bluuebunny/crossref_metadata_2025_split huggingface dataset:
Red Light Therapy Attenuates Prolonged LED light Exposure‐Associated Neuropathology and Mediates Circadian Clock Genes ‐ Per1 and Bmal1 Expression in Rats' Basal Ganglia
Authors: Obajuluwa Adejoke Olukayode , Babafemi Laoye John , Ndianefo Ogochukwu Jessica , Obajuluwa Tiwalola Madoc , Lech James Chrystopher , Okiki Pius Abimbola 
Published: January 2025

AbstractBackgroundProlonged exposure to LED‐light has been associated with impaired sleep quality and pathogenesis of various diseases, including Alzheimer’s Disease (AD). Red light therapy has been indicated as a non‐invasive way of reducing anxiety, mood and sleep optimization in neurodegenerative disorders but its endogenous mechanisms are insufficiently comprehended. Hence, we assessed the effects of scheduled red‐light exposure on clock genes‐Bmal1 and Per 1 expression, feacal boli frequency, and anxiety‐like responses in prolonged LED‐light exposed rats.MethodAnxiety‐like indices of male rats was assessed using standard neurobehavioural methods under various light settings exposures (n = 5) in groups: I) 12‐hour light/12‐hour dark (NC), II) 12‐hour light and 12‐hour dark + scheduled red light (PC), III) 24‐hour LED light, and IV) 24‐hour LED light + scheduled red light; every two weeks for a total of 60 days. Total RNA was isolated from the rats' basal ganglia and reverse transcription was performed with the ProtoScript cDNA synthesis kit. Quantification and purity of cDNA were assessed using 1μl in a DeNovix spectrometer. Sequenced primers were utilized for the analysis of mRNA expression levels of Bmal1, Per1, and the housekeeping gene (GAPDH) through real‐time PCR. The PCR products were resolved by electrophoresis on 1.5% agarose gels and visualized by SafeView staining.ResultFeacal bolus frequency (p<0.001), closed arm entries (p<0.05), and time spent in the dark area of the light‐dark box (p<0.001) were significantly reduced in the 24‐h LED light+scheduled red light and control groups rats compared to the 24‐h LED light. Real‐time gene expression analyses of Per1 showed a significant decline in the 24‐hour LED‐exposed rats, as indicated by decreased mRNA expression levels (p<0.05), when compared to other groups. Bmal1 gene expression remained unchanged in groups I and II while AGE revealed 100bp and 150 bp banding patterns for Bmal1 and Per1, respectively.ConclusionThe findings from this study revealed that red light therapy attenuates LED light‐exposure‐induced anxiogenic responses and Per1 gene expression impairment. Consequently, these findings have the potential to inform the development of non‐invasive treatment strategies targeting the improvement of sleep quality in the management of neurodegenerative disorders. However, safety assessments should be ensured for its validation.
Cognitive Disparities in the Wayuu Indigenous Population: Insights from Neuropsychological Assessment
Authors: Preciado Jose Hernandez , Torres Wanda , Vargas Alex Dominguez , Pianneta Yesenia , Medina Mauricio , Sinisterra Marybel , Vargas José 
Published: January 2025

AbstractBackgroundThe neuropsychological profile within indigenous communities is a complex interplay of cultural, social, and environmental factors that significantly influence cognitive functioning and distinct neuropsychological patterns. The aim of this study was to assess the neuropsychological profile in the Wayuu indigenous population.MethodsA cross‐sectional study. Wayuu indigenous individuals (n = 100) and non‐indigenous individuals (n = 100) from the northern coast of the Colombian Caribbean were included. The neuropsychological profile was assessed using the following tests: Hopkins Verbal Learning Test‐Revised (HVLT‐R), Clue Recall, Delayed Recall, Memory Complaint Scale (MCS), Trail Making Test Part A and B (TMT‐A/B), Symbol‐Digit test, Lawton & Brody, Yesavage, and Montreal Cognitive Assessment (MoCA). The Wilcoxon test was applied to compare median scores between Wayuu indigenous and non‐indigenous individuals. Additionally, the Spearman test was utilized to assess the correlation between the scores obtained for each test.ResultsThe Wayuu population exhibited significantly lower scores in neuropsychological tests related to memory, learning, autonomy, depression, and cognitive function in comparison to non‐indigenous individuals (p<0.01) (Figure 1). Significant positive correlations were observed between Clue Recall and HLVT‐R (Spearman r = 0.82, p<0.001), Clue Recall and Delayed Recall (Spearman r = 0.69, p<0.001), and between Lawton & Brody and MOCA (Spearman r = 0.42, p<0.001). In contrast, significant negative correlations were found between Yesavage and MOCA (Spearman r = ‐0.45, p < 0.001), and between Yesavage and Lawton/Brody (Spearman r = ‐0.45, p < 0.001).ConclusionsOur study emphasizes significant cognitive gaps within the Wayuu indigenous community. The neuropsychological landscape of this indigenous population reveals the impact of historical and contemporary factors on cognitive health, emphasizing the necessity of culturally tailored interventions to improve neurocognitive well‐being in these communities.
The effects of mild traumatic brain injury induced by a low‐intensity blast exposure on phosphoproteome networks and cognitive function influenced by mutant tau overexpression
Authors: Gu Zezong , Jackson Marcus , Chen Shanyan , Nguyen Thi Thao , Siedhoff Heather R. , Balderrama Ashley , Zuckerman Amitai , Li Runting , Greenlief C. Michael , Cole Gregory M , Frautschy Sally A. , Cui Jiankun 
Published: January 2025

