Control Brains Research Articles

Uncovering Novel Extracellular Matrix Transcriptome Alterations in Lesions of Multiple Sclerosis.

The extracellular matrix (ECM) of the central nervous system (CNS) is an interconnected network of proteins and sugars with critical roles in both homeostasis and disease. In neurological diseases, excessive ECM deposition and remodeling impact both injury and repair. CNS lesions of multiple sclerosis (MS), a chronic inflammatory and degenerative disease, cause prominent alterations of the ECM. However, there are a lack of data investigating how the multitude of ECM members change in relation to each other and how this affects the MS disease course. Here, we evaluated ECM changes in MS lesions compared to a control brain using databases generated in-house through spatial mRNA-sequencing and through a public resource of single-nucleus RNA sequencing previously published by Absinta and colleagues. These results underline the importance of publicly available datasets to find new targets of interest, such as the ECM. Both spatial and public datasets demonstrated widespread changes in ECM molecules and their interacting proteins, including alterations to proteoglycans and glycoproteins within MS lesions. Some of the altered ECM members have been described in MS, but other highly upregulated members, including the SPARC family of proteins, have not previously been highlighted. SPARC family members are upregulated in other conditions by reactive astrocytes and may influence immune cell activation and MS disease course. The profound changes to the ECM in MS lesions deserve more scrutiny as they impact neuroinflammation, injury, and repair.

A New Systemic Disease Mouse Model for Glioblastoma Capable of Single-Tumour-Cell Detection.

Glioblastoma is characterised by extensive infiltration into the brain parenchyma, leading to inevitable tumor recurrence and therapeutic failure. Future treatments will need to target the specific biology of tumour recurrence, but our current understanding of the underlying mechanisms is limited. Significantly, there is a lack of available methods and models that are tailored to the examination of tumour recurrence. NOD-SCID mice were orthotopically implanted with luciferase-labelled donor U87MG or MU20 glioblastoma cells. Four days later, an unlabelled recipient tumor was implanted on the contralateral side. The mice were euthanised at a humane end-point and tissue and blood samples were collected for ex vivo analyses. The ex vivo analyses of the firefly-labelled MU20 tumours displayed extensive invasion at the primary tumour margins, whereas the firefly-labelled U87MG tumours exhibited expansive phenotypes with no evident invasions at the tumour margins. Luciferase signals were detected in the contralateral unlabelled recipient tumours for both the U87MG and MU20 tumours compared to the non-implanted control brain. Remarkably, tumour cells were uniformly detected in all tissue samples of the supratentorial brain region compared to the control tissue, with single tumour cells detected in some tissue samples. Circulating tumour cells were also detected in the blood samples of most of the xenografted mice. Moreover, tumour cells were detected in the lungs of all of the mice, a probable event related to haematogenous dissemination. Similar results were obtained when the U87MG cells were alternatively labelled with gaussian luciferase. These findings describe a systemic disease model for glioblastoma which can be used to investigate recurrence biology and therapeutic efficacy towards recurrence.

Advancements in high-resolution 3D microscopy analysis of endosomal morphology in postmortem Alzheimer's disease brains.

Abnormal endo-lysosomal morphology is an early cytopathological feature of Alzheimer's disease (AD) and genome-wide association studies (GWAS) have implicated genes involved in the endo-lysosomal network (ELN) as conferring increased risk for developing sporadic, late-onset AD (LOAD). Characterization of ELN pathology and the underlying pathophysiology is a promising area of translational AD research and drug development. However, rigorous study of ELN vesicles in AD and aged control brains poses a unique constellation of methodological challenges due in part to the small size of these structures and subsequent requirements for high-resolution imaging. Here we provide a detailed protocol for high-resolution 3D morphological quantification of neuronal endosomes in postmortem AD brain tissue, using immunofluorescent staining, confocal imaging with image deconvolution, and Imaris software analysis pipelines. To demonstrate these methods, we present neuronal endosome morphology data from 23 sporadic LOAD donors and one aged non-AD control donor. The techniques described here were developed across a range of AD neuropathology to best optimize these methods for future studies with large cohorts. Application of these methods in research cohorts will help advance understanding of ELN dysfunction and cytopathology in sporadic AD.

