Frequent Alzheimer's disease neuropathological change in patients with glioblastoma.

Background: The incidence of brain cancer and neurodegenerative diseases is increasing with a demographic shift towards aging populations. Biological parallels have been observed between glioblastoma and Alzheimer's disease (AD), which converge on accelerated brain aging. Here, we aimed to map the cooccurrence of AD neuropathological change (ADNC) in the tumor-adjacent cortex of patients with glioblastoma. Methods: Immunohistochemical screening of AD markers amyloid beta (Abeta), amyloid precursor protein (APP), and hyperphosphorylated tau (pTau) was conducted in 420 tumor samples of 205 patients. For each cortex area, we quantified ADNC, neurons, tumor cells, and microglia. Results: Fifty-two percent of patients (N = 106/205) showed ADNC (Abeta and pTau, Abeta or pTau) in the tumor-adjacent cortex, with histological patterns widely consistent with AD. ADNC was positively correlated with patient age and varied spatially according to Thal phases and Braak stages. It decreased with increasing tumor cell infiltration (P < .0001) and was independent of frequent expression of APP in neuronal cell bodies (N = 182/205) and in tumor necrosis-related axonal spheroids (N = 195/205; P = .46). Microglia response was most present in tumor cell infiltration plus ADNC, being further modulated by patient age and sex. ADNC did not impact patient survival in the present cohort. Conclusions: Our findings highlight the frequent presence of ADNC in the glioblastoma vicinity, which was linked to patient age and tumor location. The cooccurrence of AD and glioblastoma seemed stochastic without clear spatial relation. ADNC did not impact patient survival in our cohort.

Microglial Drivers of Alzheimer's Disease Pathology: An Evolution of Diverse Participating States.

Microglia, the resident immune-competent cells of the brain, become dysfunctional in Alzheimer's disease (AD), and their aberrant immune responses contribute to the accumulation of pathological proteins and neuronal injury. Genetic studies implicate microglia in the development of AD, prompting interest in developing immunomodulatory therapies to prevent or ameliorate disease. However, microglia take on diverse functional states in disease, playing both protective and detrimental roles in AD, which largely overlap and may shift over the disease course, complicating the identification of effective therapeutic targets. Extensive evidence gathered using transgenic mouse models supports an active role of microglia in pathology progression, though results vary and can be contradictory between different types of models and the degree of pathology at the time of study. Here, we review microglial immune signaling and responses that contribute to the accumulation and spread of pathological proteins or directly affect neuronal health. We additionally explore the use of induced pluripotent stem cell (iPSC)-derived models to study living human microglia and how they have contributed to our knowledge of AD and may begin to fill in the gaps left by mouse models. Ultimately, mouse and iPSC-derived models have their own limitations, and a comprehensive understanding of microglial dysfunction in AD will only be established by an integrated view across models and an appreciation for their complementary viewpoints and limitations.

Real-time detection of Tau-381 protein using liquid crystal-based sensors for Alzheimer's disease diagnosis.

Tau is a protein found in the central nervous system (CNS) and is involved in stabilizing microtubules in axons. Given the link between Tau levels in the body and Alzheimer's disease (AD), there is a demand for straightforward and precise strategies to detect Tau in body fluids. In this study, we report liquid crystal (LC)-based sensors for the real-time detection of Tau protein, a well-known AD biomarker. The sensor uses a detection method based on the orientation change of the LC because of the competitive biomolecular interaction between Tau and Tau aptamers with the cationic polymer poly-L-lysine (PLL). Tau and its aptamers form stable complexes through electrostatic interactions. Owing to the consumption of the aptamer, the positively charged PLL fails to interact with the aptamer but binds to the negatively charged 1.2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) sodium salt (DOPG). The PLL and DOPG complex alters the orientation of the LC to ensure a planar anchoring of the 4-cyano-4'-pentylbiphenyl (5CB)/aqueous interface; this anchoring intensifies with increasing Tau concentration, thus enabling the observation of a bright optical image. Our LC-based sensor demonstrated a low detection limit of 2.77 pg/mL in phosphate buffered saline (PBS) and 10.86 pg/mL and 19.31 pg/mL in human serum and plasma, respectively. Moreover, it is anticipated to be suitable for point-of-care diagnosis of AD because it does not require specialized analytical equipment and only requires microliters of sample.

