bluuebunny/crossref_metadata_2025_split huggingface dataset:
Harnessing chromatin loops to identify susceptibility genes in different populations for Alzheimer’s disease: rs3851179 links to PICALM not EED
Authors: Wang Liyong , Xu Wanying , Rajabli Farid , Celis Katrina , Lu Leina , Gearing Marla , Bennett David A. , Flanagan Margaret E , Weintraub Sandra , Geula Changiz , Schuck Theresa , Scott William K. , Dykxhoorn Derek M. , Griswold Anthony J. , Pericak‐Vance Margaret A. , Young Juan I , Jin Fulai , Vance Jeffery M. 
Published: January 2025

AbstractBackgroundAnnotation of target genes of non‐coding GWAS loci remains a challenge since 1) regulatory elements identified by GWAS can be metabases away from its actual target, 2) one regulatory element can target multiple genes, and 3) multiple regulatory elements can target one gene. AD GWAS in populations with different ancestries have identified different loci, suggesting ancestry‐specific genetic risks. To understand the connection between associated loci (potential regulatory elements) and their target genes, we conducted Hi‐C analysis in frontal cortex of African American (AA) and Non‐Hispanic Whites (NHW) AD patients to map chromatin loops, which often represent enhancer‐promoter (EP) interactions. In our initial analyses, we applied HiC to uncover the regulatory architecture of rs3851179 linked to the embryonic ectoderm development gene (EED) in the ADSP gene verification list.MethodHi‐C libraries were derived from four AA and four NHW donors matched for age, sex, and APOE genotype. The AA samples had 68∼88% African (AF) genome while NHW samples had >95% European (EU) genome. DeepLoop was used to generate robust maps of chromatin loops. Hi‐C data from each population were pooled to generate reference chromatin loop maps for the AF and EU genomes.Resultrs3851179 (OR = 0.9, P = 3.0 × 10−48) resides between EED and PICALM, about 80 Kb away from both with each gene transcribed in opposite directions. Although PICALM is designated as a causal gene, EED is designated a susceptibility gene by ADSP based on the transcription direction and distance from rs3851179. Hi‐C data from both AF and EU genome in frontal cortex revealed that rs3851179 co‐localizes with a loop anchor, connecting H3K27ac peaks (enhancer) overlapping rs3851179 to the proximal promoter of PICALM, suggesting that PICALM but not EED is the target gene, corroborated by the GTEX e‐QTL data.ConclusionThis initial application of Hi‐C data demonstrates the utility of chromatin regulatory maps in nominating target genes of GWAS hits in non‐coding loci. The generation and eventual application of Hi‐C maps in African and Amerindian genomes (which are part of the AA or American Hispanic genomic admixture) will be key dissecting ancestry‐specific genetic loci and, thereby, broadening diversity in AD research.
Disentangling the genetic underpinnings of neuropsychiatric symptoms in Alzheimer’s Disease in the Alzheimer’s Disease Sequencing Project: study design and methodology
Authors: Kumar Ajneesh , Ray Nicholas R. , Zaman Andrew F , Manoochehri Masood , Stein Colin , Mena Pedro R. , Sweet Robert , Hohman Timothy J. , Cuccaro Michael L. , Beecham Gary W , Huey Edward D. , Reitz Christiane 
Published: January 2025

AbstractBackgroundNeuropsychiatric Symptoms (NPS) including aggression, psychosis, anxiety, apathy and depression are highly prevalent in Alzheimer’s Disease patients and are associated with accelerated decline and a detrimental impact on suffering and quality of life of both patients and caregivers. There are no effective pharmaceutical interventions targeting these symptoms, making a better understanding of the etiologic mechanisms underlying NPS in AD critical to develop improved treatments.MethodTo facilitate identification of genetic loci and mechanistic pathways underlying NPS in AD, we have initiated an effort (NIH: U01AG079850) to collate and harmonize all available NPS data in over 70 cohorts (>80,000 samples) of diverse ancestries with whole‐genome sequencing data from the Alzheimer’s Disease Sequencing Project (ADSP), and analyze these data to identify genetic loci and mechanistic pathways associated with NPS in AD.ResultA publicly available genomics resource for NPS in AD with extensive harmonized NPS phenotype data. Primary core analyses will (1) identify novel genetic risk factors associated with neuropsychiatric symptoms in AD, (2) characterize the shared genetic architecture of neuropsychiatric symptoms in AD and primary psychiatric disorders, and (3) assess the role of ancestry effects in the etiology of neuropsychiatric symptoms in AD.ConclusionExpansion of the ADSP to harmonized and refined NPS phenotypes coupled with the proposed core analyses will lay the foundation to disentangle the molecular mechanisms underlying these detrimental symptoms in AD in diverse populations.
