bluuebunny/crossref_metadata_2025_split huggingface dataset:
DAP12 deficiency increases resilience to tau toxicity by modulating oligodendrocyte state and myelination in tauopathy mice despite elevated tau inclusions
Authors: Luo Wenjie , Chen Hao 
Published: January 2025

AbstractBackgroundDAP12 (DNAX‐activation protein 12 or TYROBP) functions as a pivotal adaptor, facilitating signal transmission from surface immune receptors on microglia, including TREM2—a known risk gene for Alzheimer’s disease (AD). Previous studies showed that DAP12‐deficient mice exhibit resistance to tau toxicity in a tauopathy model, manifesting reduced brain inflammation and improved cognition, despite increased tau pathology. However, the precise mechanism underlying how DAP12 deficiency enhances resilience to tauopathy remains elusive.MethodWe conducted bulk transcriptomic analysis of the cortex and single‐nuclei RNA sequencing (snRNAseq) of the hippocampi from female homozygous P301S tauopathy mice at six months of age. Subsequent analysis involved various immunohistochemical and biochemical assays, such as multiplex bead‐based immunoassays, western blotting, and immunostaining.ResultDeletion of DAP12 led to an increase in tau inclusions but remarkably prevented tau‐induced neuroinflammation and synapse loss. DAP12 deletion disrupted the transition of microglia from a homeostatic to a disease‐associated state induced by tau, reversing neuronal transcriptomic changes. SnRNAseq analysis unveiled a tau‐inducible cluster of oligodendrocytes characterized by gene signatures resembling an intermediate state, marked by a comprised myelination function. Strikingly, DAP12 deletion significantly impeded tau‐induced formation of intermediate oligodendrocytes and promoted increased myelination in tauopathy mice.ConclusionOur findings reveal a critical role of microglial DAP12 signaling in mediating tau toxicity, enhancing our understanding of the intricate interactions among neurons, microglia, and oligodendrocytes in AD and tauopathy. Future studies will delve into dissecting the specific ligands and receptors mediating microglial interactions with other cell types.
Kv1.3 regulation of brain immune function in vitro and in vivo
Authors: Bowen Christine A , Nguyen Hai Minh , Lin Young Qingyang , Bagchi Pritha , Natu Aditya , Xiao Hailian , Espinosa‐Garcia Claudia , Kumar Prateek , Wulff Heike , Seyfried Nicholas T , Rangaraju Srikant 
Published: January 2025

AbstractBackgroundIn neurodegenerative disease such as Alzheimer’s disease and stroke, the brain transitions to pro‐inflammatory profile, where microglia and T‐cells in the brain have increase inflammatory profiles, along with increased Kv1.3 potassium channel abundance. Pharmacological blockade of Kv1.3 in vivo reduces Aβ pathology and dampens pro‐inflammatory function. To identify Kv1.3 channels regulation of neurodegenerative models, we examined the protein‐protein interactome of Kv1.3 channels in vitro, and Kv1.3 deletion in vivo.MethodTurboID, a biotin ligase, was fused to N‐term or C‐term of Kv1.3 and stably‐transduced in BV2 microglial cells and Jurkat T‐cells. Mass spectrometry (MS) of biotinylated proteins, under resting and lipopolysaccharide (LPS)‐treated conditions, was performed to identify N and C‐terminal interactomes. Kcna3(Kv1.3)‐floxed mice were generated and crossed to CMV‐Cre mice to produce a Kv1.3 KO mouse. Kv1.3 KO mice were then exposed to an LPS challenge for 4 days or (middle cerebral artery occlusion) MCAO. Changes in transcriptomic levels were evaluated via RNA‐seq of microglia and brain.ResultProximity‐based proteomics of BV2‐Kv1.3‐TurboID microglia identified distinct N‐term (n = 991) and C‐term Kv1.3 (n = 849) interactors. Kv1.3 N‐terminus interacts with plasma membrane proteins (e.g. Cars1, Psma2) and mitochondrial trafficking proteins (TIMM23 and 50). The C‐terminal interactors are modified by LPS‐stimulation (C3, STAT1, OASL1) (n = 36), and dependent on a PDZ‐binding motif (SNX3, ND3, n = 70). Jurkat T‐cell N‐terminal interactors are ER‐processing and plasma membrane (e.g. TXNL1, ACTN3, CASP3), whereas C‐terminal interactors are protein processing (e.g. EHD1, VAMP2). About 400 proteins are shared between the T‐cell and microglial Kv1.3 interactors. Kv1.3 KO mice have reduced Kv1.3 mRNA and channels in brain and microglia. PCA and differential expression highlight microglial inflammatory LPS response and an MCAO, which is reduced in brain overall. Further analysis comparing Kv1.3 KO and WT will be evaluated.ConclusionWe identified novel N and C‐terminal domain‐specific and context‐dependent interactors of Kv1.3 channels in immune cells. While the N‐terminus regulates protein processing and localization, the C‐terminus regulates immune signaling during LPS‐stimulation. Some interactions are dependent on the PDZ‐binding domain. KO of Kv1.3 impacts microglial signatures under neuroinflammatory states. microglial transcripts. Identifying microglial Kv1.3 influence in AD may provide knowledge on future biomarkers and treatments.