Histone acetylation in an Alzheimer’s disease cell model promotes homeostatic amyloid-reducing pathways

Alzheimer’s Disease (AD) is a disorder characterized by cognitive decline, neurodegeneration, and accumulation of amyloid plaques and tau neurofibrillary tangles in the brain. Dysregulation of epigenetic histone modifications may lead to expression of transcriptional programs that play a role either in protecting against disease genesis or in worsening of disease pathology. One such histone modification, acetylation of histone H3 lysine residue 27 (H3K27ac), is primarily localized to genomic enhancer regions and promotes active gene transcription. We previously discovered H3K27ac to be more abundant in AD patient brain tissue compared to the brains of age-matched non-demented controls. In this study, we use iPSC-neurons derived from familial AD patients with an amyloid precursor protein (APP) duplication (APPDup neurons) as a model to study the functional effect of lowering CBP/P300 enzymes that catalyze H3K27ac. We found that homeostatic amyloid-reducing genes were upregulated in the APPDup neurons compared to non-demented controls. We lowered CBP/P300 to reduce H3K27ac, which led to decreased expression of numerous of these homeostatic amyloid-reducing genes, along with increased extracellular secretion of a toxic amyloid-β species, Aβ(1–42). Our findings suggest that epigenomic histone acetylation, including H3K27ac, drives expression of compensatory genetic programs in response to AD-associated insults, specifically those resulting from APP duplication, and thus may play a role in mitigating AD pathology in neurons.

Heterogeneous factors influence social cognition across diverse settings in brain health and age-related diseases

AbstractAging diminishes social cognition, and changes in this capacity can indicate brain diseases. However, the relative contribution of age, diagnosis and brain reserve to social cognition, especially among older adults and in global settings, remains unclear when considering other factors. Here, using a computational approach, we combined predictors of social cognition from a diverse sample of 1,063 older adults across nine countries. Emotion recognition, mentalizing and overall social cognition were predicted via support vector regressions from various factors, including diagnosis (subjective cognitive complaints, mild cognitive impairment, Alzheimer’s disease and behavioral variant frontotemporal dementia), demographics, cognition/executive function, brain reserve and motion artifacts from functional magnetic resonance imaging recordings. Higher cognitive/executive functions and education ranked among the top predictors, outweighing age, diagnosis and brain reserve. Network connectivity did not show predictive values. The results challenge traditional interpretations of age-related decline, patient–control differences and brain associations of social cognition, emphasizing the importance of heterogeneous factors.

Association between brain imaging biomarkers and continuous glucose monitoring-derived glycemic control indices in Japanese patients with type 2 diabetes mellitus

IntroductionAlthough type 2 diabetes mellitus (T2DM) is associated with alterations in brain structure, the relationship between glycemic control indices and brain imaging markers remains unclear. This study aimed to investigate...

Concurrent functional ultrasound imaging with graphene-based DC-coupled electrophysiology as a platform to study slow brain signals and cerebral blood flow under control and pathophysiological brain states.