AbstractBackgroundThis study was to elucidate the impact of blast‐induced neurotrauma (BINT) on phosphoproteome networks and cognition in a genetically heterogeneous population of mice (rTg4510) with the human tau P301L mutation linked to Alzheimer’s disease‐related dementia (ADRD) including frontotemporal dementia.MethodMild traumatic brain injury was induced in rTg4510 mice exposed to a single low‐density blast (LIB) at an upright position. After assessment of cognitive function by the automated‐Home Cage Monitoring (aHCM) system, frontal cortex tissue was collected at 40 days post‐injury. The label‐free tandem mass spectrometry using the data‐independent acquisition and parallel accumulation‐serial fragmentation techniques for quantitative proteomics and weighted peptide co‐expression‐network analysis (WpCNA) approaches were used to evaluate phosphoproteomes in association with synaptic function and learning ability.ResultIn this study, blast‐exposed rTg4510 mice demonstrated a lower learning index, using the CognitionWall test by aHCM, compared to all other groups including non‐carrier unexposed sham controls. Among total 17,637 phosphopeptides identified, 706 and 550 were significantly changed in rTg4510 and non‐carrier LIB‐exposed mice relative to unexposed sham controls, respectively. Using WpCNA, we found phosphopeptide networks tied to associative learning and mossy‐fiber pathways, which predicted learning outcomes. Phosphopeptide expression in these networks were inversely related to learning and linked to synaptic dysfunction, cognitive decline, and dementia. LIB selectively increased pSer262 Tau in rTg4510, a site implicated in initiating tauopathy.ConclusionThis study unveils the relationship between ADRD genetic susceptibility, BINT, and cognitive decline, thus offering potential pathways as therapeutic targets for precision medicine to alleviate the disease burden among those affected by BINT.
Biomarker discovery of disrupted SORL1‐retromer recycling
Authors: Small Scott A. 
Published: January 2025

AbstractBiofluidic biomarkers concord with postmortem molecular studies, suggesting that the endosomal recycling pathway regulated by SORL1’s interaction with the retromer protein VPS2b is commonly disrupted in late‐onset, ‘sporadic’, Alzheimer’s disease (AD). Here, a program for developing a neuroimaging‐based biomarker will be reviewed. The program is anchored by findings in support of the conclusion that, because of its distinct network properties, the trans‐entorhinal cortex is heavily dependent on the recycling pathway. Functional and structural MRI have documented that the trans‐entorhinal cortex is commonly affected in AD, and ex vivo studies have found that this AD‐targeted region is co‐deficient in SORL1 and VPS26b. Since SORL1 deficiency is considered causally pathogenic in AD, we have applied our dedicated small‐animal MRI to longitudinally image SORL1 haploinsufficient mice. Remarkably, results show that SORL1 haploinsufficient mice developed MRI‐detected focal atrophy in the trans‐entorhinal cortex at 12 months of age, and which corresponded to the observed spatiotemporal pattern of SORL1 deficiency. Next, we used viral vectors to overexpress VPS26b, at 3‐month‐old mice and aged them to 12 months. Replicating the primary finding, untreated 12‐month‐old SORL1 haploinsufficient mice showed selective trans‐entorhinal cortex atrophy and SORL1 deficiency. AAV9‐VPS26b treatment was found to prevent the development of MRI‐detected atrophy. Collectively, these studies support the conclusion that MRI‐detected trans‐entorhinal cortical atrophy might represent an imaging‐based biomarker of pathway dysfunction. We are currently developing an MRI template of the AD‐targeted trans‐entorhinal cortex and plan to apply to it to future large‐scale datasets of common and rare forms of AD.
Retromer enhancement rescues endosomal recycling defects induced by SORL1 deficiency
Authors: Mishra Swati , Williams Charles A , Young Jessica E. 
Published: January 2025