Spatially defined transcriptomic changes across the hippocampus of J20 mice
Authors: Sander Millie , Lunnon Katie , Ballard Clive G , Brown Jonathan T 
Published: January 2025

AbstractBackgroundThe J20 mouse is an established model of amyloid pathology, exhibiting neuropathological and behavioural symptoms reflective of human Alzheimer’s disease (AD). Previous work, conducted by Castanho et al (2020), revealed transcriptomic change in the hippocampus of J20 mice to be associated with the accumulation of amyloid pathology. Here, we investigated the spatial distribution of such transcriptomic changes using novel spatial transcriptomic technology.Method10µm fresh‐frozen brain slices were collected from the brains of J20 mice and WT controls. Slices were mounted on 10x genomics visium slides and processed according to the manufacturer recommendations. A total of 47 spatial clusters were identified, 6 of which corresponded to the hippocampus. Differential expression analysis was conducted on the hippocampus and sub‐regions of interest (CA1 & CA3 pyramidal cell layers, and dentate gyrus granule cell layer). High dimensional weighted gene co‐expression network analysis (hdWGCNA) was conducted to identify spatially‐resolves networks of co‐expressed genes.ResultVarious differentially expressed genes (DEGs) were identified across the hippocampus of J20 mice compared with WT controls. Many of said DEGs were found to be cluster‐specific, indicating transcriptomic change to be specific to hippocampal sub‐regions. hdWGCNA modules were also highly region‐specific. Many of said genes/hdWGCNA modules, and the associated biological pathways, were associated with AD pathology and behaviour.ConclusionOverall, these results demonstrate region‐specific transcriptional changes in the hippocampus of J20 mice compared with WT controls. DEGs and networks of co‐expressed genes were found to be associated with disease‐associated pathways, giving insight into region‐specific pathological changes with disease.
“Polygenic Genetic Risk Factors in Alzheimer’s Disease: A Case‐Control Study in Peruvian Population”
Authors: Zegarra‐Valdivia Jonathan Adrian , Arana‐Nombera Harold Alessandro , Perez‐Fernandez Leandro Aron , Casimiro‐Arana Milagros del Rocio , Alamo‐Medina Reyna Elizabeth , Gallegos‐Manayay Viviana Nayelli , Oliva‐Piscoya María del Rosario , Vásquez‐Zuñe Nobuko , Abanto‐Saldaña Eduardo Sebastián , Ordinola Maria Celinda Cruz , Manrique Carmen Paredes , Renteria Miguel E. , Castro‐Suarez Sheila ,   Neuroscience and Mental Health Group
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) is the most prevalent form of dementia globally. While some familial cases are observed, sporadic AD cases are more common and reflect a high level of complexity, with individual risk determined by the interaction of polygenic and environmental factors.ObjectiveTo characterize polygenic genetic risk factors in individuals with cognitive impairment and Alzheimer’s Disease across four regions of Peru.MethodThis will be a prospective observational case‐control study. We will identify the neurocognitive profile of participants and collect saliva samples for subsequent genetic profiling. Participants will be divided into three main groups: those with cognitive impairment, those diagnosed with AD, and control subjects over 50 years old without dementia.ResultsWe expect to validate the effect of risk variants previously identified in the European population within the Peruvian population. Additionally, the aim is to identify new genetic risk factors specific to the Peruvian population. Collectively, the findings from this study could lay the groundwork for implementing a polygenic risk score model, which would estimate an individual’s genetic risk of developing Alzheimer’s Disease.ConclusionThis study aims to significantly contribute to the understanding of Alzheimer’s Disease’s genetic underpinnings in the Peruvian population. By exploring both known and novel genetic risk factors, we hope to enhance early detection strategies and personalized risk assessments for AD, ultimately guiding more targeted interventions and preventative measures.