Current methodology used to investigate how shifts in brain states associated with regional cerebral blood volume (CBV) change in deep brain areas, are limited by either the spatiotemporal resolution of the CBV techniques, and/or compatibility with electrophysiological recordings; particularly in relation to spontaneous brain activity and the study of individual events. Additionally, infraslow brain signals (<0.1 Hz), including spreading depolarisations, DC-shifts and infraslow oscillations (ISO), are poorly captured by traditional AC-coupled electrographic recordings; yet these very slow brain signals can profoundly change CBV. To gain an improved understanding of how infraslow brain signals couple to CBV we present a new method for concurrent CBV with wide bandwidth electrophysiological mapping using simultaneous functional ultrasound imaging (fUS) and graphene-based field effect transistor (gFET) DC-coupled electrophysiological acquisitions. To validate the feasibility of this methodology visually-evoked neurovascular coupling (NVC) responses were examined. gFET recordings are not affected by concurrent fUS imaging, and epidural placement of gFET arrays within the imaging window did not deteriorate fUS signal quality. To examine directly the impact of infra-slow potential shifts on CBV, cortical spreading depolarisations (CSDs) were induced. A biphasic pattern of decreased, followed by increased CBV, propagating throughout the ipsilateral cortex, and a delayed decrease in deeper subcortical brain regions was observed. In a model of acute seizures, CBV oscillations were observed prior to seizure initiation. Individual seizures occurred on the rising phase of both infraslow brain signal and CBV oscillations. When seizures co-occurred with CSDs, CBV responses were larger in amplitude, with delayed CBV decreases in subcortical structures. Overall, our data demonstrate that gFETs are highly compatible with fUS and allow concurrent examination of wide bandwidth electrophysiology and CBV. This graphene-enabled technological advance has the potential to improve our understanding of how infraslow brain signals relate to CBV changes in control and pathological brain states.

Senescence-related genes and proteins in the development of Alzheimer's disease: evidence from transcriptomic and Mendelian randomization analysis.

Alzheimer's disease (AD) is a common neurodegenerative disease, which can lead to cognitive impairment and dementia. Since AD is tightly associated with aging and cellular senescence, objective of this study was to investigate the association between senescence-related genes and proteins (SRGs and SRPs) and the development of AD. The whole study was based on transcriptomic analysis of control and AD brain tissues and Mendelian randomization (MR) analysis. For transcriptomic analysis, GSE5281 dataset from GEO database contains the transcriptomic data of human brain tissues (n = 161) from control group and AD patients. The expression of SRGs in control and AD brain tissues were compared by Student's t test. For MR analysis, the instrumental single-nucleotide polymorphisms (SNPs) associated with 110 SRPs were filtered and selected from a large genome-wide association study (GWAS) for plasma proteome. The causality between plasma levels of SRPs and AD was explored using GWAS data of AD from Lambert et al. (17,008 cases and 37,154 controls) and further validated by using data from FinnGen consortium (6,489 patients and 170,489 controls). MR estimate was performed using the inverse-variance weighted (IVW) method and the heterogeneity and pleiotropy of results were tested. Transcriptomic analysis identified 36 up-regulated (including PLAUR) and 8 down-regulated SRGs in AD brain tissues. In addition, the MR results at both discovery and validation stages supported the causality between plasma levels of PLAUR (IVW-p = 3.04E-2, odds ratio [OR] = 1.15), CD55 (IVW-p = 1.56E-3, OR = 0.86), and SERPINE2 (IVW-p = 2.74E-2, OR = 0.91) and the risk of AD. Our findings identified that PLAUR, as an SRG, may take part in the development of AD and found that high plasma levels of PLAUR was associated with increased risk of AD, indicating that this gene was a risk factor for this disease and providing the rationale of existing drugs or new preventative and therapeutic strategies.

Predictions of neural control deficits in elders with subjective memory complaints and Alzheimer’s disease

Alzheimer’s disease (AD) is a common disease, affecting over 6 million elders in the U.S in 2024. However, AD remains untreatable due to the absence of an effective biomarker to assess the underlying deficits in cognitive control. Disruptions in the brain's control systems are key factors in the learning and memory impairments that define AD. In this study, we hypothesized that we could predict neural control deficits in elders with subjective memory complaints (SMC) and AD patients using Diffusion Tensor Imaging (DTI) data and brain controllability analysis. DTI is a non-invasive neuroimaging tool that detects how fluid travels along the white matter tracts inside the brain. To test our hypothesis, we used the DTI data of 12 elders with SMC, 12 AD patients, and 12 healthy subjects from the open-source dataset Alzheimer's Disease Neuroimaging Initiative. First, we constructed individual brain connectivity networks. Using graph theory and brain controllability analysis, we assessed node degree and controllability. We then averaged these measures across brain areas to calculate global metrics for each subject. Results illustrated that the node degree could not identify SMC and AD from healthy subjects, while the controllability measure could differentiate SMC and AD from healthy subjects and distinguish between SMC and AD. In conclusion, this study provides a promising biomarker for detecting neural control deficits in elders with SMC and AD patients for future clinical application.

