bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex‐specific role of integrins in influencing tauopathy onset in htau mice
Authors: Bretland Katie , Lin Li , Terrill Sarah J , Dengler‐Crish Christine M. 
Published: January 2025

AbstractBackgroundIntegrins are essential mediators of numerous critical cellular processes. Increasing evidence indicates that aberrant function of αVβ1 integrins contributes to the onset and progression of tauopathy. Previously, our group showed that the neuroprotective exercise hormone irisin—a known αVβ integrin modulator, prevented age‐related increases in phosphorylated tau and inflammation in hippocampus of presymptomatic‐age female but not male htau tauopathy‐model mice (Bretland et al., 2021). Here, we investigated whether presymptomatic‐age female and male htau mice exhibited intrinsic differences in hippocampal αVβ integrins and whether irisin treatment impacted integrin expression and downstream signaling related to tauopathy disease mechanisms (i.e. PI3K/Akt/GSKβ pathway).MethodsPresymptomatic age (4‐month old) htau mice were administered 1 month of irisin (100 ug/kg i.p.) or vehicle control injections. Age‐ and sex‐ matched C57BL/6J mice were used as controls. An additional cohort of presymptomatic age ovariectomized and surgical sham female htau and C57BL/6J mice also underwent 1 month of irisin/vehicle treatment. Mice were sacrificed at 5 months of age, hippocampi were fresh dissected, and automated capillary‐based protein quantitation via Protein Simple Wes/Jess platform was used to measure hippocampal levels of αVβ1 integrins, relevant pathway targets, and neuropathology.ResultsPresymptomatic female htau mice had endogenously dysregulated β1 integrin expression compared to female controls; no such differences were found among males. Irisin treatment significantly reduced hippocampal αV integrin expression and trended towards decreasing β1 integrin expression in female mice while having no impact on integrin expression in males. Irisin treatment also significantly reduced intrinsically upregulated PI3K/Akt/GSKβ pathway signaling in female htau mice, but had no impact on this signaling in males. Ovariectomy prevented irisin’s neuroprotective effects against hippocampal ptau and inflammation in female htau mice; notably, irisin triggered an upregulation of β1 integrin expression in hippocampus of ovariectomized female htau mice.ConclusionsAlterations in αVβ integrin function may influence early tauopathy disease mechanisms in a sex‐specific manner. These findings emphasize a need to understand the role of integrins in dementia and emphasize the importance of identifying sex‐specific disease etiologies.
Clinical and neuropsychological variables associated with subjective cognitive decline and its progression
Authors: Villino‐Rodríguez Rafael Angel , Ríos‐Rivera Mirla , Imaz Laura , Espinoza‐Vinces Christian , Pérez‐Prol Cristina , Montoya‐Murillo Genoveva , Arrondo Carlota , Riverol Mario 
Published: January 2025

AbstractBackgroundThis study focused on comparing clinical and neuropsychological aspects in individuals with subjective cognitive decline (SCD) versus healthy controls (HCs) in a memory clinic, aiming to identify factors linked to the progression towards mild cognitive impairment (MCI) or dementia.MethodWe retrospectively analysed data from 945 SCD patients and 68 HCs at Clínica Universidad de Navarra memory clinic between 2001 and 2017, with 450 followed up until January 2020, the study involved various assessments including medical interviews, lab tests, neuropsychological evaluations (during the first interview and follow‐ups), and brain imaging. All the neuropsychological variables were adjusted for age, sex and education.ResultAmong the participants with SCD, 131 progressed to MCI or dementia. SCD individuals were younger, and had higher educated, and more vascular risk factors compared to HCs. Factors associated with MCI or dementia encompassed age at diagnosis, years of education, and hypercholesterolemia. Neuropsychologically, SCD individuals exhibited weaker global cognition, verbal memory, fluency in language, and increased depressive symptoms. Poorer performance in episodic verbal memory tests correlated with a higher likelihood of transitioning to MCI or dementia.ConclusionThe study’s discussion emphasized the complex nature of SCD development and progression, involving both clinical and neuropsychological factors. Younger age and increased vascular risk were characteristic of SCD individuals, who also showed deficiencies in global cognition, language fluency, verbal memory, and executive functions. Key indicators of disease progression included age at diagnosis, hypercholesterolemia, and poorer performance in tests assessing language fluency, verbal and visual memory, and executive functions.
Nanoscale imaging of pT217‐tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: Evidence of interneuronal trafficking and early‐stage neurodegeneration
Authors: Datta Dibyadeep 
Published: January 2025