Identification of tau UFMylation in vitro and in vivo
Authors: Yan Tingxiang , Madden Benjamin J. , Murray Melissa E. , Dickson Dennis W. , Springer Wolfdieter , Fiesel Fabienne C 
Published: January 2025

AbstractBackgroundUFMylation is an understudied ubiquitin‐like post‐translational modification (PTM). Like ubiquitin, UFM1 is conjugated to substrates via a catalytic cascade involving a UFM1‐specific E1 (UBA5), E2 (UFC1), and an E3 ligase complex (UFL1, DDRGK1 and CDK5RAP3). UFMylation is reversible, and this is mediated by UFSP2. UFMylation plays essential roles in several biological processes including the DNA damage response, endoplasmic reticulum homeostasis, unfolded protein response, autophagic functions, and immune response. Importantly, UFMylation is also crucial for healthy brain development. Alzheimer’s disease (AD), a complex neurodegenerative disorder, is characterized by the accumulation of pathologic tau and beta‐amyloid proteins and has been associated with abnormalities in the aforementioned processes. Intriguingly, the potential link between AD and UFMylation has not been investigated yet. Considering that pathological tau plays a critical role in AD, and tau also plays an important role for the DNA damage response in neurons under physiological conditions, we speculated that tau itself could be modified with UFM1.MethodWe performed Western blot and Meso Scale Discovery based ELISA to measure the protein level of UFM1, UFSP2 and other UFMylation pathway components in RIPA‐soluble and insoluble fraction in human post‐mortem frontal cortex. To test whether tau can be modified by UFM1, we performed co‐immunoprecipitation (Co‐IP), Proximity Ligation Assays (PLA) and liquid chromatography‐tandem mass spectrometry (LC‐MS/MS).ResultWe found a significant reduction of soluble UFSP2, but an increase of soluble total UFM1 in AD compared to controls. We found that tau interacts with UFL1 and DDRGK1. In addition, using immunoprecipitation of denaturing lysates we found that tau can indeed be covalently modified by UFM1 when overexpressed. We detected strong signal of HA‐UFM1‐tau in neurons but not in negative controls using PLA. Furthermore, we immunoprecipitated denatured UFM1 from human autopsy brain, and detected two specific UFM1‐tau bands with tau antibodies. Together, this data strongly indicates that tau is UFMylated under endogenous conditions. Using LC‐MS/MS, we identified 17 UFMylation sites in tau proteins.ConclusionUFMylation is dysregulated in AD; tau protein can be modified by UFM1 both in vitro and in vivo, which enables a more comprehensive understanding of tau PTMs.