Increased Collagen I/Collagen III Ratio Is Associated with Hemorrhage in Brain Arteriovenous Malformations in Human and Mouse.

Background: The increase in the collagen I (COL I)/COL III ratio enhances vessel wall stiffness and renders vessels less resistant to blood flow and pressure changes. Activated microglia enhance inflammation-induced fibrosis. Hypotheses: The COL I/COL III ratio in human and mouse brain arteriovenous malformations (bAVMs) is associated with bAVM hemorrhage, and the depletion of microglia decreases the COL I/COL III ratio and hemorrhage. Method: COL I, COL III, and hemorrhages were analyzed in 12 human bAVMs and 6 control brains, and mouse bAVMs induced in three mouse lines with activin receptor-like kinase 1 (n = 7) or endoglin (n = 7) deleted in the endothelial cells or brain focally (n = 5). The controls for the mouse study were no-gene-deleted litter mates. Mouse bAVMs were used to test the relationships between the Col I/Col III ratio and hemorrhage and whether the transient depletion of microglia reduces the Col I/Col III ratio and hemorrhage. Results: The COL I/COL III ratio was higher in the human and mouse bAVMs than in controls. The microhemorrhage in mouse bAVMs was positively correlated with the Col I/Col III ratio. Transient depletion of microglia reduced the Col I/Col III ratio and microhemorrhage. Conclusions: The COL I/COL III ratio in the bAVMs was associated with bAVM hemorrhage. The depletion of microglia reduced the bAVM Col I/Col III ratio and hemorrhage.

Association between seated trunk control and cortical sensorimotor white matter brain changes in patients with chronic low back pain.

Trunk control involves integration of sensorimotor information in the brain. Individuals with chronic low back pain (cLBP) have impaired trunk control and show differences in brain structure and function in sensorimotor areas compared with healthy controls (HC). However, the relationship between brain structure and trunk control in this group is not well understood. This cross-sectional study aimed to compare seated trunk control and sensorimotor white matter (WM) structure in people with cLBP and HC and explore relationships between WM properties and trunk control in each group. Thirty-two people with cLBP and 35 HC were tested sitting on an unstable chair to isolate trunk control; performance was measured using the 95% confidence ellipse area (CEA95) of center-of-pressure tracing. A WM network between cortical sensorimotor regions of interest was derived using probabilistic tractography. WM microstructure and anatomical connectivity between cortical sensorimotor regions were assessed. A mixed-model ANOVA showed that people with cLBP had worse trunk control than HC (F = 12.96; p < .001; ηp2 = .091). There were no differences in WM microstructure or anatomical connectivity between groups (p = 0.564 to 0.940). In the cLBP group, WM microstructure was moderately correlated (|r| = .456 to .565; p ≤ .009) with trunk control. Additionally, the cLBP group demonstrated stronger relationships between anatomical connectivity and trunk control (|r| = .377 to .618 p < .034) compared to the HC group. Unique to the cLBP group, WM connectivity between right somatosensory and left motor areas highlights the importance of interhemispheric information exchange for trunk control. Parietal areas associated with attention and spatial reference frames were also relevant to trunk control. These findings suggest that people with cLBP adopt a more cortically driven sensorimotor integration strategy for trunk control. Future research should replicate these findings and identify interventions to effectively modulate this strategy.