Can cerebrospinal fluid biomarkers tell us something about financial capacity in Alzheimer's disease patients? A preliminary study.

BACKGROUND: Although diagnostic markers in cerebrospinal fluid (CSF) have become a rapidly growing research field, they have not as yet been investigated in relation to capacities that are of interest to geriatric psychiatry and neuropsychology, such as financial capacity. The aim of this study was to assess whether CSF biomarkers can predict financial capacity in patients with a diagnosis of major neurocognitive disorder due to Alzheimer's disease (AD). METHODS: Participants were examined with a number of neuropsychological tests, with an emphasis on the Mini-Mental State Examination (MMSE), the Geriatric Depression Scale (GDS-15), and the Legal Capacity for Property Law Transactions Assessment Scale (LCPLTAS) and CSF tests. RESULTS: Amyloid ß peptide 1-42 (Aß42), total tau, and phosphorylated tau were not found to predict financial capacity performance in AD, but MMSE shows a strong positive correlation with LCPLTAS. CONCLUSIONS: These preliminary findings indicate that complex cognitive functions, such as financial capacity, may not be directly linked to CSF concentrations of the abovementioned biomarkers. Further studies with larger numbers of patients will be required to assess the reproducibility of these findings and to determine whether this approach can assist not only in diagnosis but also in neuropsychological assessment.

Imidacloprid unique and repeated treatment produces cholinergic transmission disruption and apoptotic cell death in SN56 cells.

Imidacloprid (IMI), the most widely used worldwide neonicotinoid biocide, produces cognitive disorders after repeated and single treatment. However, little was studied about the possible mechanisms that produce this effect. Cholinergic neurotransmission regulates cognitive function. Most cholinergic neuronal bodies are present in the basal forebrain (BF), regulating memory and learning process, and their dysfunction or loss produces cognition decline. BF SN56 cholinergic wild-type or acetylcholinesterase (AChE), ß-amyloid-precursor-protein (ßAPP), Tau, glycogen-synthase-kinase-3-beta (GSK3ß), beta-site-amyloid-precursor-protein-cleaving enzyme 1 (BACE1), and/or nuclear-factor-erythroid-2-related-factor-2 (NRF2) silenced cells were treated for 1 and 14 days with IMI (1 µM-800 µM) with or without recombinant heat-shock-protein-70 (rHSP70), recombinant proteasome 20S (rP20S) and with or without N-acetyl-cysteine (NAC) to determine the possible mechanisms that mediate this effect. IMI treatment for 1 and 14 days altered cholinergic transmission through AChE inhibition, and triggered cell death partially through oxidative stress generation, AChE-S overexpression, HSP70 downregulation, P20S inhibition, and Aß and Tau peptides accumulation. IMI produced oxidative stress through reactive oxygen species production and antioxidant NRF2 pathway downregulation, and induced Aß and Tau accumulation through BACE1, GSK3ß, HSP70, and P20S dysfunction. These results may assist in determining the mechanisms that produce cognitive dysfunction observed following IMI exposure and provide new therapeutic tools.

Combining cerebrospinal fluid and PI-2620 tau-PET for biomarker-based stratification of Alzheimer's disease and 4R-tauopathies.

