bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of human tau in adult Drosophila melanogaster causes a sexually dimorphic sleep phenotype
Authors: Mouofo Edmond N , Catterson James , Verstreken Patrik , Spires‐Jones Tara L. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the primary cause of dementia, characterized by early amyloid beta accumulation, subsequent tau pathology, and eventually synaptic and neuronal loss. Sleep disturbances, a clinical phenotype in AD, are linked to amyloid beta and impaired protein clearance. However, the influence of tau pathology on sleep is less explored. Utilizing Drosophila melanogaster, we investigate the effects of adult‐onset tau expression on sleep. This study addresses a knowledge gap regarding the impact of tauopathy on sleep‐related changes contributing to our understanding of AD progression.MethodWe investigated the impact of adult‐onset pan‐neuronal expression of wildtype tau and pseudo‐phosphorylated tau E14 in male and female Drosophila, induced by the gene‐switch drug RU 486 (mifepristone). The flies were exposed to the inducer added to their food from 2‐3 days post eclosion. Utilizing the Drosophila Activity Monitor (DAMs), we monitored activity and sleep patterns following expression for 2 weeks (n>47 flies per study group) and 4 weeks (n>17 flies per study group). Subsequently, we analysed and plotted data on activity and sleep. Additionally, at the 4‐week mark, we conducted immunohistochemistry on the flies to assess neurodegeneration, and performed lifespan assays.ResultResults consistently revealed that flies expressing tau exhibited a shorter median lifespan compared to the control group. Unexpectedly, our gene‐switch control flies displayed a marked heightened activity leading to confounding behavioural effects in our analysis. Despite the activity confounds in one control line, neither the genetic controls nor the RU inducer affected sleep phenotypes, allowing investigation of sleep disruptions due to tau expression. We observe female but not male flies expressing tau have increased day sleep bouts length compared to controls. The pseudrophosphorylated E14 tau expression exacerbated/accelerated the phenotype compared to wild‐type tau. Immunohistochemistry showed elevated vacuoles in tau‐expressing flies indicating neurodegeneration which likely caused the sleep phenotype.ConclusionOur results indicate that pathological tau expression in Drosophila melanogaster causes neurodegeneration and increase sleep in females. These results indicate that pathological tau may directly contribute to sleep disruption in humans and provides a new model system to further our understanding of the role of tau in neurodegeneration.
The human master circadian clock is vulnerable to tau pathology in the early stages of Alzheimer’s: a postmortem neuropathology using spatial in‐situ proteomics
Authors: Son Gowoon , Mladinov Mihovil , Pereira Felipe Luiz , Li Song Hua , Tu Chia‐Ling , Judge Grace , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Paes Vitor Ribeiro , Pasqualucci Carlos Augusto , Jacob‐Filho Wilson , Spina Salvatore , Seeley William W. , Chang Wenhan , Neylan Thomas C. , Grinberg Lea T. 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease(AD) patients experience circadian rhythm disorder. The circadian rhythm is synchronized by a master clock, the suprachiasmatic nucleus(SCN), which is spatially well‐conserved but a tiny nucleus in the hypothalamus. Little is known about the molecular and pathological changes that occur in the SCN during AD progression.MethodWe examined postmortem brains of 12 controls without AD neuropathological changes (Braak0) and 39 subjects with progressive ADNC stages. We quantified neuronal numbers‐arginine vasopression(AVP) and vasoactive intestinal protein(VIP) neurons‐ plus ADNC burden in SCN. We performed analysis in adjacent hypothalamic nuclei as regional controls: supraoptic nucleus(SON) and paraventricular nucleus(PVN) both sites of AVP+ neurons. Moreover, we performed In‐situ proteomics using GeoMx Digital Spatial Profiling(DSP) in the three nuclei (total of 897 ROIs), including probes for 39 proteins commonly dysregulated in AD.ResultSCN neurons in Braak6 had sixteen times higher p‐tau levels than Braak0. Neurofibrillary tangles were found exclusively in SCN(Fig. 1). However, there was not significant p‐tau upregulation in SON and PVN in all the same stage. Additionally, the SCN showed increases in glial proteins already in Braak1(Fig. 2), whereas these proteins remained unaltered in the other nuclei, including that they displayed a milder pattern of protein dysregulation in Braak1, consistent with its lower tau expression observed in histology and DSP.ConclusionOur study sheds light on the previously unexplored molecular and pathological changes occurring in SCN during AD progression. The SCN is vulnerable to AD‐tau pathology and show immune dysregulation even at Braak1 but protected against beta‐amyloid accumulation. This vulnerability pattern in SCN supports the idea that SCN dysfunction contributes to circadian rhythm disturbances in AD, observed even in the stage before the onset of cognitive disorder. Furthermore, the preservation of SON, a neighboring nucleus with AVP neurons but not directly connected in a neuronal circuit with the SCN, corroborates that SCN is early vulnerable to AD. PVN neurons exhibited similar but milder pattern of protein dysregulation in the early stages to the SCN, implying the effect may be caused by the efferent projection from the SCN. These results open up opportunities for tailored interventions to alleviate circadian rhythm disruptions in AD.