AbstractBackgroundAdvances in Alzheimer’s disease (AD) have revealed a novel fluid biomarker, tau phosphorylated at T217 (pT217‐tau), in CSF and plasma, that predicts AD prior to cognitive deficits. Understanding the role of pT217‐tau is important in assessing efficacy of novel treatments aimed at early‐stage disease. However, it is unknown why pT217‐tau is effective in predicting brain pathology, as little is known about early, soluble pT217‐tau brain expression. These questions are difficult to address in humans, as soluble p‐tau is rapidly dephosphorylated postmortem, and PET scans detect late‐stage, fibrillated tau. However, the etiology of pT217‐tau in aging brains can be probed in rhesus macaques, where perfusion fixation allows capture of phosphorylated proteins in their native state. Aging macaques naturally develop tau pathology with the same qualitative pattern and sequence as humans, including initial cortical pathology in layer II of the entorhinal cortex (ERC) evident early in aging, and later in layer III of the dorsolateral prefrontal cortex (dlPFC).MethodWe utilized multi‐label immunofluorescence and immunoelectron‐microscopy to examine the subcellular localization of early‐stage pT217‐tau in ERC and dlPFC of aged macaques with naturally occurring tau pathology and assayed pT217‐tau levels in plasma.ResultOur results show that pT217‐tau labeling is primarily observed in postsynaptic compartments, accumulating in: 1) dendritic spines on the calcium‐storing smooth endoplasmic reticulum spine apparatus near asymmetric glutamatergic‐like synapses, and 2) in dendritic shafts, where it aggregated on microtubules, often “trapping” endosomes associated with Aβ42. The dendrites expressing pT217‐tau were associated with autophagic vacuoles and dysmorphic mitochondria, indicative of early neurite degeneration. We observed trans‐synaptic pT217‐tau trafficking between neurons within omega‐shaped bodies and endosomes, specifically near excitatory, but not inhibitory synapses. We also examined pT217‐tau in blood plasma in macaques across age‐span and observed a statistically significant age‐related increase in pT217‐tau.ConclusionThese data provide the first direct evidence of pT217‐tau trafficking between neurons near synapses to “seed” tau pathology in higher brain circuits, interfacing with the extracellular space to become accessible to CSF and blood. The expression of pT217‐tau in dendrites with early signs of degeneration may help to explain why this tau species can herald future disease.
Sphingomyelin 14:0 ‐ a driver of neuroinflammation
Authors: McManus Roisin M. 
Published: January 2025

AbstractBackgroundWestern‐diet (WD) can induce sterile inflammation and epigenetic reprogramming of myeloid cells, affecting their immune response (Christ et al., 2018). However, the molecular signaling mediating these changes was unknown. We recently identified that WD increases circulating sphingomyelin 14:0 (S14), which was associated with peripheral inflammation and atherosclerosis. As atherosclerosis, inflammation and WD are risk factors for dementia and Alzheimer’s disease (AD), our goal was to determine whether S14 was the precise signaling factor driving neuroinflammation leading to AD.MethodWild‐type and Apoe‐/‐ mice (mouse model of atherosclerosis) were fed a high‐fat diet mimicking WD for 8 weeks, before samples were obtained for lipidomics. Microglia were isolated ex vivo for either RNA sequencing or to determine their metabolic profile. In a separate series of experiments, microglia were prepared from wild‐type mice and treated with various TLR inhibitors to assess whether these cells can recognize S14, and the exact molecular pathways induced by the lipid. Wild‐type microglia were prepared for RNA sequencing, to determine the genes and networks induced by S14, which were compared with the microglia enriched ex vivo. Pathways were confirmed at a protein and functional level.ResultLipidomic analysis confirmed that WD increased S14 in the circulation of wild‐type and Apoe‐/‐ mice. Patients with obesity also had greater levels of S14, which was associated with heart disease. We found that S14 triggers an extensive increase in pro‐inflammatory genes and pathways in microglia. We confirmed that S14 utilizes TLR4 to signal in vitro, inducing NFkB activation and ultimately the release of TNFα from microglial cells. S14 also affected microglial metabolic function and reduced phagocytic capacity ex vivo and in vitro.ConclusionWe found that S14 is a lipid significantly increased in both human and murine models of obesity or heart disease. S14 is a novel TLR4 agonist that can activate microglia and trigger extensive inflammation. Critically, S14 affects microglial function both ex vivo and in vitro. Together, our data shows that S14 is an endogenous immune stimulus, capable of triggering various innate immune responses and microglial changes that are associated with neuroinflammation and the development of dementia.
In depth comparisons of neuropsychological & neuroimaging profile of primary psychiatric disorders and behavioral variant FTD
Authors: Denève Agnès , Lebouvier Thibaud , Lopes Renaud , Kuchcinski Gregory , Pasquier Florence , Amad Ali , Bertoux Maxime 
Published: January 2025