Glial changes as result of cerebral amyloid angiopathy progression
Authors: Krick Katelynn E. , Johnson Sherika N. , Rogers Colin B , Sudduth Tiffany L. , Weekman Erica M. , Wilcock Donna M. 
Published: January 2025

AbstractBackgroundCerebral Amyloid Angiopathy (CAA) occurs at the intersection of Alzheimer’s disease and vascular contributions to cognitive impairment and dementia (VCID). In the human brain it occurs when amyloid beta (Aβ) aggregates in small/medium‐sized cerebral blood vessels, which contribute to hypoperfusion and cognitive decline by altering vascular function and integrity. The current study seeks to track the progression of CAA and associated neuroinflammation and glial cell changes in Tg2576 mice.MethodTg2576 mice were aged to 8‐, 14‐, 20‐, and 27‐months and assessed for CAA pathology via histology. Gene expression was evaluated in hippocampal tissue by qPCR and posterior cortex by nanostring (ncounter Mouse Neuroinflammation and Mouse CVD Pathophysiology panels; in progress) to compare 8‐ and 20‐month APP and wildtype groups. Protein expression was evaluated via digital spatial profiling in the same APP mice, grouped by age or CAA presence compared to wildtype controls. CAA presence was defined as Aβ surrounding lectin‐positive vessels. Regions of interest were categorized as either positive or negative for CAA based on this criterion.ResultCongophillic plaque deposition along the vasculature increased in width, length, and area in a time dependent manner in both the frontal cortex and hippocampus. Astrocyte marker GFAP and proinflammatory receptor TNFR1 gene expression both increased at 20 months compared to 8 months in the APP group. Of the protein profile assessed (Mouse Neural Cell Profiling and Mouse Glial Cell Subtyping), the most consistent changes were found in astrocyte markers. Both Aldh1l1 and S100B were increased at 20 months compared to 8 months of age in both APP and WT mice. GFAP protein expression was found to increase with both age and CAA.ConclusionThis study showed increased vascular amyloid deposition and astrocyte gene and protein expression over time, further supporting a role for astrocytes in etiology and/or reaction to CAA.
The prefrontal cortex of homozygous ε3 APOE carriers with local African ancestry has fewer transcripts compared to individuals with local European ancestry
Authors: Santos Nascimento , Naslavsky Michel Satya , Haddad Luciana Amaral , Suemoto Claudia Kimie , Ferretti‐Rebustini Renata Eloah de Lucena 
Published: January 2025

AbstractBackgroundhe APOE gene has been identified as a major risk factor for late‐onset Alzheimer’s disease (AD) and has three most common alleles: ε2, ε3, and ε4. The presence of the ε4 allele confers a dose‐dependent increased risk for the disease (odds ratio 12.9 for homozygous individuals and between 3.2 and 4.2 for heterozygous individuals). The most prevalent form of Alzheimer’s disease has a multifactorial etiology where factors such as age and sex and the ancestry around the APOE gene is relevant to the disease’s risk. Individuals of African‐American local ancestry have a reduced risk of developing AD compared to European whites and Asians.Methodthis project aims to quantitatively characterize the role of different local ancestry in the different APOE genotypes using 49 post‐mortem frontal cortex tissues with different genotypes and local ancestry combinations (ε3ε3 European‐European, African‐African and ε3ε4 European‐European, African‐African, European‐African, African‐European) and to associate them with the expression of this gene using allele‐specific and non allele‐specific molecular markers and RT‐qPCR techniques.ResultWithin the heterozygous groups, we observed a constant reduced mean expression of the ε4 allele compared with ε3, but these differences did not achieve statistical significance, as didn’t the total APOE expression between these groups with different ancestries. Although we identified a significant difference (p‐value = 0.039) between the homozygous individuals of different ancestry (ε3 European ε3 European versus ε3 African ε3 African), the total expression of individuals of European local ancestry was twice superior to that of African ancestry (European mean: 0.416; African mean: 0.218).ConclusionThese data support the hypothesis that the lower expression of APOEε3 may be part of the explanation for the reduced African risk of DA in homozygous individuals.