Omics analysis of Alzheimer’s disease stratified by the microglial polygenic effect
Authors: Kikuchi Masataka , Miyashita Akinori , Hirota Yu , Hara Norikazu , Hasegawa Mai , Sakakibara Yasufumi , Sekiya Michiko , Saito Yuko , Murayama Shigeo , Iijima Koichi M. , Ikeuchi Takeshi 
Published: January 2025

AbstractBackgroundRecent single‐cell omics analyses have revealed that microglia change into reactive microglia when Aβ accumulates in the brain and exhibit Aβ phagocytosis. However, reactive microglia are less likely to be induced in TREM2 mutation carriers. This microglia‐centred pathological mechanism may be considered one of the pathologies of AD. However, a single gene mutation, such as a TREM2 mutation, can rarely explain the pathology of AD. Therefore, polygenic effects involving multiple gene mutations have been proposed. In this study, we propose a polygenic risk score (PRS) to quantify the microglial polygenic effect. We stratified patient groups by this PRS and examined differences in pathogenesis based on omics analysis using postmortem brains.MethodsWhole‐genome sequencing and bulk brain tissue RNA‐seq of the frontal cortex were performed using postmortem brain samples from 100 subjects with Braak senile plaque (SP) and neurofibrillary tangle (NFT) staging information. In addition, single‐nuclei RNA‐seq (snRNA‐seq) was performed on 15 of these subjects (healthy subjects: 8 subjects, AD patients: 7 subjects).ResultWe divided AD patients into low and high groups by microglial PRS and performed bulk brain tissue RNA‐seq analysis. We identified 112 differentially expressed genes and found that those genes were related to autophagy and inflammation. To further validate these findings at the single‐cell level, we identified cell clusters containing microglia based on snRNA‐seq. Gene expression analysis of microglia in 3 AD patients with low PRS and 4 AD patients with high PRS suggested altered transcriptional profiles of immune cells and phagocytosis. In addition we observed different microglial subtypes in different PRS.ConclusionThe stratification analysis of AD by PRS suggests that microglial reactivity differs among AD patient groups. Future detailed microglial observations in postmortem brains from AD patients with low PRS and those with high PRS will further elaborate our results.
Synergistic associations of CD33 variants and hypertension with poor cognitive function, brain atrophy, and cerebral blood flow among dementia‐free older adults: a population‐based study
Authors: Zhu Min , Tian Xunyao , Han Xiaodong , Liu Cuicui , Tian Na , Zhang Heng , Song Lin , Tang Shi , Cong Lin , Wang Yongxiang , Hou Tingting , Qiu Chengxuan , Du Yifeng 
Published: January 2025

AbstractBackgroundEvidence has emerged that the inflammation and immune mechanisms are involved in the relationship between hypertension (HTN) and cognitive impairment. We sought (1) to examine the combined effects of HTN and CD33, an immune‐related and robust cognitive impairment susceptibility locus, with cognitive function in older adults and further (2) to explore the underlying mechanisms.MethodThis population‐based study included 4444 dementia‐free participants (age ≥65 years) in MIND‐China; of these, data on gray matter volume were available in 1047 persons and cerebral blood flow (CBF) in 85 persons. We used general linear regression models to examine the associations of CD33 rs3865444 and HTN with cognition, brain atrophy, and CBF, and the mediation models to explore associations among them.ResultAmong participants carrying CD33 rs3865444 CC genotype, HTN history, high pulse pressure, and late‐life HTN were significantly associated with low cognitive performance, HTN history as well as midlife HTN was correlated with small volume of gray matter. Notably, rs3865444 CC genotype significantly moderated the mediation effect of gray matter volume on the association between HTN and global cognition (mediation effect: 9.33%). Furthermore, HTN was correlated with low CBF in individuals carrying rs3865444 CC. Similar results were obtained among individuals free of mild cognitive impairment.ConclusionThe current study reveals the synergistic associations of immune‐related CD33 rs3865444 and HTN with low cognitive function and brain atrophy in dementia‐free older adults. These joint effects of HTN and CD33 on cognition may be related to the disruption of CBF and blood brain barrier function.
