bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lexical access failure in Alzheimer’s Disease through the lens of semantic knowledge
Authors: Banerjee Anamika , Khan Azizuddin 
Published: January 2025

AbstractBackgroundLexical access refers to the generation or retrieval of conceptual representation. Representation of concepts or semantic knowledge involves the organization of concepts in an associative manner building up the mental lexicon. Several studies have pointed out an early presence of lexical access failure in Alzheimer’s Disease(AD). While lexical access deficit is rampant among patients with AD, the underlying processes involved in retrieval failure remain debatable. Some findings suggest that the difficulty in lexical access can be due to a deterioration in the conceptual representation. Therefore, to understand the nature of the difficulty underlying lexical access failure among people with AD, the current study aims to understand the involvement of semantic knowledge in lexical access.MethodIn this study, three groups of participants will be recruited, Healthy Controls (HC), Mild Cognitive Impairment (MCI) and Dementia with AD. According to apriori sample size calculation, a total sample size of 54 would be required for the present study, with 18 participants per group. In the current study, the semantic priming task is used to understand the ongoing debate about the involvement of semantic knowledge in Lexical access. The experiment consists of 4 tasks to probe their semantic knowledge and visual perception. Each trial consists of a prime‐ image or word, presented for some duration followed by a related or unrelated target. The participant needs to report whether the target was related to the prime or not.ResultThe lexical retrieval is expected to be differentiated along the different phases of the disease as a function of semantic priming. It is expected that the lexical retrieval in the HC group would be least impacted across the three conditions and AD with Dementia to be the most impacted. The performance on each condition could be differentiated across each disease severity group, along with a difference in the prime type, that is, primes related to the target would show better performance than unrelated primes across all the conditions in each of the groups.ConclusionThe findings from this study would contribute towards understanding processes underlying lexical access failure among people with Alzheimer’s Disease.
Altered T and B lymphocyte subtype abundance in the blood of APP/PS1 mice at 6, 9 and 12 months old
Authors: Sun Jiaqi , Low Yi Ling Clare , Huang Xin , Kagawa Yoshiteru , Masters Colin L. , Jin Liang , Pan Yijun 
Published: January 2025

AbstractBackgroundMounting evidence support the involvement of adaptive immune system in the pathogenesis of Alzheimer’s disease (AD). The current study investigated the age‐dependent changes in the abundance of B and T cell subtypes in APP/PS1 mice, a commonly used model for AD.MethodPeripheral blood was collected through cardiac puncture from 6‐, 9‐, 12‐month‐old APP/PS1 transgenic (TG) mice (APPsw+ and PSEN1dE9+, n = 8‐12) and their wildtype (WT) littermates (C57BL/6J, n = 12‐15). Flow cytometry (BD FACSCalibur™) was employed to quantify B and T lymphocytes and their subtypes. Surface markers such as CD19, Gl7, CD93, CD3, CD4, CD8 and CD25 were used for identifying early and activated B cells, as well as helper T cells, cytotoxic T cells and regulatory T cells, respectively.ResultA 3‐fold increase in the abundance of early B cells were observed in 6‐month‐old TG mice compared to WT, while their abundance decreased (42.4% P = 0.0106, and 46.2% P = 0.0431) in 9‐ and 12‐month‐old TG mice compared to WT. The abundance of activated B cells was significantly decreased in 6‐, 9‐, and 12‐month‐old TG mice compared to WT (54.3% P = 0.0499, 36.7% P = 0.0071, 45.6% P = 0.0082). A significant reduction in helper T cells (10.6%, P = 0.0056) was observed only in 6‐month‐old TG mice compared to WT. The abundance of cytotoxic T cells was found increase in 9‐ and 12‐month‐old TG mice compared to WT (1.25‐fold P = 0.0001, 1.20‐fold P = 0.0252, respectively). A significant decrease in regulatory T cells (34.5% P = 0.048) was noted in TG mice compared to WT at 12‐month‐old but not at earlier age.ConclusionThe study on APP/PS1 mice revealed an age‐dependent alteration in the abundance of B and T cell subtypes, supporting the involvement of adaptive immune system in AD. Future studies could address how these changes are related to AD pathological changes and confirm these changes in human blood samples.