AbstractBackgroundOver the past years, social cognition has been envisaged as a promising domain to distinguish behavioral variant frontotemporal degeneration (bvFTD) from its main differential diagnoses that is primary psychiatric disorders (PPD). The core‐processes approach, which has emphasized the importance of emotion recognition and mentalizing, has been particularly useful to better characterize each condition and enhance the earliness of FTD’s diagnosis. However, new findings evidencing conflicting results regarding the ability of social cognition to distinguish bvFTD from PPD have underlined the importance of moving beyond the core processes approach.MethodWe reviewed all cases with a suspission of bvFTD in the last 8 years in the Lille memory clinic, at least followed‐up for 24 months with a neuropsychological assessment and an MRI and/or PET‐scan. We then applied a quantitative comparison approach based on total scores, then a qualitative approach, based on responses and errors types. Then, neuroimaging analyses were run, and biomarkers were analyzed.ResultData of 56 patients with a probable to certain bvFTD and 47 patients with a primary psychiatric disorders (late major depression, bipolar disorders, schizophrenia…) were analyzed at classical and social cognitive (mini‐SEA) tests. Overall, clinical groups were not different on executive functionning, attention, motor & perceptual functions. Minor differences were retrieved in memory and langage processing. Important differences were retrieved in social cognition. Qualitative differences were retrieved in facial emotion recognition (inter & intra valence errors) and mentalizing (type of mental inference, emotional labelling), as well as memory functioning (primacy/recency ratio, intrusions). Anatomical and functional brain networks involved showed a combination of overlaping and distincts areas. Regarding biomarkers, NFLs showed promising results with AUC = 0.88).ConclusionWhile the usual approach (considering general or subscores scores) may not be the more efficient way, a more qualitative neuropsychological approach has the potential to provide relevant cognitive markers for the clinical distinction between bvFTD and PPD, particularly regarding social cognition.
Diverse Patterns and Impact of Mitochondrial DNA Alteration in Parietal Cortex of Diabetic and Non‐diabetic Alzheimer’s Disease
Authors: Shi Anqi , Kaikini Aakruti , Hodgkinson Alan , Malik Afshan N 
Published: January 2025

AbstractBackgroundDiabetes increases the risk of Alzheimer’s disease (AD), and mitochondrial dysfunction is implicated in both diseases. We previously detected mitochondrial DNA copy number (MtDNA‐CN) changes in human parietal cortex that differed between diabetic AD and non‐diabetic AD. We hypothesize that MtDNA‐CN changes may be indicative of different underlying mechanisms. In the current study, we aim to evaluate the impact of MtDNA‐CN changes on MtDNA damage and proteins involved in energy production in the mitochondria.MethodTotal DNA and protein were isolated from human post‐mortem parietal cortex (n = 24). MtDNA‐CN was determined as the ratio of MtDNA to nuclear DNA using qPCR. MtDNA damage was measured using the surveyor nuclease method in 11 overlapping mitochondrial genome regions, and next generation sequencing (NGS) after removing the nuclear DNA using exonuclease V.NDUFB8(I), SDHB(II), UQCRC2(III), MTCO1(IV), and ATP5A(V) expression were measured as the representatives of 5 complexes in OXPHOS chain by western blotting. Data were compared as 4 groups: non‐cognitive impairment (NCI) and AD, ± diabetes using ANOVA.ResultIn AD groups, MtDNA‐CN was reduced in cases without diabetes (P<0.05), however, no reduction was seen in diabetic AD. In diabetic groups, irrespective of cognitive status, higher MtDNA‐CN were found compared to non‐diabetic groups. Putative mutations with various intensities and patterns were observed, especially in the displacement loop area in AD and diabetic AD groups. Among 4 groups, the expression of 2 nuclear‐encoded subunits NDUFB8 and ATP5A were higher than the level of other 2 nuclear‐encoded subunits (SDHB and UQCRC2) and 1 mitochondrial‐encoded subunit MTCO1. However, no significant difference was found in the expression of these 5 subunits between diabetic and non‐diabetic groups in parietal cortex.ConclusionOur data show that in human parietal cortex, the MtDNA‐CN changes differently in diabetic and non‐diabetic AD suggesting of different underlying mechanisms. The presence of MtDNA changes without any impact on levels of OXPHOS subunits indicates an MtDNA‐based pathology. We propose that different patterns of MtDNA damage may impact energy production in specific brain regions and contribute to disease progression. The level of MtDNA heteroplasmy in the groups determined by NGS and its potential impact will be presented.
Identification of regulators of microglia lipotoxicity
Authors: Therrien Martine , Weider Nicolas , Monti Giulia , Meyer Daniel , Atkeson Trevor , McCarroll Steven , Greka Anna , Stevens Beth 
Published: January 2025

