using inhibitor 3-methyladenine suppressed nimodipine-induced autophagy. The absence of autophagy increased neuronal cytotoxicity and mitochondrial dysfunction, decreased the release of anti-inflammatory cytokines, and increased the release of proinflammatory cytokines. Furthermore, blocking autophagy exacerbated neuronal apoptosis worsened neurological outcomes, and nullified the neuroprotective effects of nimodipine in the SAH mouse model. These findings highlight a mechanism where SIRT3 mediates nimodipine's neuroprotective effects by regulating mitochondrial function and autophagy. This suggests that SIRT3 serves as a promising therapeutic target for SAH.

Advancing EEG classification for neurodegenerative conditions using BCI: a graph attention approach with phase synchrony

Advancing EEG classification for neurodegenerative conditions using BCI: a graph attention approach with phase synchrony

Molecular Mechanisms Underlying Neuroinflammation Intervention with Medicinal Plants: A Critical and Narrative Review of the Current Literature.

Neuroinflammation is a key factor in the progression of neurodegenerative diseases, driven by the dysregulation of molecular pathways and activation of the brain's immune system, resulting in the release of pro-inflammatory and oxidative molecules. This chronic inflammation is exacerbated by peripheral leukocyte infiltration into the central nervous system. Medicinal plants, with their historical use in traditional medicine, have emerged as promising candidates to mitigate neuroinflammation and offer a sustainable alternative for addressing neurodegenerative conditions in a green healthcare framework. This review evaluates the effects of medicinal plants on neuroinflammation, emphasizing their mechanisms of action, effective dosages, and clinical implications, based on a systematic search of databases such as PubMed, SCOPUS, and Web of Science. The key findings highlight that plants like Cleistocalyx nervosum var. paniala, Curcuma longa, Cannabis sativa, and Dioscorea nipponica reduce pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), inhibit enzymes (COX-2 and iNOS), and activate antioxidant pathways, particularly Nrf2. NF-κB emerged as the primary pro-inflammatory pathway inhibited across studies. While the anti-inflammatory potential of these plants is significant, the variability in dosages and phytochemical compositions limits clinical translation. Here, we highlight that medicinal plants are effective modulators of neuroinflammation, underscoring their therapeutic potential. Future research should focus on animal models, standardized protocols, and safety assessments, integrating advanced methodologies, such as genetic studies and nanotechnology, to enhance their applicability in neurodegenerative disease management.

In silico analysis of hub genes and regulatory networks implicates the putamen in non-motor Parkinson’s disease disorders

BackgroundParkinson’s disease (PD) is a neurodegenerative condition marked by the gradual degeneration of dopaminergic neurons in the substantia nigra, leading to depletion of the dopaminergic neurons in the substantia nigra as well as degeneration as and decreased activity in the putamen. This study aims to identify the role of putamen in non-motor PD symptoms as well as potential therapeutic target in the putamen of PD.MethodsTranscriptome profiles of PD (dataset number: GSE205450, obtained from postmortem putamen and caudate samples from forty controls and thirty-five PD patients) were retrieved from the Gene Expression Omnibus (GEO) database. Specifically, we focused on putamen data for controls and PD patients. Differential gene expression analysis was carried out using with Limma, filtering for genes with |logFC|> 1 (fold change) and p < 0.05 (p-value). Protein–Protein Interaction networks were constructed using stringDB (combined score > 0.7) and analyzed in Cytoscape to identify hub genes based on various topological measures (EPC, MCC, MNC, Degree, and EcCentricity). Enrichment analysis of target genes was conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Also, we constructed transcription factor (TF)-hub gene expression networks, miRNA-hub gene expression networks, and disease hub gene association networks using the JASPAR database, Tarbase database, and DisGeNET via NetworkAnalyst platform, respectively.ResultsSeven genes, namely SST, NPY, IL6, PVALB, ALB, NTS, and TH were identified as hub genes in PD putamen. Notable miRNAs included hsa-mir-34a-5p, hsa-mir-15a-5p, hsa-mir-424-5p, and hsa-mir-19b-3p, while key transcription factors include GATA2, CREB1, FOXC1, FOXL1, TID1, NFKB1, YY1, SPIB, GATA3, and STAT3.ConclusionsOur findings revealed close associations between the hub genes of PD putamen and non-motor symptoms of PD such as major depressive disorder, mood disorders and schizophrenia. These findings may provide a new direction for developing therapy for non-motor symptoms of PD and wet lab research is encouraged.