Hyperpolarization‐activated cyclic nucleotide‐gated channel inhibitor, Ivabradine, attenuates brain mitochondrial oxidative stress without reducing cognitive impairment in Dox‐induced chemobrain
Authors: Pintana Hiranya , Apaijai Nattayaporn , Sripusanapan Adivitch , Piriyakunthorn Chotrawee , Chunchai Titikorn , Jinarat Damrongsak , Arunsak Busarin , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: January 2025

AbstractBackgroundDoxorubicin (Dox), a chemotherapeutic agent, is known to cause chemobrain leading to cognitive decline and brain mitochondrial dysfunction. Ivabradine (Iva), hyperpolarization‐activated cyclic nucleotide‐gated channel blocker used for angina and arrhythmia, has been shown to be an anticonvulsant, antioxidant, and neuroprotective agent. However, the effects of Iva on cognitive function, and brain mitochondrial function in Dox‐induced chemobrain are still not determined. This study aimed to investigate whether Iva attenuates Dox‐induced brain toxicity in male rats by affecting cognitive dysfunction, synaptic dysplasticity, and brain mitochondrial dysfunction.MethodTwenty male Wistar rats were divided into 4 groups: vehicle‐treated control, Iva‐treated control, vehicle‐treated Dox, and Iva‐treated Dox. The control rats were received normal saline, while the Dox‐treated rats were received Dox at a dose of 3 mg/kg/day intraperitoneally on days 0, 4, 8, 15, 22, and 29. Iva (10 mg/kg) was administered by oral gavage from day 0 to day 29. On day 30, novel object location (NOL) test was performed to assess cognitive function. Hippocampal‐synaptic plasticity and brain mitochondrial function were measured after euthanasia.ResultDox‐treated rats showed a decreased % preference index of a new location in the NOL test, decreased % of field excitatory postsynaptic potential (fEPSP), and impaired brain mitochondrial function as indicated by increased mitochondrial ROS, impaired brain mitochondrial membrane potential change, and caused mitochondrial swelling (Figure 1A‐G). Iva‐treated control rats showed no effects on the NOL, % fEPSP, and brain mitochondrial function compared to vehicle‐treated control rats. Iva‐treated Dox rats exhibited a decrease in brain mitochondrial reactive oxygen species (ROS), but showed no significant difference in NOL, % fEPSP, brain mitochondrial membrane potential change, and mitochondrial swelling compared to vehicle‐treated Dox rats (Figure 1A‐G).ConclusionDox‐induced chemobrain manifested in cognitive impairment, synaptic dysplasticity, and brain mitochondrial dysfunction. Iva treatment showed a reduction in brain mitochondrial ROS, with no improvement in mitochondrial membrane potential changes and swelling in Dox‐induced chemobrain. Iva did not improve cognitive function and hippocampal‐synaptic plasticity in Dox‐treated rats. These findings suggest the antioxidant properties of Ivabradine in chemobrain, but this dose of Iva was not enough to protect brain injury in Dox‐induced chemobrain.
Regularity of blood transfusion influences the severity of systemic iron burden, cognitive decline, and gut dysbiosis in thalassemia patients
Authors: Suparan Kanokphong , Trirattanapa Kornkanok , Sriwichaiin Sirawit , Kerdphoo Sasiwan , Tantiworawit Adisak , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: January 2025

AbstractBackgroundThalassemia is a hereditary disease with impaired red blood cell production, resulting in cumulative systemic iron burden. The life‐long therapeutic blood transfusion with or without iron chelators in those patients leads to the development of early‐onset neurocognitive decline. However, the effects of regularity of blood transfusion on the severity of iron burden, cognitive decline, and gut dysbiosis in thalassemia patients are still unclear.MethodSixty participants, including 20 transfusion‐dependent (TDT) patients, 20 non‐transfusion‐dependent (NTDT) patients, and 20 healthy controls, underwent evaluation for neurocognitive function using the Montreal Cognitive Assessment (MoCA). The current systemic iron burden was determined by the levels of serum ferritin. Amplicon‐based sequencing of the bacterial 16s rRNA V3‐V4 regions of stool DNA was employed to delineate profiles of gut microbiota.ResultThe TDT patients showed greater severity of systemic iron burden, cognitive decline and gut dysbiosis than the NTDT patients. The TDT group was particularly afflicted with systemic iron burden as indicated by the highest levels of serum ferritin (Fig. 1A). Compared to the controls, the TDT and NTDT groups had significantly lower MoCA scores (Fig. 1B). In addition, there was a negative correlation between MoCA scores and the levels of serum ferritin (Fig. 1C). The thalassemia patients also exhibited gut dysbiosis, with microbial compositions among the three groups being distinct from each other (Fig. 1D and 1E). Interestingly, an increase in abundance of Paraclostridium was associated with cognitive decline.ConclusionThese findings suggest that the severity of systemic iron burden, based on the regularity of blood transfusion, impacts on the magnitude of cognitive decline and gut dysbiosis in thalassemia patients. It is possible that systemic iron potentially serves as a dose‐dependent factor in the pathogenesis of neurodegeneration through gut dysbiosis. Therefore, therapeutic approaches via well‐control of systemic iron levels and balanced gut microbiota could prevent early‐onset cognitive decline in thalassemia patients.