CSF sTREM2 is associated with neuroprotective microglial states early in Alzheimer’s disease and deleterious effects later in the disease trajectory
Authors: Crook Harry , Wahdan Malak , Tuil Marie Emilie , Livingston Nicholas R , Raza Sanara , Nowell Joseph , Edison Paul 
Published: January 2025

AbstractBackgroundNeuroinflammation is a key component of Alzheimer’s Disease (AD) pathology. Triggering receptor expressed on myeloid cells 2 (TREM2) is crucial to microglial involvement in AD, mediating trem2‐dependent activation and Disease‐Associated Microglia (DAM) polarization. However, GWAS revealed that loss‐of‐function mutations of its encoding gene are an important risk factor for AD. There is mounting evidence supporting a biphasic microglial response in AD trajectory, and such contrasting effects would support this.We evaluated the influence of cerebrospinal fluid soluble TREM2 (CSF sTREM2) on AD pathology in healthy, Mild Cognitive Impairment (MCI), and AD patients.MethodPatients were grouped by diagnosis and each group segmented according to amyloid and tau, into amyloid‐positive (Aβ+) and negative (Aβ‐), and tau‐positive (tau+) and negative (tau‐). We used a combination of CSF biomarkers and positron emission tomography (PET) scans to assess neuropathological substrates of AD: CSF p‐tau181 for tau pathology, CSF Amyloid‐β 42 (Aβ42) and 18F‐florbetapir (18F‐AV45) PET scans for amyloid deposition, and magnetic resonance imaging (MRI) scans for neurodegeneration.ResultWe observed higher sTREM2 levels in Aβ+/tau+ AD compared with Aβ+/tau‐ AD and Aβ‐/tau‐ MCI patients. Likewise, Aβ+/tau+ MCI patients showed higher sTREM2 than Aβ‐/tau‐MCI patients. Furthermore, sTREM2 levels were negatively associated with cortical volume in MCI and AD, and with MMSE scores in AD.sTREM2 was positively associated with CSF p‐tau181 in all groups except Aβ+ controls. However, a positive association with CSF Aβ42 was only observed in the Aβ‐ control and the Aβ+ and Aβ‐ MCI groups. Similarly, sTREM2 was positively correlated with amyloid load (18F‐AV45 uptake) in controls and MCI patients yet negatively correlated in the AD group.ConclusionThe MCI and AD stages of the disease showed contrasting associations between sTREM2 and neuroimaging markers for AD pathology. These suggest diverging effects of the microglial response along AD trajectory, with a neuroprotective phase in early AD and a neurotoxic one later on. This could indicate that microglia polarize first towards an anti‐inflammatory phenotype before switching to a pro‐inflammatory one as neuropathology progresses.
Exploring the Relationship Between Adipose Tissue and Alzheimer’s Disease Pathogenesis
Authors: Bettinetti‐Luque Miriam , Trujillo‐Estrada Laura , Andreo‐Lopez Juana , Campos‐Moreno Cynthia , Fatuarte‐Juli Ivan , Morales‐Cabello Mario , Da Cunha Celia , Sanchez‐Mejias Elisabeth , LaFerla Frank M , Gutierrez Antonia , Baglietto‐Vargas David 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a complex disorder and multiple cellular and molecular mechanisms are involved in AD onset and progression. Recent evidences have suggested that metabolic alterations are an important pathological feature in disease progression in AD. Likewise, diabetes and obesity, two mayor metabolic illnesses, are risk factors for AD. These two overwhelming diseases are associated with a significant expansion of visceral adipose tissue. Here, we hypothesize that the visceral adipose tissue may serve as a key communicator organ between the brain and peripheral metabolic illnesses and affecting both types of disorders.MethodWe used histological stains, immunohistochemistry and biochemical means to determine changes in the visceral adipose tissue from WT and db/db mice. Moreover, similar techniques were used in 3xTg‐AD mice that received white fat pads from WT and db/db donors to determine any changes in amyloid and tau pathology.ResultOur study shows that recipient 3xTg‐AD mice from db/db fat pads mice develop profound changes in tau pathology due to increased CDK5 expression compared to 3xTg‐AD mice that received fad pads from WT mice. This increment in tau level was associated with elevated levels in IL‐1β and profound microglia activation. Moreover, we found the opposite effect on amyloid pathology, in which insoluble Aβ levels and Thioflavin positive plaques were reduced in recipient 3xTg‐AD mice from db/db fat pads compared to 3xTg‐AD mice that received fad pads from WT mice. These reduction in Aβ levels were correlated with an increment in microglia phagocytic capacity.ConclusionOverall, our study demonstrate a novel important crosstalk between Alzheimer´s disease and obesity/diabetes type II through visceral adipose cells and a differential effect on tau and Aβ pathology mediated by an activated immune response.This study was supported by Minister of Science and Innovation grant PID2019‐108911RA‐100 (D.B.V.), Alzheimer’s Association grant AARG‐22‐9282/9, Beatriz Galindo program BAGAL18/00052 (D.B.V.), University of Malaga grant PPIT.UMA.B1‐2021_32(LTE) and Institute of Health Carlos III (ISCiii) grant PI18/01557 (A.G.) co‐financed by FEDER funds from European Union.