Targeted Metabolomics for the Analysis of p-Cresol in Mouse Brain: Impact of Biological Sex and Strain.

p-Cresol, an environmental contaminant and endogenous metabolite derived primarily from the conversion of l-tyrosine by intestinal microflora, is gaining increasing attention, due to its potential impact on human health. Recent studies have highlighted elevated levels of p-cresol and its metabolites, including p-cresyl sulfate and p-cresyl glucuronide, in various populations, suggesting a correlation with neurodevelopmental and neurodegenerative conditions. While the role of this compound as a uremic toxin is well established, its presence and concentration within the central nervous system (CNS) remain largely unexplored. To address this gap, an high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method was optimized and validated for the first time in this work for the targeted metabolomics of p-cresol in brain tissues. This method enabled the quantification of this compound in different brain areas of adult male and female C57BL/6J mice and in the cortex of various mouse strains, including CD-1 and the idiopathic autism model BTBR T+Itpr3tf/J. Additionally, preliminary analyses of human cortex samples confirmed the presence of p-cresol, suggesting its relevance in human brain health. Moreover, metabolomic analyses have further explored the correlations between p-cresol and neurotransmitters, with a particular focus on dopaminergic and noradrenergic pathways. These findings pave the way for understanding the potential impact of p-cresol on neurochemical networks and its implications for neurodevelopmental and neurodegenerative disorders.

New Insights into Chemical Profiles and Health-Promoting Effects of Edible Mushroom Dictyophora indusiate (Vent ex. Pers.) Fischer: A Review.

Mushrooms are valued for their culinary and medicinal benefits, containing bioactive compounds like polysaccharides, terpenoids, phenolics, lectins, and ergosterols. This review aims to encourage research on D. indusiata by summarizing its chemistry, health benefits, pharmacology, and potential therapeutic applications. Molecules from D. indusiata offer anti-diabetic, antioxidant, anti-tumor, hepatoprotective, and anti-bacterial effects. In particular, polysaccharides from Dictyophora indusiata (DIP) enhance immune function, reduce oxidative stress, and promote gut health as prebiotics. DIP shows neuroprotective effects by reducing oxidative damage, improving mitochondrial function, and regulating apoptosis, making them beneficial for neurodegenerative diseases. They also activate immune responses through TLR4 and NF-κB pathways. Additionally, compounds like dictyophorines and quinazoline from D. indusiata support nerve growth and protection. Mushrooms help regulate metabolism and improve lipid profiles, with potential applications in managing metabolic disorders, cancer, cardiovascular diseases, diabetes, and neurodegenerative conditions. Their wide range of bioactive compounds makes D. indusiata mushrooms functional foods with significant therapeutic potential.

Evolution of Alzheimer's Disease Therapeutics: From Conventional Drugs to Medicinal Plants, Immunotherapy, Microbiotherapy and Nanotherapy.

Alzheimer's disease (AD) represents an escalating global health crisis, constituting the leading cause of dementia among the elderly and profoundly impairing their quality of life. Current FDA-approved drugs, such as rivastigmine, donepezil, galantamine, and memantine, offer only modest symptomatic relief and are frequently associated with significant adverse effects. Faced with this challenge and in line with advances in the understanding of the pathophysiology of this neurodegenerative condition, various innovative therapeutic strategies have been explored. Here, we review novel approaches inspired by advanced knowledge of the underlying pathophysiological mechanisms of the disease. Among the therapeutic alternatives, immunotherapy stands out, employing monoclonal antibodies to specifically target and eliminate toxic proteins implicated in AD. Additionally, the use of medicinal plants is examined, as their synergistic effects among components may confer neuroprotective properties. The modulation of the gut microbiota is also addressed as a peripheral strategy that could influence neuroinflammatory and degenerative processes in the brain. Furthermore, the therapeutic potential of emerging approaches, such as the use of microRNAs to regulate key cellular processes and nanotherapy, which enables precise drug delivery to the central nervous system, is analyzed. Despite promising advances in these strategies, the incidence of Alzheimer's disease continues to rise. Therefore, it is proposed that achieving effective treatment in the future may require the integration of combined approaches, maximizing the synergistic effects of different therapeutic interventions.