The Effect of Amyloid‐Beta on Empathy‐like Behavior in Rats
Authors: Rostami Zahra , Parvin Hadi Choubdar , Khodagholi Fariba , Ansari Mitra 
Published: January 2025

AbstractBackgroundEmpathy is a complex behavior enabling individuals to recognize and sense the emotional situation of others. Empathy requires cognitive, emotional, and learning abilities to understand and react to the suffering of others. The current study evaluates the effect of Amyloid‐Beta (Aβ), an aggregated peptide involved in Alzheimer’s disease on empathy‐like behavior.MethodAβ was injected bilaterally in the hippocampal tissue of 14 Wistar rats. Aβ‐injected rats were compared to the control group during an empathic behavioral task for 12 days. Empathy was evaluated using the helping behavior of the subject toward his soaking cage‐mate rat. Opening time latencies with or without soaker response were considered as empathy indicators, and their change in two groups was modeled with a linear mixed‐effect model.ResultResults of the model demonstrated that opening time latency with soaker response, as the major empathy indicator, had decreased in the Aβ group (p‐value = 0.002). Furthermore, the opening time latency without soaker response, the indicator of the helper rat’s solid action independent from social interaction, showed alteration in the Aβ group, the same as the opening time latency with soaker response, which was significantly decreased compared to the control animals (p‐value<0.001).ConclusionThis result provides good evidence for the disruption of empathy due to a cognitive defect in helper rats’ emotional cue perception during Aβneurotoxicity. Together, these findings help to understand the impact of neurodegenerative disorders on empathic behavior and decode the altered components of empathy in the course of the disease.
Examining the shared genetic liability between late‐life onset psychosis and major psychiatric, cognitive and personality phenotypes
Authors: Creese Byron , Ismail Zahinoor , Ballard Clive G , Corbett Anne , Aarsland Dag , Gibbs Olly , Moodie Ellie 
Published: January 2025

AbstractBackgroundWhen assessed in the Mild Behavioral Impairment (MBI) framework, late‐life onset psychotic like symptoms (MBI‐psychosis) are associated with incident cognitive decline and dementia. One approach to examining the genetic basis of this association, is to use Polygenic Risk Scores (PRS) to determine whether genetic propensity for late‐life onset psychosis is shared with other traits. We aimed to elucidate the shared genetic liability between Educational Attainment, Intelligence, Reasoning, Memory, Neuroticism, Alzheimer’s Disease, Major Depression, Schizophrenia and Bipolar Disorder and Mild Behavioral Impairment (MBI)‐Psychosis in later life.MethodA total of 7,307 older adults without dementia were included in the analytical sample. MBI‐Psychosis status (present or absent) was determined by the Mild Behavioral Impairment Checklist (MBI‐C) rated by participants and study partners (that is ‘self’ and ‘informant’ ratings). Each PRS was tested in a logistic regression model with MBI‐Psychosis status as the dependent variable, and with age, sex and ancestry as covariates.ResultHigher PRS for Major Depression, Schizophrenia and Neuroticism were all associated with an higher odds of MBI‐Psychosis. PRS for schizophrenia was only associated with self‐reported MBI‐psychosis, not informant reported MBI‐psychosis (see Figure 1). Higher PRS for Educational Attainment and Intelligence were both associated with lower odds of MBI‐Psychosis. In analysis stratified by self‐reported education level, the relationship between higher PRS for educational attainment and lower odds of MBI‐psychosis was only present in those we left school at 16.ConclusionIn early life, psychosis is known to overall with cognitive, psychiatric and personality traits. These data extend this observation to later‐life psychosis. The significance of the differences between self and informant reported symptoms are yet to be determined but may be a mix of measurement error and the different respondents having a propensity to report symptoms which reflect different etiologies. We also show that established protective factors against cognitive decline, like educational attainment, in later life may also extend to late life neuropsychiatric syndrome.