Associations between brain metabolism and financial capacity in Alzheimer’s disease
Authors: Michel Luca Marie , Borelli Wyllians Vendramini , Schlickmann Thomas Hugentobler , Gehres Sarah Wehle , De Bastiani Marco , Bieger Andrei , Povala Guilherme , Machado Luiza Santos , Zimmer Eduardo R. 
Published: January 2025

AbstractBackgroundIndividuals with early stages of cognitive decline face a significant stagnation in their financial capacity, leading to a decrease in quality of life. However, whether changes in brain function are associated with financial capacity remains unclear. Here, we evaluate the association between financial capacity and brain glucose metabolism.MethodIndividuals across the Alzheimer’s disease (AD) clinical continuum with complete FCI‐SF total scores and FDG‐PET imaging data were selected from the ADNI dataset. We performed a Pearson correlation with 79 brain regions of interest, extracted using the ICBM152 atlas, and the total FCI score. A multiple linear regression model was fitted to assess the relationship between FCI and different brain regions, corrected for age, gender, and education. Analyses were adjusted by Bonferroni, with p considered significant if < 0.05.ResultA total of 1364 individuals were analyzed in this study (44% female, mean age 73.4). There were 26 brain areas in which glucose metabolism significantly correlated with FCI scores (adjusted p < 0.05, Figure 1A). The highest correlation coefficients were bilaterally located in the Caudate Nucleus and Fornix (r > 0.3, Figure 1A). The regression model demonstrated multiple significant brain regions (adjusted p < 0.05, Figure 1B). The left Fornix (β = 14.8, Figure 1C) and right Fornix (β = 13.7, Figure 1D), as well as the left Caudate Nucleus (β = 14.15, Figure 1E) and right Caudate Nucleus (β = 12.66, Figure 1F), had the highest significance (adjusted p < 0.001).ConclusionWe observed positive associations between regional brain glucose metabolism and the FCI‐Score. Thus, our findings suggest a relationship between metabolic patterns, serving as an index of brain function, and the financial capacity of individuals.
Anti‐Amyloid Immunotherapy for AD: A Potential Link between ARIA and Complement
Authors: Bathini Praveen , Schilling Stephan , Lemere Cynthia A. 
Published: January 2025

AbstractBackgroundAnti‐amyloid antibodies have been associated with amyloid‐related‐imaging‐abnormalities (ARIA) in AD patients, causing vasogenic edema and microhemorrhages, especially in ApoE4 carriers. Here, we compared recombinant 3D6‐L, a murine version of bapineuzumab, and an isotype control IgG2a monoclonal antibody (mAb) to investigate potential mechanisms, including complement activation, involved in these side effects (ARIA‐H or microhemorrhages) following passive immunization.MethodPlaque‐rich 16.5‐mo‐old APP/PS1dE9; hApoE4 mice were treated weekly (i.p.) for 13 weeks with ∼15 mg/kg (500 µg) 3D6‐L or IgG2a (n = 5 per group). amyloid‐beta (Aβ), ApoE, and complement C3 levels from the brain homogenates were determined using ELISA and microhemorrhages with Prussian‐blue staining. Additionally, 20‐month‐old APP/PS1dE9;hApoE4 mice underwent a shorter 7‐week passive immunization (500 µg/week 3D6‐L or IgG2a, n = 3 per group) followed by RNAseq to evaluate differentially expressed genes (DEGs) in the brain and FACS sorted CD31+ vascular endothelial cells. Pathological analyses are underway.ResultIn the 13‐week study, 3D6‐L significantly reduced guanidium‐HCL‐soluble Aβx‐42 and Aβx‐40; ApoE levels showed a trend for reduction. Soluble C3 levels rose significantly, correlating with increased microhemorrhages in leptomeninges and large blood vessels in the cortex and cerebellum. In the shorter immunization study, brain transcriptome revealed significant upregulation of many genes related to complement activation (C1qa, C1qb, Cq1qc, C4b, C3), glial activation (GFAP), IgG receptor activity (Fcgr1, Fcgr2, Fcgr3), lysozyme (Lyz2) and Galectin‐3 (LGALS3). Endothelial cell transcriptome revealed increased expression of genes involved in inflammation and lipid metabolism. Some of these include IL1r1, Cxcl12, Lcn2, Abca1, CH25H, vWf, and Cfh. Notably, 3D6‐L induced microhemorrhages, microbleeds, and our preliminary analysis indicate an increase in cerebral amyloid angiopathy (CAA)‐associated complement activation and endothelial inflammation. Based on our RNAseq data, we are investigating potential markers including, iC3b, C5b‐9, MMP‐9, and vWf involved in immunotherapy‐associated microhemorrhages.ConclusionPassive immunization against Aβ using 3D6‐L amplified CAA‐associated complement activation and altered expression of genes related to extracellular matrix degradation and vascular inflammation. The observed microhemorrhages appear to result from complement‐mediated vascular inflammation induced by the binding of 3D6‐L to vascular amyloid. These findings suggest potential biomarkers or targets for therapeutic interventions in the context of anti‐Aβ immunization.