The Human Microglia Atlas (HuMicA) unravels changes in disease-associated microglia subsets across neurodegenerative conditions

Dysregulated microglia activation, leading to neuroinflammation, is crucial in neurodegenerative disease development and progression. We constructed an atlas of human brain immune cells by integrating nineteen single-nucleus RNA-seq and single-cell RNA-seq datasets from multiple neurodegenerative conditions, comprising 241 samples from patients with Alzheimer’s disease, autism spectrum disorder, epilepsy, multiple sclerosis, Lewy body diseases, COVID-19, and healthy controls. The integrated Human Microglia Atlas (HuMicA) included 90,716 nuclei/cells and revealed nine populations distributed across all conditions. We identified four subtypes of disease-associated microglia and disease-inflammatory macrophages, recently described in mice, and shown here to be prevalent in human tissue. The high versatility of microglia is evident through changes in subset distribution across various pathologies, suggesting their contribution in shaping pathological phenotypes. A GPNMB-high subpopulation was expanded in AD and MS. In situ hybridization corroborated this increase in AD, opening the question on the relevance of this population in other pathologies.

Virginia Memory Project: Using the Healthy Brain Initiative Roadmap to design a statewide dementia registry.

The Virginia Memory Project (VMP) is a statewide epidemiological registry for Alzheimer's disease and related disorders (ADRD) and other neurodegenerative conditions. It aims to support dementia research, policy, and care by leveraging the Centers for Disease Control (CDC) Healthy Brain Initiative (HBI) Roadmap. To capture comprehensive data, the VMP integrates self-enrollment and automatic enrollment using Virginia's All-Payer Claims Database (APCD). It also adapts Behavioral Risk Factors Surveillance Survey (BRFSS) modules for self-reported cognitive and caregiving data, offering connections to research, clinical services, and education. Virginia successfully codified the VMP in the 2024 general assembly session. The VMP demonstrates a novel approach to Alzheimer's Disease and Related Disorders (ADRD) surveillance by combining traditional registry functions with community engagement and workforce development. Future efforts will focus on increasing enrollment, especially among underrepresented groups, to enhance data-driven dementia policy and care in Virginia. Integrated the Healthy Brain Initiative (HBI) domains into the newest statewide epidemiological dementia registry in the Commonwealth of Virginia. Collected data and identified gaps in the current research related to dementia and Alzheimer's related diseases. Aimed to mitigate barriers to dementia registry enrollment by identifying significant underdiagnosis and underrepresentation of racial and ethnic minority groups. Developed solutions to alleviate the current data and enrollment disparities and to connect individuals to research, physicians, and community groups.

Phytomedicine Potential of Oroxylum indicum Root and Its Constituents: Targeting Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by a gradual decline in cognitive function, for which few effective treatments exist. This study investigated the neuroprotective potential of Oroxylum indicum root extract and its key constituents (baicalein, chrysin, oroxylin A) against AD hallmarks. The extract and its constituents exhibited antioxidant activity in the DPPH assay. They inhibited β-amyloid aggregation as measured by the thioflavin T assay and acetylcholinesterase activity using the Ellman method. In cell culture models, O. indicum extract showed an ability to protect neurons from the toxic effects of H2O2. Western blot analysis revealed the extract and its major active component, baicalein, downregulated pro-apoptotic markers (cleaved caspase-3, and BAX) upon H2O2 exposure. Furthermore, they reduced the expression of amyloidogenic proteins (BACE1) and phosphorylated tau. These findings suggest that O. indicum root extract, particularly baicalein, possesses multifaceted neuroprotective properties, targeting various aspects of AD pathogenesis, including oxidative stress, cholinergic dysfunction, β-amyloid formation, aggregation, and apoptosis. O. indicum root thus warrants further investigation as a promising source of therapeutic agents for AD.

Trends and Disparities in Parkinson's Disease Mortality in the United States with Predictions Using Machine Learning.

Parkinson's disease (PD) is a progressive neurodegenerative condition characterized by the degradation of dopaminergic pathways in the brain. As the population in the United States continues to age, it is essential to understand the trends in mortality related to PD. This analysis of PD's mortality characterizes temporal shifts, examines demographic and regional differences, and provides machine-learning predictions. PD-related deaths in the United States were gathered from CDC WONDER. Age-adjusted mortality rates (AAMR) were collected, and trends were analyzed based on gender, race, region, age, and place of death. Annual percent change and average annual percent change were calculated using Joinpoint Regression program. Forecasts were obtained using the optimal Autoregressive Integrated Moving Average (ARIMA) model. Overall mortality rate due to Parkinson's increased from 1999 to 2022. Male gender, White race, Southern region, and older ages were associated with higher mortality compared to other groups. Deaths at home decreased and hospice deaths increased during the study period. This study highlights the increasing rate of PD AAMR and how it may become even more prevalent with time, emphasizing the value of increasing knowledge surrounding the disease and its trends to better prepare health systems and individual families for the burden of PD.