Sex-Specific Vulnerability to Externalizing Problems: Sensitivity to Early Stress and Nucleus Accumbens Activation Over Adolescence

BackgroundExposure and sensitivity to early-life stress (ELS) are related to increased risk for psychopathology in adolescence. While cross-sectional studies have reported blunted nucleus accumbens (NAcc) activation in the context of these associations, researchers have not yet assessed the effects of ELS on developmental trajectories of activation. We examined whether trajectories are affected by stress and the moderating role of biological sex in predicting vulnerability to symptoms of psychopathology. MethodsAdolescents (n = 173) completed 3 assessments at 2-year intervals across puberty (ages 9–18 years). At baseline, we assessed objective ELS and stress sensitivity using the Traumatic Events Screening Inventory for Children. At all time points, we assessed NAcc activation using the Monetary Incentive Delay task and externalizing, internalizing, and total problems using the Youth Self-Report. We examined correlations between NAcc trajectories (extracted using linear mixed-effects models) with ELS and stress sensitivity and conducted multivariate regression analysis to examine the interaction of NAcc trajectories and biological sex in predicting symptoms of psychopathology. ResultsSymptoms increased over adolescence. Stress sensitivity, but not objective ELS, was associated with decreasing trajectories of NAcc activation. Biological sex interacted with NAcc trajectories to predict psychopathology; boys, but not girls, with decreasing NAcc activation had more severe externalizing problems in adolescence. These findings were replicated in the putamen and caudate but not in the medial prefrontal cortex or control brain regions. ConclusionsNAcc activation may be a sex-specific marker of externalizing problems in adolescence. Efforts to reduce stress sensitivity may help to decrease symptoms of psychopathology in adolescent boys.

The Distant Molecular Effects on the Brain by Cancer Treatment.

Cancer survivors experience cancer-related cognitive impairment (CRCI) secondary to treatment. Chemotherapy and radiation therapy independently contribute to cognitive dysfunction; however, the underlying mechanisms leading to dysfunction remain unclear. We characterized brain gene expression changes in a mouse model of CRCI to identify the mechanistic underpinnings. Eleven-to-twelve-week-old SKH1 mice were treated with doxorubicin (DOX), hindlimb radiation (RT), concurrent hindlimb radiation and doxorubicin (DOX-RT), or no treatment (control). Sixteen days following treatment, gene expression was measured from murine brains using the NanoString nCounter® glial profiling panel. Gene expression was normalized and compared between groups. No two groups shared the same expression pattern, and only Gnb1 and Srpr were upregulated in multiple treatment groups. Brains from DOX-treated mice had upregulated Atf2, Atp5b, Gnb1, Rad23b, and Srpr and downregulated Sirt5 expression compared to control brains. Brains from RT-treated mice demonstrated increased Abcg2 and Fgf2 and decreased C1qa and C1qb expression compared to control brains. Brains from DOX-RT-treated mice had upregulated Adar, E2f3, Erlec1, Gnb1, Srpr, Vim, and Pdgfra expression and downregulated Rock2 and Inpp5f expression compared to control brains. The gene expression changes demonstrated here highlight roles for neuronal transmission and oxidative stress in the pathogenesis of doxorubicin-related CRCI and inflammation in RT-related CRCI.

Multitracer Approach to Understanding the Complexity of Reactive Astrogliosis in Alzheimer's Brains.

A monoamine oxidase B (MAO-B) selective positron emission tomography (PET) tracer [11C]-deuterium-l-deprenyl holds promise for imaging reactive astrogliosis in neurodegenerative diseases, such as Alzheimer's disease (AD). Two novel PET tracers ([11C]-BU99008 and [18F]-SMBT-1) have recently been developed to assess the complexity of reactive astrogliosis in the AD continuum. We have investigated the binding properties of SMBT-1, l-deprenyl, and BU99008 in AD and cognitively normal control (CN) brains. Competition binding assays with [3H]-l-deprenyl and [3H]-BU99008 versus unlabeled SMBT-1 in postmortem AD and CN temporal and frontal cortex brains demonstrated that SMBT-1 interacted with [3H]-deprenyl at a single binding site (nM range) and with [3H]-BU99008 at multiple binding sites (from nM to μM). Autoradiography studies on large frozen postmortem AD and CN hemisphere brain sections demonstrated that 1 μM SMBT-1 almost completely displaced the [3H]-l-deprenyl binding (>90%), while SMBT-1 only partly displaced the [3H]-BU99008 binding (50-60% displacement) in cortical regions. In conclusion, SMBT-1, l-deprenyl, and BU99008 interact at the same MAO-B binding site, while BU99008 shows an additional independent binding site in AD and CN brains. The high translational power of our studies in human AD and CN brains suggests that the multitracer approach with SMBT-1, l-deprenyl, and BU99008 could be useful for imaging reactive astrogliosis.