INTRODUCTION: Recent advances in biomarker research have improved the diagnosis and monitoring of Alzheimer's disease (AD), but in vivo biomarker-based workflows to assess 4R-tauopathy (4RT) patients are currently missing. We suggest a novel biomarker-based algorithm to characterize AD and 4RTs. METHODS: We cross-sectionally assessed combinations of cerebrospinal fluid measures (CSF p-tau181 and t-tau) and 18F-PI-2620 tau-positron emission tomography (PET) in patients with AD (n = 64), clinically suspected 4RTs (progressive supranuclear palsy or corticobasal syndrome, n = 82) and healthy controls (n = 19). RESULTS: Elevated CSF p-tau181 and cortical 18F-PI-2620 binding was characteristic for AD while normal CSF p-tau181 with elevated subcortical 18F-PI-2620 binding was characteristic for 4RTs. 18F-PI-2620-assessed posterior cortical hypoperfusion could be used as an additional neuronal injury biomarker in AD. DISCUSSION: The specific combination of CSF markers and 18F-PI-2620 tau-PET in disease-specific regions facilitates the biomarker-guided stratification of AD and 4RTs. This has implications for biomarker-aided diagnostic workflows and the advancement in clinical trials. HIGHLIGHTS: Novel biomarker-based algorithm for differentiating AD and 4R-tauopathies. A combination of CSF p-tau181 and 18F-PI-2620 discriminates AD versus 4R tauopathies. Hypoperfusion serves as an additional neuronal injury biomarker in AD.

Alzheimer disease-like neuropathologic changes in a geriatric baboon (Papio hamadryas).

IMPORTANCE: Alzheimer's disease (AD) is the most common cause of dementia in the elderly with the incidence rising exponentially after the age of 65 years. Unfortunately, effective treatments are extremely limited and definite diagnosis can only be made at autopsy. This is in part due to our limited understanding of the complex pathophysiology, including the various genetic, environmental, and metabolic contributing factors. In an effort to better understand this complex disease, researchers have employed nonhuman primates as translational models. CASE PRESENTATION: This report aims to describe the AD-like neuropathology in the brain of a 37-year-old female baboon (Papio hamadryas), which at the time of her death made her the oldest hamadryas baboon at any member institution of the Association of Zoos and Aquariums. A diagnostic necropsy was performed, and the brain was evaluated for neurodegenerative disease. Frequent amyloid-ß deposits were identified, consistent with what has been described in other geriatric nonhuman primates. Phospho-tau pathology, including neurofibrillary tangles, a feature not well-described in other primate models, was also abundant. CONCLUSIONS AND RELEVANCE: Our results suggest that more detailed, prospective, longitudinal studies are warranted utilizing this particular species to see if they represent a viable model for human brain aging.

Syk inhibitors reduce tau protein phosphorylation and oligomerization.

Spleen tyrosine kinase (Syk), a non-receptor-type tyrosine kinase, has a wide range of physiological functions. A possible role of Syk in Alzheimer's disease (AD) has been proposed. We evaluated the localization of Syk in the brains of patients with AD and control participants. Human neuroblastoma M1C cells harboring wild-type tau (4R0N) were used with the tetracycline off (TetOff) induction system. In this model of neuronal tauopathy, the effects of the Syk inhibitors-BAY 61-3606 and R406-on tau phosphorylation and oligomerization were explored using several phosphorylated tau-specific antibodies and an oligomeric tau antibody, and the effects of these Syk inhibitors on autophagy were examined using western blot analyses. Moreover, the effects of the Syk inhibitor R406 were evaluated in vivo using wild-type mice. In AD brains, Syk and phosphorylated tau colocalized in the cytosol. In M1C cells, Syk protein (72 kDa) was detected using western blot analysis. Syk inhibitors decreased the expression levels of several tau phosphoepitopes including PHF-1, CP13, AT180, and AT270. Syk inhibitors also decreased the levels of caspase-cleaved tau (TauC3), a pathological tau form. Syk inhibitors increased inactivated glycogen synthase kinase 3ß expression and decreased active p38 mitogen-activated protein kinase expression and demethylated protein phosphatase 2 A levels, indicating that Syk inhibitors inactivate tau kinases and activate tau phosphatases. Syk inhibitors also activated autophagy, as indicated by increased LC3II and decreased p62 levels. In vivo, the Syk inhibitor R406 decreased phosphorylated tau levels in wild-type mice. These findings suggest that Syk inhibitors offer novel therapeutic strategies for tauopathies, including AD.