AbstractBackgroundEmerging studies have identified changes in lipid processing in Alzheimer’s disease patients. However, how the various brain cell types respond to these changes is unclear. Multiple Alzheimer’s disease risk genes are expressed in microglia and involved in lipid sensing and processing.MethodIn this project, we assessed unbiasedly how various fatty acids impact microglia states and functions. Using the iPSC‐derived microglia platform, our lab has recently developed (Dolan*, Therrien* et al. Nature Immunology 2023), we characterized the impact of 48 different fatty acids on human microglia.ResultWe identified 5 distinct transcriptional signatures produced in response to various lipids, including a toxic lipotoxicity signature independent of TREM2 signaling. Using microglia villages, we assessed the toxicity across 25 iPSC donors and identified genetic modifiers of microglia lipotoxicity.ConclusionTogether, our data identifies genetic regulators of microglia states and presents new insight into understanding how to protect synapses in Alzheimer’s that could lead to new therapies and biomarkers for early diagnoses.
Signatures of resolution reprogramming in amyloid‐challenged microglia
Authors: Kondrikova Galina , Hamlett Eric D , Pytel Dariusz 
Published: January 2025

AbstractBackgroundSpecialized pro‐resolving mediators (SPMs) promote inflammatory resolution and homeostasis and are thought to have specific reprogramming effects on hman microglia. Decreased SPM levels have been correlated with chronic neuroinflammation, late‐stage Alzheimer’s disease (AD) and neuropathology in humans, yet few studies have explored the cellular signatures of resolution. Amyloid is though to bind one target resolution receptor, ChemR23, leading to internalization. In this study we explore if internalized ChemR23 receptor is part of a signaling endosome in microglial cells and how this interfaces with amyloid challenge and/or SPM mitigation.MethodWe then challenged human microglial cell culture models (HMC3) with amyloid‐beta oligomer activation and/or administered RvE1 to promote resolution. We quantified resolution signaling responses using standard immunoblot. We measured microglial activation using immunofluorescence and cell characterization software. We examined the occurrence of ChemR23 receptor internalization and several endosomal markers by super‐resolution immunofluorescence microscopy.ResultRvE1 significantly reduces microglial activation and cytokine expression under amyloid challenge. We discovered that RvE1 leads to compensatory response in specific G protein coupled receptors within the resolution family 2) specific signaling events 3) unique endosome signatures, We are quantifying functionality of endosomes and other objectives to share at the poster at AAIC.ConclusionWe have demonstrated that RvE1 modulates inflammation in a mouse model and in a microglial cell line. Understanding the molecular signatures of resolution reprogramming in cells will be key to identifying prognostic indicators and molecular mechanisms of this unique understudied GPCR system and response in the brain.
The X‐chromosome in Alzheimer’s disease genetics, stratified by APOE*4 and sex
Authors: Belloy Michael E. , Guen Yann Le , Napolioni Valerio , Greicius Michael D 
Published: January 2025