Linking Adverse Childhood Experiences and Other Risk Factors to Subjective Cognitive Decline in an Aging Population.

The Centers for Disease Control and Prevention's Healthy Brain Initiative (HBI) encourages an interdisciplinary approach to addressing the burden of subjective cognitive decline (SCD) among the aging US population as that population continues to increase. Our study is one of the first to evaluate associations between SCD and adverse childhood experiences (ACEs) and other modifiable risk factors to support implementation of the initiative. We used multivariate logistic regression to assess data from the 2020 Behavioral Risk Factor Surveillance System survey to evaluate associations between SCD and ACEs scores and sociodemographic, behavioral, and clinical risk factors. Models were weighted to account for the complex survey design. Approximately 8.1% of survey respondents reported experiencing SCD within the past 12 months. Adjusted regression analysis showed that conditions such as depression (AOR, 2.85; 95% CI, 2.29-3.55), arthritis (AOR, 1.30; 95% CI, 1.05-1.60), and diabetes (AOR, 1.33; 95% CI, 1.05-1.68) were significantly associated with SCD. SCD was also associated with experiencing more than 3 falls per year (AOR, 2.95; 95% CI, 2.13-4.09), sleeping more than 9 hours per night (AOR, 2.06; 95% CI, 1.37-3.09), and physical inactivity (AOR, 1.32; 95% CI, 1.03-1.68). Two or more ACEs also significantly increased the odds of SCD (AOR, 1.69; 95% CI, 1.36-2.10). Findings from our study can be used to inform policy, environment, and systems change efforts aimed at addressing modifiable risk factors to support healthy aging. The role of ACEs as determinants of brain health across the life course should also be considered in the design of clinical and community-based interventions.

Understanding the Role of CDH4 in Multiple System Atrophy Brain.

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease clinically characterized by parkinsonism, cerebellar ataxia, and autonomic dysfunction. A major pathological feature of MSA is the presence of α-synuclein aggregates in oligodendrocytes, the myelinating cells of the central nervous system. A genome-wide association study revealed that the CDH4 gene is associated with MSA. However, virtually nothing is known about the role of CDH4 in the context of MSA. Our aim was to compare the expression of CDH4 between MSA and control brains, and to investigate its relationship with α-synuclein in oligodendrocytes. RNA and protein were prepared from putamen, motor cortex white matter, cerebellum, and superior occipital cortex tissues collected from MSA (N = 11) and control (N = 13) brains. The expression of CDH4 was measured at mRNA and protein levels by qPCR and western blotting. Oligodendrocyte cells were cultured on plates and transfected with CDH4 cDNA and its impact on α-synuclein was analyzed. Firstly, we found that CDH4 in MSA brain was significantly elevated in the disease-affected motor cortex white matter in MSA (N = 11) compared to controls (N = 13) and unaltered in the disease-unaffected superior occipital cortex. Secondly, we determined that increases in CDH4 expression caused changes in the cellular levels of α-synuclein in oligodendrocytes. When put together, these results provide evidence that support the GWAS association of CDH4 with MSA.

Dysregulated miRNAs in a canine model of haemangiosarcoma metastatic to the brain.