Association of long‐term blood pressure variability with plasma neurofilament light underlies the comorbidity of Alzheimer's Disease and cerebral small vessel disease
Authors: Li Qin , Li Xiaofeng 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) frequently coexists with cerebral small vessel disease (CSVD) is common in the aging population, yet the underlying mechanisms are not yet fully understood. Both long‐term blood pressure variability (BPV) and plasma neurofilament light (PNFL) were identified as potential biomarkers for AD and CSVD. This study aims to understand the mechanisms of comorbidity between AD and CSVD by investigating the associations among BPV, PNFL, and comorbidity. The severity of CSVD was visualized as white matter hyperintensities (WMH).MethodData was collected from the Alzheimer’s Disease Neuroimaging Initiative database. Participants with cognitively normal and mild cognitive impairment were included in the data analyses as clinical dementia rating (CDR) = 0 and 0.5. Aβ status was determined by cerebrospinal fluid Aβ levels and the WMH burden was defined by adjusting the WMH volume for intracranial volume. The differences in BPV and PNFL levels among participants with different Aβ status and varying WMH burdens were compared. Causal mediation analyses were conducted to explore whether the relationships of BPV with brain structural changes and cognition were mediated by PNFL.ResultAβ positive participants with high WMH burden had higher BPV and PNFL compared to Aβ negative individuals with low WMH burden. Systolic BPV (estimate [est] = 0.022, p = 0.004) was associated with WMH volume, and diastolic BPV (est = ‐0.053, p = 0.002) was associated with hippocampal volume. Both systolic BPV and diastolic BPV were associated with memory and executive function. Moreover, systolic (est = 0.013, p<0.001) and diastolic BPV (est = 0.012, p < 0.001) were associated with PNFL independent with average blood pressure. Mediation analyses revealed that PNFL mediated the association between systolic BPV and both WMH volume and executive function. PNFL also mediated the relationship between diastolic BPV and both hippocampal volume and memory function.ConclusionElevated BPV was linked with axonal damage, hippocampal atrophy, WMH progression, and cognitive decline. This finding suggests that the same risk factor may result in pathological changes in different brain regions and cognitive decline, which in turn may be associated with the comorbidity of AD and CSVD.