Cerebrospinal fluid in the differential diagnosis of Alzheimer's disease: an update of the literature.

INTRODUCTION: The importance of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) diagnosis is rapidly increasing, and there is a growing interest in the use of CSF biomarkers in monitoring the response to therapy, especially in the light of newly available approaches to the therapy of neurodegenerative diseases. AREAS COVERED: In this review we discuss the most relevant measures of neurodegeneration that are being used to distinguish patients with AD from healthy controls and individuals with mild cognitive impairment, in order to provide an overview of the latest information available in the scientific literature. We focus on markers related to amyloid processing, markers associated with neurofibrillary tangles, neuroinflammation, neuroaxonal injury and degeneration, synaptic loss and dysfunction, and markers of α-synuclein pathology. EXPERT OPINION: In addition to neuropsychological evaluation, core CSF biomarkers (Aß42, t-tau, and p-tau181) have been recommended for improvement of timely, accurate and differential diagnosis of AD, as well as to assess the risk and rate of disease progression. In addition to the core CSF biomarkers, various other markers related to synaptic dysfunction, neuroinflammation, and glial activation (neurogranin, SNAP-25, Nfl, YKL-40, TREM2) are now investigated and have yet to be validated for future potential clinical use in AD diagnosis.

Emerging microglial biology highlights potential therapeutic targets for Alzheimer's disease.

Alzheimer's disease is a chronic degenerative disease of the central nervous system, which primarily affects elderly people and accounts for 70-80 % of dementia cases. The current prevailing amyloid cascade hypothesis suggests that Alzheimer's disease begins with the deposition of amyloid ß (Aß) in the brain. Major therapeutic strategies target Aß production, aggregation, and clearance, although many clinical trials have shown that these therapeutic strategies are not sufficient to completely improve cognitive deficits in AD patients. Recent genome-wide association studies have identified that multiple important regulators are the most significant genetic risk factors for Alzheimer's disease, especially in the innate immune pathways. These genetic risk factors suggest a critical role for microglia, highlighting their therapeutic potential in treating neurodegenerative diseases. In this review, we discuss how these recently documented AD risk genes affect microglial function and AD pathology and how they can be further targeted to regulate microglial states and slow AD progression, especially the highly anticipated APOE and TREM2 targets. We focused on recent findings that modulation of innate and adaptive neuroimmune microenvironment crosstalk reverses cognitive deficits in AD patients. We also considered novel strategies for microglia in AD patients.

Thonningianin A from Penthorum chinense Pursh as a targeted inhibitor of Alzheimer's disease-related ß-amyloid and Tau proteins.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by complex pathogenesis mechanisms. Among these, ß-amyloid plaques and hyperphosphorylated Tau protein tangles have been identified as significant contributors to neuronal damage. This study investigates thonningianin A (TA) from Penthorum chinense Pursh (PCP) as a potential inhibitor targeting these pivotal proteins in AD progression. The inhibitory potential of PCP and TA on Aß fibrillization was initially investigated. Subsequently, ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry and biolayer interferometry were employed to determine TA's affinity for both Aß and Tau. The inhibitory effects of TA on the levels and cytotoxicity of AD-related proteins were then assessed. In 3xTg-AD mice, the therapeutic potential of TA was evaluated. Additionally, the molecular interactions between TA and either Aß or Tau were explored using molecular docking. We found that PCP-total ethanol extract and TA significantly inhibited Aß fibrillization. Additionally, TA demonstrated strong affinity to Aß and Tau, reduced levels of amyloid precursor protein and Tau, and alleviated mitochondrial distress in PC-12 cells. In 3xTg-AD mice, TA improved cognition, reduced Aß and Tau pathology, and strengthened neurons. Moreover, molecular analyses revealed efficient binding of TA to Aß and Tau. In conclusion, TA, derived from PCP, shows significant neuroprotection against AD proteins, highlighting its potential as an anti-AD drug candidate.