Haemangiosarcoma is a highly metastatic and lethal cancer of blood vessel-forming cells that commonly spreads to the brain in both humans and dogs. Dysregulations in phosphatase and tensin (PTEN) homologue have been identified in various types of cancers, including haemangiosarcoma. MicroRNAs (miRNAs) are short noncoding single-stranded RNA molecules that play a crucial role in regulating the gene expression. Some miRNAs can function as oncogenes or tumour suppressors, influencing important processes in cancer, such as angiogenesis. This study aimed to investigate whether miRNAs targeting PTEN were disrupted in canine haemangiosarcoma and its corresponding brain metastases (BM). The expression levels of miRNA-10b, miRNA-19b, miRNA-21, miRNA-141 and miRNA-494 were assessed in samples of primary canine cardiac haemangiosarcomas and their matched BM. Furthermore, the miRNA profile of the tumours was compared to samples of adjacent non-cancerous tissue and healthy control tissues. In primary cardiac haemangiosarcoma, miRNA-10b showed a significant increase in expression, while miRNA-494 and miRNA-141 exhibited downregulation. Moreover, the overexpression of miRNA-10b was retained in metastatic brain lesions. Healthy tissues demonstrated significantly different expression patterns compared to cancerous tissues. In particular, the expression of miRNA-10b was nearly undetectable in both control brain tissue and perimetastatic cerebral tissue. These findings can provide a rationale for the development of miRNA-based therapeutic strategies, aimed at selectively treating haemangiosarcoma.

Biochemical characterization of chamomile essential oil: Antioxidant, antibacterial, anticancer and neuroprotective activity and potential treatment for Alzheimer's disease

Alzheimer’s disease (AD) causes dementia among older adults, increasing the global burden of dementia. Therefore, this study investigates the potential neuroprotective, antioxidant, and anticancer effects of chamomile essential oil (CCO) in Alzheimer’s disease. CCO’s main volatile compounds (VOCs) were α-bisabolol, camazulene, and bisabolol oxide A, representing 81 % of all VOCs. CCO scavenged 93 % of DPPH free radicals and inhibited the pathogenic bacteria, i.e., Staphylococcus aureus and Salmonella typhi, besides reducing 89 % of brain cancer cell lines (U87). Eighty albino rats were randomized into four groups: standard control, Alzheimer’s disease group caused by AlCl3, and treated groups. The results indicated that the mean value of tumor necrosis factor α (TNF-α), amyloid precursor protein (APP), amyloid beta (Aβ), caspase-3, & B-cell lymphoma 2 (Bcl-2) was significantly elevated due to the harmful effect of AlCl3; however, CCO downregulated these values, and this effect was attributed to the considerable volatile compounds and phenolic compounds content. Additionally, CCO rats showed a significant increment in noradrenergic (NE), dopaminergic (DO), and serotoninergic systems with relative increases of 50, 50, and 14 % compared to diseased rats. The brain histology of CCO-treated rats showed a significant reduction in neuronal degeneration and improved brain changes, and its histology was close to that of the control brain. The results indicated that CCO offers a new strategy that could be used as an antioxidant and neuroprotective agent for AD due to its considerable contents of antioxidants and anti-inflammatory compounds.