A systematic review with meta‐analysis of the GABAergic system in transgenic rodent models of amyloidosis and tauopathy
Authors: Mensch André Nunes , Carello‐Collar Giovanna , Ramos Vanessa G. , Bellaver Bruna , Ferreira Pamela C.L. , Rosa‐Neto Pedro , Pascoal Tharick A. , de Bastiani Marco Antônio , Zimmer Eduardo R. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is characterized by the accumulation of amyloid‐β (Aβ) plaques and tau tangles in the brain, and neurotransmission dysfunctions. Indeed, our group recently demonstrated that the γ‐aminobutyric acid (GABA)ergic system is vulnerable to AD pathology in humans. However, whether this vulnerability is also present in AD rodent models is still unknown. Thus, we aimed to examine the GABAergic system in rodent models of amyloidosis and tauopathy.MethodWe systematically reviewed the literature following the PRISMA 2020 Statement. We searched PubMed and Web of Science from database inception to March 2023 for studies reporting GABA, glutamate decarboxylase (GAD) 65/67, GABA transporters (GAT), and GABAA and GABAB receptors in the brain of 3xTg‐AD, 5xFAD, APP/PSEN1, McGill‐R‐Thy1‐APP, Tg2576, TauPS2APP, TgCRND8, APP SweDI, and hAPP‐J20 AD rodent models. Then, we performed a random‐effects meta‐analysis of standardized mean differences (SMD) using the metafor and metaviz packages in R (FDR‐adjusted p‐value < 0.05).ResultThe search identified 3,631 articles and 27 met the inclusion criteria (Table 1 and Figure 1A). The systematic review showed decreased levels of GAD65/67 in the hippocampus, dentate gyrus, and hilus of TauPS2APP, hippocampus of TgCRND8, hippocampus and cortex of APP SweDI, and suprachiasmatic nucleus of Tg2576 mouse models. However, no differences in the cortex and cerebellum of APP/PSEN1 and hippocampus of hAPP‐J20 mice were found (Figure 1B). APP/PSEN1 had decreased vGAT in the hippocampus and increased in cortex (Figure 1B). GABAA receptors (Figure 1B) were decreased in APP/PSEN1 mice, while GABAB receptors (Figure 1B) remained unchanged. Due to insufficient number of studies, we meta‐analyzed only GABA. There were no differences in GABA levels in the cortex of APP/PSEN1 and Tg2576 mouse models (Figures 2A and 2B, p = 0.226 and 0.968, respectively), and in the hippocampal GABA levels in 5xFAD mice (Figure 2C, p = 0.924).ConclusionHere, we show decreased levels of GABAergic synthesis enzymes and GABAA receptors, and alterations in GABA transporters in AD rodent models. By contrast, there were no changes in GABA levels and GABAB receptors. Our results suggest that the AD rodent models recapitulate the GABAergic system vulnerability seen in human AD.