AMPA receptors in Alzheimer disease: Pathological changes and potential therapeutic targets.

Alzheimer disease (AD) is a prevalent neurodegenerative disorder that affects synapses and leads to progressive cognitive decline. The role of N-methyl-D-aspartic acid (NMDA) receptors in the pathogenesis of AD is well-established as they contribute to excitotoxicity and neurodegeneration in the pathological process of extrasynaptic glutamate concentration. However, the therapeutic potential of the NMDA receptor antagonist memantine in rescuing synaptic damage is limited. Research indicates that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors also play a significant role in AD. Abnormal transcription, expression, and localization of AMPA receptors lead to synaptic dysfunction and damage, contributing to early cognitive impairment in AD patients. Understanding the impact of AMPA receptors on AD pathogenesis and exploring the potential for the development of AMPA receptor-targeting drugs are crucial. This review aims to consolidate recent research findings on AMPA receptors in AD, elucidate the current state of AMPA receptor research and lay the foundation for future basic research and drug development.

Molecular Modeling Insights on the Pharmaceuticals and Hypotheses of Alzheimer's Disease.

Alzheimer's disease (AD) stands as the predominant contributor to dementia cases. The ongoing developments in our understanding of its pathogenesis have sparked the interest of researchers, driving them to explore innovative treatment approaches. Existing therapies incorporating cholinesterase inhibitors and/or NMDA antagonists have shown limited improvement in alleviating symptoms. This, in turn, highlights the urgency for the pursuit of more effective therapeutic options. Given the annual rise in the number of individuals affected by dementia, it is imperative to allocate resources and efforts towards the exploration of novel therapeutic options. This review aims to provide a comprehensive overview of the AD-related hypotheses, along with the computational approaches employed in research within each hypothesis. In this comprehensive review, the authors shed light on using various computational tools, including diverse case studies, in the pursuit of finding efficacious treatments for AD. The development of more sophisticated diagnostic techniques is crucial, enabling early detection and intervention in the battle against this challenging condition. The potential treatments investigated in this analysis are poised to assume ever more significant functions in both preventing and treating AD, ultimately enhancing the management of the condition and the overall well-being of individuals affected by AD.

Dissecting the immune response of CD4+ T cells in Alzheimer's disease.

The formation of amyloid-ß (Aß) plaques is a neuropathological hallmark of Alzheimer's disease (AD), however, these pathological aggregates can also be found in the brains of cognitively unimpaired elderly population. In that context, individual variations in the Aß-specific immune response could be key factors that determine the level of Aß-induced neuroinflammation and thus the propensity to develop AD. CD4+ T cells are the cornerstone of the immune response that coordinate the effector functions of both adaptive and innate immunity. However, despite intensive research efforts, the precise role of these cells during AD pathogenesis is still not fully elucidated. Both pathogenic and beneficial effects have been observed in various animal models of AD, as well as in humans with AD. Although this functional duality of CD4+ T cells in AD can be simply attributed to the vast phenotype heterogeneity of this cell lineage, disease stage-specific effect have also been proposed. Therefore, in this review, we summarized the current understanding of the role of CD4+ T cells in the pathophysiology of AD, from the aspect of their antigen specificity, activation, and phenotype characteristics. Such knowledge is of practical importance as it paves the way for immunomodulation as a therapeutic option for AD treatment, given that currently available therapies have not yielded satisfactory results.

Pathways to personalized medicine-Embracing heterogeneity for progress in clinical therapeutics research in Alzheimer's disease.