Resonant Young's Slit Interferometer for Sensitive Detection of Low-Molecular-Weight Biomarkers.

The detection of low-molecular-weight biomarkers is essential for diagnosing and managing various diseases, including neurodegenerative conditions such as Alzheimer's disease. A biomarker's low molecular weight is a challenge for label-free optical modalities, as the phase change they detect is directly proportional to the mass bound on the sensor's surface. To address this challenge, we used a resonant Young's slit interferometer geometry and implemented several innovations, such as phase noise matching and optimisation of the fringe spacing, to maximise the signal-to-noise ratio. As a result, we achieved a limit of detection of 2.9 × 10-6 refractive index units (RIU). We validated our sensor's low molecular weight capability by demonstrating the detection of Aβ-42, a 4.5 kDa peptide indicative of Alzheimer's disease, and reached the clinically relevant pg/mL regime. This system builds on the guided mode resonance modality we previously showed to be compatible with handheld operation using low-cost components. We expect this development will have far-reaching applications beyond Aβ-42 and become a workhorse tool for the label-free detection of low-molecular-weight biomarkers across a range of disease types.

Unraveling the transcriptomic landscape of brain vascular cells in dementia: A systematic review.

Cerebrovascular dysfunction plays a critical role in the pathogenesis of dementia and related neurodegenerative disorders. Recent omics-driven research has revealed associations between vascular abnormalities and transcriptomic alterations in brain vascular cells, particularly endothelial cells (ECs) and pericytes (PCs). However, the impact of these molecular changes on dementia remains unclear. We conducted a comparative analysis of gene expression in ECs and PCs across neurodegenerative conditions, including Alzheimer's disease (AD), Huntington's disease, and arteriovenous malformation, utilizing transcriptomic data from published postmortem human tissue studies. We identified differentially expressed genes (DEGs) consistently dysregulated in ECs and PCs across these pathologies. Notably, several DEGs are linked to vascular cell zonation and genetic risks for AD and cerebral small vessel disease. Our findings provide insights into the cellular and molecular mechanisms underlying vascular dysfunction in dementia, highlight the knowledge gaps, and suggest potential novel vascular therapeutic targets, including genes not previously investigated in this context. Systematic review of differentially expressed genes (DEGs) in vascular cells from neurodegenerative single-nuclear RNA-sequencing (snRNA-seq) studies. Identify overlapping DEGs in multiple vascular cell types across studies. Examine functional relevance and associations with genetic risk for common DEGs. Outline future directions for the vascular omics field.

Exome sequencing reveals a rare damaging variant in GRIN2C in familial late-onset Alzheimer's disease

BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder with both genetic and environmental factors contributing to its pathogenesis. While early-onset AD has well-established genetic determinants, the genetic basis for late-onset AD remains less clear. This study investigates a large Italian family with late-onset autosomal dominant AD, identifying a novel rare missense variant in GRIN2C gene associated with the disease, and evaluates the functional impact of this variant.MethodsAffected and unaffected members from a Northern Italian family were included. Genomic DNA from family members was extracted and initially screened for pathogenic mutations in APP, PSEN1, and PSEN2, and screened for 77 genes associated with neurodegenerative conditions using NeuroX array assay. Exome sequencing was performed on three affected individuals and two healthy relatives. Bioinformatics analyses were conducted. Functional analysis was performed using primary neuronal cultures, and the impact of the variant was assessed through immunocytochemistry and electrophysiology.ResultsPathogenic variants were not identified in APP, PSEN1, or PSEN2, nor in the 77 genes in NeuroX array assay. Exome Sequencing revealed the c.3215C > T p.(A1072V) variant in GRIN2C gene (NM 000835.6), encoding for the glutamate ionotropic receptor N-methyl-D-aspartate receptor (NMDA) type subunit 2C (GluN2C). This variant segregated in 6 available AD patients in the family and was absent in 9 healthy relatives. Primary rat hippocampal neurons overexpressing GluN2CA1072V showed an increase in NMDAR-induced currents, suggesting altered glutamatergic transmission. Surface expression assays demonstrated an elevated surface/total ratio of the mutant GluN2C, correlating with the increased NMDAR current. Additionally, immunocytochemistry revealed in neurons expressing the mutant variant a reduced colocalization between the GluN2C subunit and 14-3-3 proteins, which are known to facilitate membrane trafficking of NMDARs.DiscussionWe identified a rare missense variant in GRIN2C associated with late-onset autosomal dominant Alzheimer's disease. These findings highlight the role of GluN2C-containing NMDARs in glutamatergic signaling and their potential contribution to AD pathogenesis.