AbstractBackgroundThe X‐chromosome remains largely unexplored in Alzheimer’s disease (AD). We performed the first, stratified X‐wide association study (XWAS) of AD to chart the role of X‐chromosome genetic variation in AD sexual dimorphism and heterogeneity of APOE*4‐related AD risk.MethodThe study overview is shown in Figure 1A. SNP‐array AD XWAS datasets primarily composing the ADGC, together with whole‐genome sequencing (WGS) from ADSP (NG00067.v7), provided case‐control diagnoses for phase‐1. The UK Biobank provided subjects with ICD codes and family history of AD status for phase‐2. Subjects were of European ancestry. Linear mixed model regressions were performed (LMM‐BOLT v.2.3.4) on AD outcome measures, adjusting for sex, APOE*4/APOE*2 dosage, genetic principal components, and array/batch/center. XWAS hits (cf. Figure 1) were evaluated for interaction effects (meta‐regression for phase1+2 meta‐analyses) and assessed in functional follow‐up analyses, including colocalization with QTL datasets from the eQTL Catalogue.ResultStratified AD XWAS identified 17 loci (Figure 1B). These included KDM6A, which has previously been shown as an important risk gene for AD through rodent work. The MAP7D3 locus contains NHE6, which has also been implicated as a possibly important AD risk gene. The variant rs6629203, with a rare allele frequency of 0.3%, in the REPS2 locus reached genome‐wide significance (P<5e‐8) in APOE*4 negative individuals. At the NROB1 locus, the AD XWAS signal and eQTL signal on the EK gene, as expressed in monocytes, colocalized (PP4 = 0.77) (Figure 2). Other functional follow‐up results will be shared during the conference.ConclusionFor the first time, we identified X‐chromosome loci/variants differentially associated with AD risk across APOE*4 and/or sex. Our findings contribute to our understanding of the genetic etiology of AD, which in turn contributes to advancing personalized genetic medicine. Additional follow‐up and replication work is in progress.
Quantitative effects of sleep‐disrupting medications on real‐world sleep metrics in older adults at risk for neurodegeneration
Authors: Chang Jun Ha , Scalzo Anthony J. , Shaffer Christopher L. , Rizzo Matthew 
Published: January 2025

AbstractBackgroundThis pilot study addresses unmet needs for empirical evidence on real‐world data (RWD) on sleep to inform pharmacological management in older adults at‐risk for neurodegenerative conditions. Polypharmacy is prevalent among older adults, with potential adverse effects on physiological functions, including sleep. Sleep disturbances are prevalent in aging, may signal onset of Alzheimer’s disease (AD), potentially contributing to the underlying pathology.Methods82 participants identified with cognitive decline (9 mild AD, 73 Mild Cognitive Impairment) (mean age = 76yrs; 47 male) and 56 age‐ and education‐matched controls (mean age = 75yrs; 19 male) (Table 1) self‐reported their prescribed medications. Only medications known to disrupt sleep (e.g., Cholinesterase inhibitors, ACE inhibitors) and administered orally daily were included in the analysis. Cognitive abilities were measured in all 138 participants at study induction using a battery of standard neuropsychological tests. Four weeks of nightly sleep data were collected using wrist‐worn actigraphy to estimate sleep duration and quality, including sleep efficiency [SE], wakefulness after sleep onset [WASO], and awakening count [AC]). Multivariate linear regressions examined the effects of the number of sleep‐disrupting medications and cognitive status on sleep variables, adjusting for age, gender, and education.Results45 participants did not take sleep‐disrupting medications, 46 took one, and 47 took two or more (Table 2). Greater numbers of the medications were linked to poorer SE (b = ‐0.26, p = 0.01), increased WASO (b = 0.27, p = 0.01), and greater variability in sleep duration (b = 0.23, p = 0.03), SE (b = 0.26, p = 0.02), WASO (b = 0.28, p = 0.009), and AC (b = 0.26, p = 0.01). Controls showed less variability in SE (b = ‐0.43, p = 0.01) and WASO (b = ‐0.37, p = 0.03) than those with cognitive decline.ConclusionOur results, using RWD of sleep and medications, underscore that polypharmacy in older adults is associated with disrupted sleep patterns, with a greater number of sleep‐disrupting medications exacerbating poor sleep outcomes. These findings highlight needs for careful medication management to preserve sleep and suggest that targeted pharmacological strategies can mitigate medication‐related sleep disturbances, thereby enhancing brain health, behavior, and overall health.