Neuroprotective potential of quetiapine against streptozotocin‐induced sporadic Alzheimer’s disease
Authors: Kumari Shilpa , Attri Paras , Deshmukh Rahul Renukadas 
Published: January 2025

AbstractBackgroundIn previous studies, we found that quetiapine activates the AKT signaling which further inhibits the action of GSK3β. Quetiapine has been reported to possess neuroprotective potential in schizophrenia and other neurodegenerative models.MethodOn day 1st and 3rd, rats received bilateral intracerebroventricular (i.c.v.) administration of STZ (3 mg/kg). From day 8 to day 21 of treatment of quetiapine, a GSK3‐β inhibitor and neuroprotective medication, was given at dose levels of 2.5, 5, and 10 mg/kg/i.p. Morris water maze and Object recognition test was performed for the evaluation of cognitive impairment, whereas biochemical, histopathological, neuroinflammatory were evaluated by hippocampal and cortical brain region on 22nd day.ResultICV‐STZ results in cognitive impairment, spatial and non‐special learning deficit in OFT, MWM and ORT tests respectively, including elevation in the levels of nitrite and MDA and decreased antioxidant enzymes GSH, SOD and Catalase levels, also produced degenerative changes in dentate gyrus, CA1, CA2 and CA3 region of hippocampus as well as cortex in rat brains. Whereas, Quetiapine treatment significantly attenuated STZ‐induced cognitive deficit, oxidative stress and improved density of surviving neurons in hippocampal/cortical region of rat brains.ConclusionThe conclusive outcomes of the present study, clearly indicate neuroprotective potential of quetiapine in neurodegenerative pathogenesis associated with cognitive dysfunction.
The relationship between psychosocial factors and cognitive test performance in a South African cohort
Authors: Dreyer Anna Jane , Nightingale Sam , Roux Celine Le , Thomas Kevin G. F. , Sabin Caroline , Winston Alan , Khoo Saye , Joska John 
Published: January 2025

AbstractBackgroundAccurate assessment of cognitive impairment in low‐income settings may require consideration of complex psychosocial variables (PV). Failure to consider the association of PV with biological factors, such as HIV, could lead to false classification of cognitive impairment. We investigated the impact of PV on cognitive performance in people with HIV (PWH) and without in a low‐income area of Cape Town, South Africa.Method273 (178 PWH) participants were recruited and 185 (145 PWH) followed‐up at 1‐year. We investigated the relationship between comprehensive cognitive testing (7 domains) and 12 PV: 5 current (income, employment, assets, accommodation, mood) and 7 recalled at childhood (assets, quality of education, exposure to trauma and violence, parental education and employment), as well as standard variables typically measured in cognition studies (age, sex, years of education). Univariable and multivariable linear regression models investigated relationships between PV (clustered using principal component analysis) and global cognitive performance (measured by global T‐score). Propensity score modelling adjusted for variables significantly associated with HIV status, to determine the direct effect of HIV status on global T‐score.ResultPWH had significantly lower scores than people without HIV in 9/12 PV (ps<.015). At baseline, 8/12 PV significantly predicted global T‐score (ps<.007), which clustered into 3 components reflecting current PV, childhood PV and experience of childhood trauma. In addition to standard variables, residing in a shack remained in multivariable analysis at baseline (β = 2.40, p = .007), and lower childhood PV at follow‐up (β = 0.82, p = .035). Unadjusted, HIV status was associated with a reduction in global T‐score of 3.72 units at baseline and 2.46 at follow‐up. At baseline, after adjustment for standard variables, the HIV association was reduced by 25.8% to 2.76, and additional adjustment for PV reduced by 41.4% to 2.18. At follow‐up, adjustment for standard measures reduced by 41.9% to 1.43 and addition of PV by 56.1% to 1.08.ConclusionPWH in this setting have lower psychosocial indices, both now and in childhood, which are associated with lower cognitive test performance as an adult. This is incompletely mitigated by adjustments for standard variables which could result in misclassification of PWH as cognitively impaired if PV are not taken into account.