AbstractBackgroundThe SORL1 gene (SORLA) is strongly associated with risk of developing Alzheimer’s disease (AD). SORLA is a regulator of endosomal trafficking in neurons and interacts with retromer, a complex that is a “master conductor” of endosomal trafficking. Because of its size, SORLA is difficult to target therapeutically. In this study, we used small molecules that enhance retromer expression to rescue cellular phenotypes induced by SORLA deficiency or by SORLA missense variants in hiPSC‐derived cortical neurons and microglia.MethodsWe treated SORLA KO, SORLA ± and SORLA variant (SORLAVar) neurons and microglia with TPT‐260, a small molecule that enhances retromer expression and function. We tested the effects of TPT‐260 on endosome size, SORLA‐retromer cargo localization, Amyloid beta secretion, phospho‐tau expression in neurons and phagocytosis and cytokine release.ResultsWe observed that TPT‐260 significantly induced expression of retromer subunits in our cells. In neurons, TPT‐260 treatment rescued endosome swelling and abnormal SORL1‐cargo localization. In addition, we observe significant reductions in Amyloid‐beta secretion and intracellular phospho‐Tau. Interestingly, rescue of these phenotypes was dependent on whether at least one functional copy of SORLA was expressed and on which AD‐associated variant was present. Evaluation of phenotypes in microglia are currently in progress.ConclusionOur work shows that treatment with a small molecule that increases retromer expression in vitro and enhances retromer‐related trafficking can reduce important cellular and neuropathologic phenotypes in human AD neuronal models. Using TPT‐260, we broadly show that enhancement of retromer‐related trafficking can fully or partially rescue deficits induced by loss of SORL1. This study builds on previous work that has used these and other retromer‐targeting small molecules in animals and human cells, suggesting that studies such as this could represent an important preclinical step in identifying new therapeutic molecules for AD.
MAPT Families Fighting for a Future
Authors: Jacobs Linde L 
Published: January 2025

AbstractBackgroundFrontotemporal dementia is the most common form of dementia impacting those under the age of 60. It is estimated that 30% of affected persons have a genetic predisposition to this disease, with mutations in the genes encoding progranulin (GRN), chromosome 9 open reading frame 72(C9orf72), and microtubule associated protein tau (MAPT). Mutations in MAPT were discovered in 1998, yet to date, there have been no therapies or multisite clinical trials available to families.MethodTo coordinate the sharing of information and advocacy efforts, a group of family kindreds impacted by MAPT created a non‐profit organization and database for families in November 2023.ResultSpanning over 5 generations across the United States, Canada, and Europe, we have identified 17 family kindreds with 70 members living or deceased with symptomatic disease, 22 presymptomatic positive carriers, 34 tested negative/non‐carriers, and 116 at risk or untested family members.ConclusionWe are aware of the burden of this disease on patients and families and the lack of resources to efficiently diagnose and treat FTD. We are working collaboratively with other genetic FTD organizations and institutions to further reach MAPT families in an international effort to provide support for MAPT families and gene carriers, identify areas for advocacy, promote research, and to contribute to future therapeutics. Fueled by the past trauma of watching my loved ones succumb to FTD, terrified of how FTD will dictate my future, and fighting for those whose minds are currently failing them.
Sodium glucose transporter 2 inhibitor alleviates cognitive impairment in rats with ischemic heart failure
Authors: Apaijai Nattayaporn , Attachaipanich Tanawat , Maneechote Chayadom , Arunsak Busarin , Kongkaew Apisek , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: January 2025