Biological and clinical heterogeneity is a major challenge in research for developing new treatments for Alzheimer's disease (AD). AD may be defined by its amyloid beta and tau pathologies, but we recognize that mixed pathologies are common, and that diverse genetics, central nervous system (CNS) and systemic pathophysiological processes, and environmental/experiential factors contribute to AD's diverse clinical and neuropathological features. All these factors are rational targets for therapeutic development; indeed, there are hundreds of candidate pharmacological, dietary, neurostimulation, and lifestyle interventions that show benefits in homogeneous laboratory models. Conventional clinical trial designs accommodate heterogeneity poorly, and this may be one reason that progress in translating candidate interventions has been so difficult. We review the challenges of AD's heterogeneity for the clinical trials enterprise. We then discuss how advances in repeatable biomarkers and digital phenotyping enable novel "single-case" and adaptive trial designs to accelerate therapeutics development, moving us closer to personalized research and medicine for AD. HIGHLIGHTS: Alzheimer's disease is diverse in its clinical features, course, risks, and biology. Typical randomized controlled trials are exclusive and necessarily large to attain arm comparability with broad outcomes. Repeated blood biomarkers and digital tracking can improve outcome measure precision and sensitivity. This enables the use of novel "single-case" and adaptive trial designs for inclusivity, rigor, and efficiency.

Felodipine attenuates neuroinflammatory responses and tau hyperphosphorylation through JNK/P38 signaling in tau-overexpressing AD mice.

We previously demonstrated that felodipine, an L-type calcium channel blocker, inhibits LPS-mediated neuroinflammatory responses in BV2 microglial cells and wild-type mice. However, the effects of felodipine on tau pathology, a hallmark of Alzheimer's disease (AD), have not been explored yet. Therefore, in the present study, we determined whether felodipine affects neuroinflammation and tau hyperphosphorylation in 3-month-old P301S transgenic mice (PS19), an early phase AD mice model for tauopathy. Felodipine administration decreased tauopathy-mediated microglial activation and NLRP3 expression in PS19 mice but had no effect on tauopathy-associated astrogliosis. In addition, felodipine treatment significantly reduced tau hyperphosphorylation at S202/Thr205 and Thr212/Ser214 residues via inhibiting JNK/P38 signaling in PS19 mice. Collectively, our results suggest that felodipine significantly ameliorates tau hyper-phosphorylation and tauopathy-associated neuroinflammatory responses in AD mice model for tauopathy and could be a novel therapeutic agent for AD.

Association of quantitative histopathology measurements with antemortem medial temporal lobe cortical thickness in the Alzheimer's disease continuum.

The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer's disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies.

Heterogeneity of factors associated with cognitive decline and cortical atrophy in early- versus late-onset Alzheimer's disease.

The objectives of this study were to investigate the variable factors associated with cognitive function and cortical atrophy and estimated variable importance of those factors in affecting cognitive function and cortical atrophy in patients with EOAD and LOAD. Patients with EOAD (n = 40), LOAD (n = 34), and healthy volunteers with normal cognition were included (n = 65). All of them performed 3T MRI, [18F]THK5351 PET (THK), [18F]flutemetamol PET (FLUTE), and detailed neuropsychological tests. To investigate factors associated with neuropsychological test results and cortical thickness in each group, we conducted multivariable linear regression models, including amyloid, tau, cerebral small vessel disease markers on MRI, and vascular risk factors. Then, we estimated variable importance in associating cognitive functions and cortical thickness, using relative importance analysis. In patients with EOAD, global THK retention was the most important contributor to the model variances for most neuropsychological tests, except for memory. However, in patients with LOAD, multiple contributors beyond tau were important in explaining variance of neuropsychological tests. In analyses with mean cortical thickness, global THK retention was the main contributor in patients with EOAD, while in LOAD patients, multiple factors contributed equally to mean cortical thickness. Therefore, EOAD and LOAD may have different pathomechanistic courses.