Identifying partial haplotypes that are associated with late‐onset Alzheimer disease
Authors: Climer Sharlee 
Published: January 2025

AbstractBackgroundHaplotypes are patterns of nucleotides in close proximity along a chromosome that are passed together across time and space. These patterns dictate the specific properties of proteins produced and the regulation of this production. General haplotype inference methods phase all provided genotypes within the region of interest into two haplotypes without regard for the ages or evolutionary impact of each mutation, thus force the inclusion of more recent and/or neutral mutations. Alternatively, BlocBuster (www.blocbuster.org) identifies partial haplotypes that include only highly correlated nucleotides using a unique correlation metric that anticipates heterogeneity of the individuals and an expanded network scaffolding. Given the heterogeneous nature of late‐onset Alzheimer disease (AD), we utilize BlocBuster to identify genetic risk patterns.MethodWe analyzed WGS_Omni2.5M_20140220 data for chromosome 19 provided in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database(adni.loni.usc.edu). The data were arbitrarily split into 70% Discovery (42 AD, 69 MCI, 87 control) and 30% Validation (18 AD, 29 MCI, 37 control). BlocBuster builds a network model using AD, MCI, and control individuals (without labeling), where nodes represent SNP alleles and edges represent pairwise correlations between alleles, extracts clusters of inter‐correlated SNP alleles representing a partial haplotype, then tests the pattern for association with the given phenotype.ResultBlocBuster identified two patterns that are significantly associated with AD in both the Discovery and the independent Validation datasets(Table 1). The first represents a variant of the RUVBL2 gene and the second is a large allelic combination beginning upstream from DIRAS1 and spanning across SLC39A3, SGTA, and THOP1(Table 2).ConclusionThe network model was created blindly using all individuals in the Discovery dataset, yet two of the clusters were significantly associated with AD risk in both the Discovery and Validation data. Interestingly, THOP1 is a zinc‐activated oligopeptidase that is capable of cleaving beta‐amyloid precursor protein into amyloidogenic peptides. Furthermore, SLC39A3 is predicted to enable zinc transport across the membrane, SGTA is suggested to play a role in aggregate formation in neurodegenerative diseases, and methylation of DIRAS1 is associated with AD risk. These results identify interesting signatures that may pinpoint specific AD biological pathways, motivating further validation efforts.
Deterioration of neuronal primary cilia in Alzheimer’s disease
Authors: Miller Emiko , Bambakidis Peter , Reitsch Niklas , Templin Phoebe , Vázquez‐Rosa Edwin , Bud Zea , Yu Youngmin , Fujioka Hisashi , Cheng Feixiong , Bykova Marina , Koh Yeojung , Sridharan Preethy , Cintrón‐Pérez Coral , Franke Kathryn , Pieper Andrew A. 