HSV1 infection elicits distinct immune responses in microglia and macrophages
Authors: Singal Chitra Mohinder Singh , Bradshaw Elizabeth M , Elyaman Wassim 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia. The neurotropic virus herpes simplex virus 1 (HSV1) has been linked to the pathogenesis of AD. While ∼65% of the US population is infected with HSV1, in the majority of cases the virus is dormant and infected individuals are asymptomatic. HSV1 infects immune cells such as macrophages and microglia, essential components of the innate immune response that are involved in neuroinflammation and neurodegeneration in AD.MethodMonocytes were isolated from PBMCs of healthy donors and differentiated into macrophages and monocyte‐derived microglia‐like cells (MDMi) in the presence of stimulatory cytokines for 6 days and 10 days respectively. The differentiated cells were infected with HSV1 and the cytokine profiles were measured by the LegendPlex assay. Additionally, fluorescently‐labeled Abeta1‐42 uptake was analyzed after 24 hours of infection.ResultThere was a significant increase in several inflammatory cytokines including IL‐4, IL‐6, TNFα, and IP‐10 in macrophages, whereas there was no significant change in MDMi after 4 or 24 hours of infection. Interestingly, Abeta1‐42 uptake in HSV1‐infected macrophages was decreased compared to their controls, whereas in HSV1‐infected MDMi, there was an enhancement of Abeta1‐42 uptake.ConclusionMacrophages exhibit an enhanced inflammatory response in contrast to microglia upon HSV1 infection and an opposite reaction in Abeta1‐42 uptake. Our findings indicate distinct responses of these two cell types to HSV1 infection, providing novel insight into our understanding of their unique tissue‐specific roles.
Investigating the Role of Mitochondrial DNA in Alzheimer’s Disease Biomarker Expression
Authors: Kemna Riley E , Weidling Ian , Kueck Paul J , Johnson Chelsea N , John Casey S. , Swerdlow Russell H , Wilkins Heather M , Morris Jill K 
Published: January 2025

AbstractBackgroundImpaired metabolic function and mitochondrial metabolism increase risk of Alzheimer’s Disease (AD) development, which is the leading form of dementia and one of the main causes of death in older adults. Altered mitochondrial function can reduce efficiency of cellular maintenance processes like mitophagy and proteostasis, leading to protein aggregation and cytotoxicity. Mitochondria differ from other organelles, as they have their own unique genetic component (mtDNA), which encodes proteins essential for mitochondrial translation and oxidative metabolism. Differences in mtDNA between individuals affect mitochondrial function and can increase risk of certain diseases; it is not well studied how mtDNA impacts AD pathology.MethodSH‐SY5Y cytoplasmic hybrid (cybrid) cell lines were generated using mtDNA from clinical research volunteers (n = 18 cognitively healthy (CH) older adults (mean age 73.8), n = 7 MCI (mean age 78.1), n = 10 AD (mean age 75.3)) enrolled in the Relationship of Energetics and Cognitive Trajectory study. Groups did not differ by sex. Cells were analyzed for protein expression by western blot, metabolic flux by Agilent Seahorse XF Analyzer, and protein secretion by ELISA. Plasma pTau217 (AlzPATH) and Aβ42 (N4PE) were assessed by Simoa HD‐X (Quanterix) to compare blood biomarker values with cellular outcomes.ResultCybrids from individuals with MCI and AD had elevated intracellular pTau217 (p = 0.033, p = 0.006 respectively). Cybrids from CH individuals secreted significantly more Aβ42 than those from individuals with AD (p = 0.002). Cybrid pTau217 and plasma pTau217 from the same subjects correlated significantly (p<0.001). Cybrids showed altered mitochondrial function by diagnostic group in all ETC complexes (p<0.05), and altered ETC complex expression in all proteins except Complex II, which is not encoded by mtDNA. Mitochondrial transcription factor A (TFAM) was significantly reduced in cybrids from AD individuals (p = 0.010) compared to those from CH subjects.ConclusionCytoplasmic hybrid cell lines generated with mtDNA from individuals with and without AD express diagnostic differences in novel AD biomarkers. This suggests that mitochondrial function, specifically that which is influenced by mtDNA, plays an imperative role in AD pathology. Ongoing research in the cybrid cell model will help elucidate how altered cellular and bioenergetic function contribute to AD etiology.