Single Cell RNASeq Analysis of AD and Control Post Mortem Brain Samples

Alzheimer’s disease (AD) is a devastative late life disease, molecularly characterized by biochemical lesions of amyloid β plaques and Tau tangles. the 2nd most frequent one worldwide with no early detection methods/cure. I have applied single cell sequencing and analysed post mortem brain samples (using a Chromium machine) from 2 AD and 2 control frontal cortex samples. All the samples had ethics approval, and the RNA was tested for quality. The samples were obtained from the Edenborough MRC brain bank. Very few genes have been linked to far to AD (mainly through GWAS studies [1]). Overall, I quantified about 24,000 nuclei. Using statistical, bioinformatics and computational analyses I have detected significant differential expression changes in astrocyte, neuronal and microglial marker genes. I also conducted network analyses. The percentage of reads passing filter was slightly low (68%). Overall output was a bit lower than optimal. There was still over 1.6Bn clusters generated though, which is within the specification for an S1 flow-cell, and base call quality (quality control) was excellent: 97% &gt;Q30. The read counts mapping to genome occupancy rate was also fairy low (63-81%). The number of barcodes is as follows: sample 1 (AD, Braak I-II) - 6,223 sample 2 (control) 6,262 sample 3 (AD Braak I-II) 5,332 sample 4 (AD, Braak I-II) 5,332 as well. The data is available for download under the GEO (accession number GSE175814). to assess global and cell-type specific gene expression impacts in Alzheimer’s versus control brain samples, we performed a holistic comparison of matching cell populations in AD and controls with the software cell Harmony. To identify possible gene regulatory network underlying transcriptional regulation in these distinct populations, we further explored prior evidenced transcription factor targets relationships from cell Harmony. Importantly, we observe both common and cell-type specific core transcription factors regulators, with both enriched downstream targets and regulated transcription factors. Upregulated networks in Astrocytes were associated with broad regulation by HIF1A, SOX2, NRF1, and RB1. the proportion of endothelial cells was higher in the Alzheimer’s disease samples than the neurological control samples. results reveal that the cell type-specific transcriptomic changes in Alzheimer’s disease are associated with 4 molecular pathways: angiogenesis in endothelial cells, immune response in endothelial cells and microglia, myelination in oligodendrocytes, and synaptic signalling in astrocytes and neurons. I also compared the results with microarray data from large cohort studies that examined samples from the prefrontal cortex (Alzheimer’s disease: n = 310; Neurological controls: n = 157) or temporal cortex (Alzheimer’s disease: n = 106; Neurological controls: n = 135). Among the DEGs identified in our snRNA-seq analysis, 1,113 and 764 genes were significantly differentially expressed in the microarray data from the prefrontal cortex and temporal cortex, respectively. subcluster analysis of microglia identified 13 subpopulations; VGF signalling was also found as changed. In the future, imaging of post mortem Alzheimer’s patients may verify brain cellular morphology/cell volume of vascular changes in the Alzheimer’s compared to control samples. My study findings [2] may open new venues to our understanding of the disease underlying molecular processes and cellular signaling. Regarding the glial cell changes, our main conclusion is that the glial cells may be reactive in the disease and not causal.

Dysregulation of Human Juvenile Huntington's Disease Brain Proteomes in Cortex and Putamen Involves Mitochondrial and Neuropeptide Systems.

Huntington's disease (HD) is a genetic neurodegenerative disease caused by trinucleotide repeat CAG expansions in the human HTT gene. Early onset juvenile HD (JHD) in children is the most severe form of the disease caused by high CAG repeat numbers of the HTT gene. To gain understanding of human HD mechanisms hypothesized to involve dysregulated proteomes of brain regions that regulate motor and cognitive functions, this study analyzed the proteomes of human JHD cortex and putamen brain regions compared to age-matched controls. JHD and age-matched control brain tissues were assessed for CAG repeat numbers of HTT by PCR. Human brain JHD brain cortex regions of BA4 and BA6 with the putamen region (n = 5) were analyzed by global proteomics, compared to age-matched controls (n = 7). Protein interaction pathways were assessed by gene ontology (GO), STRING-db, and KEGG bioinformatics. JHD brain tissues were heterozygous for one mutant HTT allele containing 60 to 120 CAG repeats, and one normal HTT allele with 10 to 19 CAG repeats. Proteomics data for JHD brain regions showed dysregulated mitochondrial energy pathways and changes in synaptic systems including peptide neurotransmitters. JHD compared to control proteomes of cortex and putamen displayed (a) proteins present only in JHD, (b) proteins absent in JHD, and (c) proteins that were downregulated or upregulated. Human JHD brain cortex and putamen regions display significant dysregulation of proteomes representing deficits in mitochondrial and synaptic neurotransmission functions. These findings advance understanding of JHD brain molecular mechanisms associated with HD disabilities.