Causal network analysis on multi‐omics data from Alzheimer’s brain reveals strong connection between mitochondria functions and AD outcomes
Authors: Sun Li , Sanjay Apoorva Bharthur , Isacson Ole , Shin So‐Youn , Latourelle Jeanne 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease and the most prevalent type of senile dementia affecting more than 6 million Americans in 2023. Most of these AD cases are sporadic or late‐onset AD with unclear etiology. Recent clinical trials on antibody drug clearing Ab plagues in brain show modest benefits of slowing down cognitive decline. This indicates that a deeper and more comprehensive understanding of AD mechanism is needed for better therapeutic developments.MethodUsing Aitia’s proprietary REFSTM platform, Bayesian network models were built on clinical, demographic, and multi‐omic data from 287 postmortem brain samples of ROSMAP project. In silico perturbations were performed to assess causal effects among the variables. Hierarchical clustering was conducted to identify RNA‐ and protein‐ modules and to summarize a module‐level causal network, where a module‐level causal effect was computed as summated causal effects normalized to module sizes. For each module, gene ontology (GO) terms were annotated using Metascape.ResultA total of 119 RNA‐ and 33 protein‐ modules were identified, of which 22 RNA‐ and 8 protein‐ modules were enriched with top genes driving AD outcomes identified through in silico perturbations. These modules were significantly over‐presented with various GO terms. Notably, three out of eight protein‐ modules are strongly related to mitochondria functions. Moreover, three pairs of RNA‐ and protein‐ modules identified for their similar enrichment patterns are related to synaptic signaling & neuron development, mitochondria translation, and complex I assembly.The module‐level causal network highlighted that the paths from AD risk factors (e.g. age, sex, APOE4) to AD outcomes (e.g. MMSE, Braak, Cerad) were strongly connected through three protein modules annotated for mitochondria function and three RNA modules annotated for nervous system development, while the paths to the cognitive outcome only (e.g. MMSE) included two immune response related and one cytoskeleton related modules as well.ConclusionClustering analysis based on in silico causal relationships of clinical and multi‐omic data revealed a strong connection of genes involved in mitochondria functions with cognition and AD pathology, reminiscing “mitochondria cascade hypothesis” of AD first proposed two decades ago.
Amyloid, iron and cerebrovasculopathy in a new mouse model combining hemochromatosis mutations and Alzheimer’s amyloidosis and the etiological and diagnostic implications for dementia subtypes
Authors: Milward Adrienne (Lz) , Aryal Ritambhara , Acquah Elvis , Johnstone Daniel 
Published: January 2025

AbstractBackgroundUK Biobank data show mutations related to the iron disorder hemochromatosis can approximately double the risk of dementia, in particular clinically diagnosed vascular dementia. Insights into the etiology of this dementia may be provided by cerebrovasculopathy in our new “Aβ+Irondys” mouse model, which combines hemochromatosis‐related mutations and amyloidosis, with increases in soluble Aβ species and plaques. This was created by crossing an established APP/PS1 model of β‐amyloidosis with our reported Hfe‐/‐xTfr2mut model of hemochromatosis‐related mutations exhibiting brain iron dyshomeostasis (Heidari Mol. Psych. 2016).MethodDeposition of amyloid and other Aβ species was visualized by Congo red, thioflavins and Aβ immunolabeling. Iron was visualized by diaminobenzidine (DAB)‐enhanced Perls’ or transcardially perfused DAB+Turnbull’s staining.ResultCompared to regular APP/PS1 mice, Aβ+Irondys mice have extensive cerebrovasculopathy, sometimes severe, at 6 months and older. This is typically accompanied by iron deposition in vessel walls, sometimes co‐localizing with amyloid (Congo Red birefringence). Cerebrovasculopathy includes enlarged perivascular spaces, tortuosity, wall thickening, lumenal stenosis, microaneurysm, anastomosis and other changes in vessel profiles and diameter, wall rupture and microhemorrhage. Intense parenchymal staining for iron adjoining cortical vessels may arise from ruptured vessels.ConclusionCo‐deposition of iron and Aβ within blood vessels is exacerbated by hemochromatosis‐related mutations and can cause severe cerebrovasculopathy and amyloid angiopathy. This could lead to neuronal hypoperfusion and dysfunction throughout the brain in early disease stages and ultimately to neurodegeneraion. This has potential implications for understanding the etiology of dementia related to hemochromatosis mutations and for the clinical diagnosis of dementia subtypes.