Published: January 2025

AbstractBackgroundEmerging evidence links Alzheimer’s disease (AD) to dysfunction of the primary cilium, a historically overlooked organelle that serves as the neuron’s antenna. All neurons harbor a single primary cilium that projects from the membrane to sense changes in the extracellular environment. Primary cilia dysfunction leads to a group of diseases called ‘ciliopathies’, which are associated with reduced hippocampal and cortical mass, as well as neurocognitive impairment. Ciliopathies place individuals at higher risk for dementia, and genetic defects in primary cilia proteins in mice lead to a phenotype resembling AD.MethodTo establish whether primary cilia are disrupted in AD, we conducted unbiased analysis of differentially expressed genes (DEGs) in postmortem brains from AD subjects, compared to age‐matched non‐AD controls. Using the DAVID bioinformatics platform, we performed a gene ontology analysis on the significantly changed genes related to the primary cilia. Additionally, we performed immunohistochemical and electron microscopy analysis of primary cilia in the brains of 5xFAD mice, a mouse model of AD. Primary cilia were visualized with antibodies to adenylate cyclase 3 (AC3).ResultOur systematic survey of the published literature in AD revealed very few studies to date of cilia, compared to other organelles. Our analysis of DEGs in postmortem human AD brains revealed a high prevalence of DEGs intricately linked to processes that maintain primary cilia structure and function. Furthermore, the proportion of DEGs related to the primary cilia was comparable to that observed in other heavily implicated organelles in AD, such as mitochondria. Additionally, we found that the gene ADCY3, which encodes for primary cilia‐specific adenylate cyclase 3 (AC3), is significantly downregulated in human AD brains. Primary cilia are dependent on AC3, and loss of functional AC3 in primary cilia reveals consequences reminiscent of symptoms associated with AD. We observed reduced levels of AC3 throughout the hippocampus of 5xFAD mice. Additionally, electron microscopy analysis of primary cilia revealed shortened primary cilia length in advanced stages of disease in 5xFAD mice.ConclusionAC3 loss and primary cilia deterioration may drive progression of AD pathology and provide a basis for development of a new neuroprotective therapy for AD.
White blood cell types and tau deposition in the medial temporal lobe of cognitively normal older adults
Authors: Braskie Meredith N , Lee Noelle , Davison Marylan , Tennant Victoria R , Wheeler Koral V , Tubi Meral A , Terner Jamie , Hand Maxwell W , Toga Arthur W. , O'Bryant Sid E. , Yaffe Kristine 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) and other dementia risk may be influenced by the immune function and associated with several white blood cell type counts. In cognitively normal Black, Hispanic, and non‐Hispanic white older adults we related three white blood cell types previously associated with AD risk to tau positron emission tomography (PET) values in the medial temporal lobe (MTL), where tau accumulates early. We assessed whether amyloid positivity moderated this relationship.MethodWe evaluated 430 cognitively normal older adults (Table 1) from the Health & Aging Brain Study‐Health Disparities (HABS‐HD) study who had: 1) MTL tau PET values 2) counts for three types of white blood cells: absolute monocytes, lymphocytes, and neutrophils and 3) global brain amyloid values. Tau was assessed using [18F]PI‐2620 PET standardized uptake value ratios (SUVR; inferior cerebellar gray matter reference region). The MTL region included FreeSurfer‐derived hippocampus, amygdala, and entorhinal cortex. Global amyloid ([18F]Florbetaben PET) was calculated as mean SUVR in frontal, cingulate, lateral parietal, and lateral temporal cortex using a whole cerebellar reference region. Multiple linear regression related log‐transformed absolute counts of white blood cell types to MTL tau, covarying for age, sex, education, ethnicity (Hispanic or non‐Hispanic) and race (Black or white) with white blood cell type by amyloid positivity (global amyloid SUVR >1.08) interactions modeled on MTL tau.ResultAmyloid‐positivity interacted with lymphocytes on MTL tau (p = 0.02); in amyloid‐positive participants there was a stronger relationship between higher lymphocytes and more MTL tau (β = 0.21) than in amyloid‐negative participants (b = 0.02). There was a trend level interaction between amyloid positivity and monocytes on MTL tau (p = 0.06); in amyloid‐positive participants there was a stronger relationship between lower monocytes and more MTL tau (β = ‐0.23) than in amyloid‐negative participants (β = ‐0.10). Older age (β = 0.40, p<0.001), female sex (β = 0.11, p = 0.02), Black race (β = 0.20, p<0.001), and Hispanic ethnicity (β = 0.22, p<0.001) also were associated with greater MTL tau.ConclusionHigher lymphocyte and lower monocyte values were associated with more MTL tau, particularly in amyloid‐positive older adults suggesting a complex relationship between the peripheral immune system and early AD neuropathology.