AbstractBackgroundSodium glucose transporter 2 inhibitor (SGLT2i) is the latest guideline‐directed medical therapy for patients with heart failure, as it has demonstrated favorable cardiovascular outcomes in heart failure (HF) patients with or without diabetes. Furthermore, SGLT2i has effectively improved cognitive function in older adults with diabetes and HF. However, the effects of SGLT2i on cognitive function and brain mitochondrial function in rats with ischemic HF have never been investigated.MethodMale rats underwent left anterior descending coronary artery ligation to induce myocardial ischemia or sham operation. Heart failure (HF) was confirmed after one week of surgery by a reduction of left ventricular ejection fraction less than 50%. Subsequently, HF rats were divided into three groups to receive: 1) Vehicle, 2) SGLT2i (dapagliflozin; 1 mg/kg), and 3) Enalapril (10 mg/kg) for 8 weeks. Then, cognitive function and brain mitochondrial function were then determined.ResultThe ischemic HF rats exhibited a reduced LVEF compared to the sham group, and treatment with dapagliflozin and enalapril effectively improved LVEF compared to the vehicle group. Cognitive impairment was observed in the ischemic HF rats, and this was associated with brain mitochondrial dysfunction, as indicated by increased mitochondrial oxidative stress, mitochondrial membrane depolarization, and mitochondrial swelling. Treatment with dapagliflozin showed a similar degree of improved cognitive function as enalapril. We found that although both drugs did not reduce brain mitochondrial oxidative stress, they effectively reduced brain mitochondrial membrane depolarization and mitochondrial swelling in ischemic HF rats (p<0.05; Figure 1).ConclusionSGLT2i and enalapril effectively improved cognitive function by reducing brain mitochondrial dysfunction in ischemic HF rats.
Microglial priming induced by high‐fat diet consumption causes complement C1q‐mediated synaptic elimination leading to cognitive decline and depressive‐like behavior
Authors: Chunchai Titikorn , Chinchapo Thirathada , Pintana Hiranya , Pantiya Patcharapong , Arunsak Busarin , Donchada Suriphan , Apaijai Nattayaporn , Pratchayasakul Wasana , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: January 2025

AbstractBackgroundMicroglia play an important role in immune memory. Lipopolysaccharide (LPS) triggers immune memory and primes microglia, resulting in brain pathologies and brain dysfunction following a second stimulus (1, 2). An increase in the C1q/ PSD95 expressions within microglia and excessively synaptic pruning were observed in mouse model of Alzheimer’s disease (3). However, the effects of microglial priming induced by high‐fat diet (HFD) on microglial function, synaptic plasticity, cognition, and depressive‐like behavior after the secondary LPS stimulation have not been investigated.MethodTwenty‐four male Wistar rats were randomly assigned to be three primed conditions to receive either normal saline (NSS: intraperitoneal injection (i.p., as single dose)), LPS (0.5 mg/kg, i.p. as a single dose), or 4 weeks of 60% HFD consumption. Then at week 8, rats in each condition were divided into 2 groups. Each group was received the single dose of second stimulus of either NSS (i.p.) or LPS (0.5 mg/kg, i.p.). After 12‐16 hrs from second stimulus, the cognitive function and depressive‐like behavior were determined in all rats. Then animals were euthanized, and brains were removed for further analysis.ResultAll rats receiving LPS injection as the second stimulation with or without primed condition, equally increased microglial numbers, when compared to rats without any LPS stimulation or control rats (p<0.05, Figure 1). Interestingly, rats receiving second LPS injection increased C1q/PSD95 colocalized with microglia, decreased dendritic spine density, and increased freezing duration, when compared to the control rats (p<0.05, Figure 1). LPS‐stimulated rats with both LPS and HFD‐primed conditions showed the highest levels of these parameters (p<0.05, Figure 1). In addition, All LPS‐stimulated rats with or without primed conditions exhibited cognitive decline, when compared to the control rats (p<0.05, Figure 1).ConclusionOur findings suggest that only 4‐week HFD consumption effectively primed microglia to a similar extent as primed with a single dose of LPS injection, leading to excessive synaptic engulfment, as well as cognitive decline and depressive‐like behavior in the second LPS stimulation after 4‐week of HFD withdrawal period.
A prospective study of a rapid adaptive version of the Boston Naming Test for Alzheimer’s disease
Authors: Cho Julia H. , Muthupalaniappan Siva , Giauque Thomas A. , Smith Maurice , Press Daniel Z. 
Published: January 2025