Studying the Role of Brain Enriched E3 Ubiquitin Ligase TRIM9 in Alzheimer’s Disease
Authors: Frasineanu Anca Gabriela , Gupton Stephanie L. , Gupton Stephanie 
Published: January 2025

AbstractBackgroundIn the last decade, we have demonstrated that the brain‐enriched E3 ubiquitin ligase TRIM9 regulates cytoskeletal dynamics, membrane remodeling, and netrin‐dependent signaling pathways in all stages of neuron development, including the maturation of dendritic spines and electrophysiological activity. Moreover, TRIM9 protein levels increase in the adult brain and are maintained throughout adulthood. In the adult mouse TRIM9 is enriched within the postsynaptic density (PSD), a proteinaceous rich region in the post synapse, containing neurotransmitter receptors, scaffolding proteins, and cytoskeletal elements. The PSD proteome is significantly altered in adolescent mice when TRIM9 is lost, which is linked to changes in synaptic function. Our published proximity labelling experiments to characterize the TRIM9 interactome identified several proteins implicated in synaptic function and Alzheimer’s disease (AD), including Tau.MethodCross‐referencing this list with a published dataset of differentially expressed proteins (123) in the hippocampal PSD of 9 month old Tau P301S mice (PS19 AD model) versus non‐transgenic control, revealed a significant percent (56 proteins, 45.5%) overlap. Here we investigate the role of TRIM9 in tau‐mediated neurodegeneration, since TRIM9 is poised to interact with many AD‐associated proteins, and published work indicates that TRIM9 expression in HEK293T cells increased aggregated tau species. Four genotypes were compared (Trim9+/+, Trim9‐/‐, Trim9+/+:PS19, and Trim9‐/‐:PS19), and 3‐4 animals per genotype and sex were used in each experiment. We analyzed changes in dendritic spine density of six month old murine cortical and hippocampal neurons using the Golgi‐Cox staining method. We also investigated changes in pathological tau accumulation, microglia and astrocytes activation using multiplexed immunofluorescence imaging and biochemical analysis.ResultIba1 positive microglia were significantly enriched in the hippocampus and entorhinal cortex of six month old Trim9‐/‐:PS19 mice compared to the other genotypes. Pathological tau accumulation had an increase trend in the hippocampus of Trim9‐/‐:PS19 mice compared to PS19 only mice.ConclusionDeletion of Trim9 exacerbated the progression of Alzheimer’s disease in six month old PS19 mice. Future experiments will use primary cultured hippocampal neurons to further determine the mechanism through which Trim9 deletion increases pathological tau accumulation.
Mild inhibition of mitochondrial complex I improves glucose metabolism and energy homeostasis in a cellular model of Alzheimer’s disease
Authors: Nguyen Thi Kim Oanh , Trushin Sergey A , Ostroot Mark , Trushina Eugenia 
Published: January 2025

AbstractBackgroundWhile disease‐modifying treatments that reduce Aβ have been recently approved by the FDA, the identification of novel therapeutic targets and strategies that target underlying mechanisms to delay the AD development are still needed. Abnormal brain energy homeostasis and mitochondria dysfunction are observed early in AD. Therefore, the development of treatments to restore these defects could be beneficial. We identified small molecule (code name CP2) as a mild and specific mitochondrial complex I (MCI) inhibitor. Application of CP2 improved brain energy homeostasis, restored synaptic and cognitive function in APP/PS1 and 3xTgAD mice. However, mechanistic relationship between MCI inhibition, glucose uptake/utilization and mitochondrial function remains to be determined.MethodCellular energy metabolism was assessed in the neuroblastoma SH‐SY5Y cells that express either mutant human APP protein (APPswe) or empty vector (control) treated with vehicle or CP2. A Seahorse Extracellular Flux Analyzer was used to measure glycolysis, oxygen consumption rate, and fatty acids β‐oxidation (FAO). Flow cytometry allowed determining the translocation of glucose transporters to the cell surface. Changes in protein expression in response to treatment were assessed using Western Blot analysis. Changes in mitochondrial morphology were monitored using electron microscopy. The non‐radioactive Glucose Uptake‐Glo™ assay was utilized for measuring glucose uptake in cells. Metabolic flux analysis was done using 13C D‐Glucose stable isotope‐labeling.ResultsAPPswe cells have a significant decrease in glycolysis and spare respiratory capacity, an indicator of the mitochondrial ability to produce energy under stress conditions. These observations were consistent with decreased glucose uptake, which was compensated by an increased FAO to provide axillary fuel for ATP production. Mechanistically, at the concentrations relevant to in vivo treatment in APP/PS1 and 3xTgAD mice, acute CP2 treatment increased glucose uptake and utilization through the translocation of glucose transporters to the plasma membrane while prolong CP2 treatment activated metabolic sensors and mitochondrial morphofunctional pathways (e.g., fission, fusion, biogenesis, and turnover) consistent with the improved cellular bioenergetics in the AMPK‐dependent pathway.ConclusionData suggested that mild MCI inhibition activates multiple neuroprotective mechanisms improving cellular energy homeostasis and mitochondrial function in vivo and in vitro, representing promising strategy that target early AD mechanisms.