A scoping review of the wide array of Alzheimer’s disease theories and hypotheses supports a multifactorial etiology
Authors: Duchesne Simon , Rousseau Louis‐Simon , Potvin Olivier , Belzile Florence , Welch Laurie‐Ann , Cournoyer Béatrice , Arseneau Marianne , Lapierre Véronick , Poulin Sara‐Maude , Hudon Carol 
Published: January 2025

AbstractBackgroundThere is a common agreement that Alzheimer’s disease (AD) is inherently complex; otherwise, a general disagreement remains on its etiological underpinning, with numerous alternative hypotheses having been proposed. Our objective was to perform a scoping review of original manuscripts describing hypotheses and theories of AD published in past decades.MethodsWe reviewed 127 original manuscripts that fulfilled our inclusion criteria out of more than 13,807 references extracted from open databases (from inception to 14 Sept 2023). Each entry was characterized as having a single or multifactorial focus and assigned to one of 15 theoretical groupings. Impact was tracked using open citation tools.ResultsWe found that three quarter of studies proposed a hypothesis characterized as being single‐focus (97/127), with the most important theoretical groupings being the Amyloid group, followed by Metabolism and Mitochondrial dysfunction, then Infection and Cerebrovascular. Three stages can be discerned in terms of hypotheses generation. The first phase (∼1980‐1995) included the establishment of the main thrusts that have endured to this day (Amyloid, Glial, Infection, Inflammation, Metabolism, Oxidative stress, and Proteinopathies hypotheses; multifactoriality; and neurotoxicity). In the second phase (1995‐2005), the importance of the Cerebrovasculature, Mitochondrial dysfunction, and Neurotransmitters were recognized. Lately (2005‐2023), evidence towards Genetics (outside of the autosomal dominant form of AD), and especially Gut/Brain interactions came to the fore. Impact, as measured by total citations count, followed a similar pattern. Out of a total of 19,996 citations for the 127 papers, the most cited single‐focused grouping was Amyloid (52%), followed by Mitochondrial dysfunction (6%, reaching 10.0% when adding Metabolism articles), then Cerebrovascular (5%) and Oxidative Stress (4%).ConclusionWhen viewed together, these multi‐faceted reports reinforce the notion that AD affects multiple sub‐cellular, cellular, anatomical, and physiological systems at the same time but at varying degree between individuals. Future work should integrate these competing views into a comprehensive, systemic framework able to capture individual and combinatorial factor evolutions and interactions, to manage its inherent complexity.
Unveiling molecular mechanism of ET‐1 induced vascular insult through RNAseq analysis
Authors: Gupta Mayank , Talukdar Ankita , Hussain Rehab , Diwakar Latha 
Published: January 2025

AbstractBackgroundVascular Dementia (VaD) is the second most prevalent cause of dementia, arising from the blockage of blood vessels in the brain. One event responsible for the blockage or narrowing of small blood vessels is transient ischemic attack (TIA), and these changes resolve within 24 hours in humans. The molecular mechanism underlying these changes in recovery in small vessels still needs to be investigated. To address this gap, we have developed a mouse model by administering endothelin‐1 (ET‐1) into the lateral ventricles. This disrupts small vessel integrity, which leads to learning and memory deficits after 3 days of a single ET‐1 injection. Intriguingly, there is a subsequent recovery in these deficits after 30 days, mimicking the clinical scenario of TIAs. Bulk RNA sequencing from microvessels was performed to elucidate further the factors involved in recovery mechanisms.MethodET‐1 injection was given to 4 groups of C57BL6/J mice, and mice were sacrificed at different time points of 3, 15, and 30 days along with saline counterparts. Microvessels were extracted from the pooled cortex and hippocampus, followed by RNA isolation. RNA samples were subjected to the cDNA library preparation, and RNA sequencing was conducted using the Illumina NovaSeq 6000® instrument. Transcriptomic analysis was carried out in the Linux environment. Differential gene expression was performed using R.ResultWe observed biological processes such as vasculature development, angiogenesis, and wound healing start upregulating after 3 days of a single ET‐1 injection, whereas several processes involved in ion transport chains were downregulated. Further, biological processes for muscle development, mitochondrial electron transport chain, and neuronal development were upregulated after 15 days of a single ET‐1 injection. No biological processes were affected after 30 days of a single ET‐1 injection, suggesting a possible complete recovery from ET‐1‐mediated vascular insult by the 30th day.ConclusionOur results highlight the temporal dynamics of biological processes in response to a single ET‐1 injection. It offers valuable insight for understanding the mechanism behind the recovery and factors involved in this process after vascular insult, paving the way for therapeutic targets.