AbstractBackgroundCognitive tests of naming ability have been shown to have diagnostic and prognostic utility in both mild cognitive impairment (MCI) and Alzheimer’s disease (AD; Taler & Phillips, 2008). The Boston Naming Test (BNT) is the most common naming test, which consists of 60 black‐and‐white drawings and takes 20‐30 minutes to administer. Retrospective analysis has shown that administering the BNT in an adaptive fashion could result in a comparable measure of the patient’s naming ability in only 8 items instead of 60. A prospective administration of this adaptive naming test (ANT) was necessary to assess its utility in clinical practice.MethodUsing item response theory (IRT) and published information about each BNT item’s difficulty and discriminability (Pedraza et al., 2011), we created an algorithm to administer the traditional BNT in an adaptive format. Patients were recruited from the Cognitive Neurology clinic at Beth Israel Deaconess Medical Center. Participants completed both a 30‐item traditional BNT (either odd or even‐numbered items) and a 10‐item ANT (selected from the remaining set of 30 items). Randomization was used to decide which test would be first, and which would use the odd or even‐numbered items. Z‐scores were calculated for BNT scores using normative data from Katsumata et al. (2015). ANT scores were calculated according to IRT principles (Pedraza et al., 2011). Total administration time from the two tests were compared using paired t‐tests, and descriptive statistics results are presented as mean±SD.ResultWe have begun testing patients with the traditional and adaptive forms of the BNT (n = 7). 28% of patients have MCI and 57% have mild‐to‐moderate AD. Average administration times were 611±222 seconds for the BNT and 59±13 seconds for the ANT (difference = 552 seconds, p = 0.0013). After removing one outlier, the standardized BNT scores and ANT scores exhibit a linear relationship with an r‐squared value of 0.977.ConclusionThis prospective administration of the ANT confirms prior research that an adaptive BNT performs significantly faster while still giving a reliable measure of one’s naming ability. We expect ongoing data collection to further strengthen the robustness of our findings.
pTau‐associated gene expression signatures in the middle temporal gyrus
Authors: Rachleff Victoria M , Mahoney Joseph T , Travaglini Kyle J , Gabitto Mariano I , Hodge Rebecca D , Keene C Dirk , Lein Ed S 
Published: January 2025

AbstractBackgroundApplying single‐cell RNA sequencing (scRNA‐seq) to the study of neurodegenerative disease has propelled the field towards a more refined cellular understanding of Alzheimer’s disease (AD); however, directly linking protein pathology to transcriptomic changes has not been possible at scale. Recently, a high‐throughput method was developed to generate high‐quality scRNA‐seq data while retaining cytoplasmic proteins. Tau is a cytoplasmic protein and when hyperphosphorylated is integrally involved in AD progression. The relationship between pTau accumulation and the molecular changes underlying cell type specific selective vulnerability remains poorly understood and has not been assessed in the Middle Temporal Gyrus (MTG), a critical transition zone in AD neuropathologic progression.MethodHuman brain tissue was collected at rapid autopsy (postmortem interval (PMI) <12hrs). One hemisphere was embedded in alginate for fresh coronal slicing (4mm). Slabs were frozen in a dry ice isopentane slurry. Sampled MTG was processed by mechanical dissociation using a Potter‐Elvehjem tissue grinder without enzymes or detergents, followed by iodixanol gradient centrifugation, and immunolabeling (AT8/pTau and MAP2/neurons) for FACS. For each donor, MAP2+/pTau+ and MAP2+/pTau‐ fractions were collected and sequenced using the 10x Genomics Chromium Single Cell Assay. Analysis was performed using standard pipelines in R (Seurat) and Python.ResultsNine donors from Seattle Alzheimer’s Disease Brain Cell Atlas (SEA‐AD) were selected for advanced pTau pathologic distribution without end stage neurodegeneration by including Braak Stages IV‐VI (Table 1). After QC and filtering, 125,505 cells were confidently mapped to the SEA‐AD taxonomy with approximately half being pTau+ (Figure 1). While the pTau+ population primarily consisted of supragranular excitatory neurons (L2/3_IT), several less abundant supertypes also had large fractions of pTau+ cells (Figure 2). Differential expression analysis within L2/3_IT identified several upregulated AD‐related genes such as NEFM, NPTXR, and NAP1L5 in the pTau+ population.ConclusionDisentangling the relationship between cellular vulnerability and pathology is critical to understand early AD pathogenesis. By adopting a standardized cell taxonomy and integrating datasets, we refined the definition of vulnerable cells to distinguish highly resolved pTau‐prone cell types and identified a pTau‐specific gene expression signature in the MTG.