RNA-seq analyses on gametogenic tissues of alfalfa (Medicago sativa) revealed plant reproduction- and ploidy-related genes.

BACKGROUND: In alfalfa (Medicago sativa), the coexistence of interfertile subspecies (i.e. sativa, falcata and coerulea) characterized by different ploidy levels (diploidy and tetraploidy) and the occurrence of meiotic mutants capable of producing unreduced (2n) gametes, have been efficiently combined for the establishment of new polyploids. The wealth of agronomic data concerning forage quality and yield provides a thorough insight into the practical benefits of polyploidization. However, many of the underlying molecular mechanisms regarding gene expression and regulation remained completely unexplored. In this study, we aimed to address this gap by examining the transcriptome profiles of leaves and reproductive tissues, corresponding to anthers and pistils, sampled at different time points from diploid and tetraploid Medicago sativa individuals belonging to progenies produced by bilateral sexual polyploidization (dBSP and tBSP, respectively) and tetraploid individuals stemmed from unilateral sexual polyploidization (tUSP). RESULTS: Considering the crucial role played by anthers and pistils in the reduced and unreduced gametes formation, we firstly analyzed the transcriptional profiles of the reproductive tissues at different stages, regardless of the ploidy level and the origin of the samples. By using and combining three different analytical methodologies, namely weighted-gene co-expression network analysis (WGCNA), tau (τ) analysis, and differentially expressed genes (DEGs) analysis, we identified a robust set of genes and transcription factors potentially involved in both male sporogenesis and gametogenesis processes, particularly in crossing-over, callose synthesis, and exine formation. Subsequently, we assessed at the same floral stage, the differences attributable to the ploidy level (tBSP vs. dBSP) or the origin (tBSP vs. tUSP) of the samples, leading to the identification of ploidy and parent-specific genes. In this way, we identified, for example, genes that are specifically upregulated and downregulated in flower buds in the comparison between tBSP and dBSP, which could explain the reduced fertility of the former compared to the latter materials. CONCLUSIONS: While this study primarily functions as an extensive investigation at the transcriptomic level, the data provided could represent not only a valuable original asset for the scientific community but also a fully exploitable genomic resource for functional analyses in alfalfa.

Minimum spanning tree analysis of unimpaired individuals at risk of Alzheimer's disease.

Identifying early and non-invasive biomarkers to detect individuals in the earliest stages of the Alzheimer's disease continuum is crucial. As a result, electrophysiology and plasma biomarkers are emerging as great candidates in this pursuit due to their low invasiveness. This is the first magnetoencephalography study to assess the relationship between minimum spanning tree parameters, an alternative to overcome the comparability and thresholding problem issues characteristic of conventional brain network analyses, and plasma phosphorylated tau231 levels in unimpaired individuals, with different risk levels of Alzheimer's disease. Seventy-six individuals with available magnetoencephalography recordings and phosphorylated tau231 plasma determination were included. The minimum spanning tree for the theta, alpha and beta bands for each subject was obtained, and the leaf fraction, tree hierarchy and diameter were calculated. To study the relationship between these topological parameters and phosphorylated tau231, we performed correlation analyses, for the whole sample and considering the two risk sub-groups separately. Increasing concentrations of phosphorylated tau231 were associated with greater leaf fraction and tree hierarchy values, along with lower diameter values, for the alpha and theta frequency bands. These results emerged for the whole sample and the higher risk group, but not for the lower risk group. Our results indicate that the network topology of cognitively unimpaired individuals with elevated plasma phosphorylated tau231 levels, a marker of Alzheimer's disease pathology and amyloid-ß accumulation, is already altered, shifting towards a more integrated network increasing its vulnerability and hub-dependency, mostly in the alpha band. This is indicated by increases in leaf fraction and tree hierarchy, along with reductions in diameter. These results match the initial trajectory proposed by theoretical models of disease progression and network disruption and suggest that changes in brain function and organization begin early on.