bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing Mild Behavioral Impairment and Its Relationship to Cognition in Community‐dwelling older Latinos from the Boston Latino Aging Study
Authors: Alcina Jorge , Munera Diana , Badillo‐Cabrera Alex L , Félix Nikole A Bonillas , Martinez Lusiana , Giudicessi Averi , Kaplan Elizabeth , Martinez Jairo E. , Vila‐Castelar Clara , Schwab Nadine A , Gomez Liliana A Ramirez , Catalan Marta Gonzalez , Saldana Daniel G , Gatchel Jennifer R. , Quiroz Yakeel T. 
Published: January 2025

AbstractBackgroundLatinos represent the fastest‐growing subpopulation of U.S. older adults and are 1.5 times more likely than non‐Latino Whites to be diagnosed with Alzheimer’s disease and related dementias. Mild Behavioral Impairment (MBI) describes emergence of new neuropsychiatric symptoms in individuals over 50, and is associated with late‐life depression, cognitive decline, and dementia. Despite its clinical relevance, the relationship between MBI and dementia risk is poorly understood in diverse populations. Here, we assessed MBI symptoms in older, community‐dwelling Latinos and examined the relationship of these symptoms to objective and subjective cognition.Method53 participants from the Boston Latino Aging Study were included, ages 55 years and older, 71% female, mean age 64.13 ± 6.79 years, mean education 12.30 ± 5.12 years, 49 cognitively unimpaired, and 4 with mild cognitive impairment. Objective cognition was measured using the Preclinical Alzheimer’s Cognitive Composite‐5 (PACC5). Neuropsychiatric symptoms were measured with the Mild Behavioral Impairment Checklist (MBI‐C; self‐report) domains of interest motivation and drive (IMD) and mood anxiety (MA). Subjective cognitive decline was assessed with the Cognitive Function Instrument (CFI; self‐report). Associations among MBI‐C domains, CFI, and cognition were examined using Spearman’s correlation, controlling for age, sex, and education.ResultMean total MBI‐C IMD domain score was 2.37 ± 3.59, mean total MBI‐C MA domain score was 2.45 ± 3.79 and mean total CFI score was 3.60 ± 3.51. Higher scores on the MBI‐C IMD were associated with higher CFI (r = .606, p < .001) and lower PACC scores (r = ‐.333, p = .015). Higher scores on the MBI‐C MA were associated with higher CFI (r = .384, p = .005). There were no other significant associations.ConclusionCommunity dwelling older Latinos endorsed MBI symptoms of IMD and MA captured using the MBI‐checklist self‐report. MBI IMD symptoms were associated with greater subjective decline and worse objective cognition. Findings underscore the need for screening and management of neuropsychiatric symptomatology in Latino/a/e/x adults, and that such symptoms can be captured using the MBI‐checklist. Future longitudinal studies with larger samples are needed to further understand cognitive effects of neuropsychiatric functioning in Latino/a/e/x and other minoritized groups.
Alzheimer’s disease pathologies are pathogen‐driven
Authors: Hyde Vanesa R. , Zhou Chaoming , Fernandez Juan R. , D'Aiuto Leonardo , Shemesh Or A. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is diagnosed via postmortem detection of extracellular amyloid beta (Aβ) plaques or oligomers and intracellular hyperphosphorylated tau. These canonical pathologies are key players in AD etiology. A complementary line of research suggests that common human pathogens serve as the initial seeding agents which facilitate the pathologies of AD.MethodLow (n = 8), mild (n = 9), and advanced (n = 10) Alzheimer’s disease brain samples were subjected to expansion microscopy (ExM), a tissue manipulation method which enables the imaging of biological samples at 40nm resolution. For our purposes, we used a novel version of ExM, decrowding expansion pathology (dExPath), which exposes inaccessible protein epitopes to antibody staining while enabling super resolution imaging. Observations from these human brain samples were then modeled using human iPSC neuronal 3D brain organoids and primary rodent cultures.ResultUsing dExPath, we visualized pathogen‐related proteins within our Alzheimer’s disease human brain samples. We discovered a clear colocalization between AD pathologies and pathogen‐derived proteins. When utilizing human brain organoids and rodent cultures as model systems for the human brain, we used pathogen infection to replicate the AD pathologies observed in the AD human brain.ConclusionOur results suggest that (1) neurons exposed to pathogens produce human AD pathologies and (2) AD pathologies may be antimicrobial. With these important roles in mind, our continued research focuses on isolating the mechanisms by which AD pathologies arise in response to common pathogens.
Exploring Protective Alleles in the Pathogenesis of Alzheimer’s Disease Using Mouse Models
Authors: Green Kim N. 
Published: January 2025

AbstractBackgroundSeveral variants have been identified that protect against the development of Alzheimer’s disease (AD). Understanding how these alleles convey protection inform us not only about the disease pathogenesis, but also guide therapeutic strategies. The UCI MODEL‐AD consortium has developed several protective alleles including a putative gain of function variant of ABCA7, and the APOE Christchurch variant. Here we have explored the impacts on these variants in animal models of AD to elucidate their mechanisms of protection.MethodCRISPR‐Cas9 was used to introduce either murine equivalent of ABCA7 V1613M, or APOE R136S (Christchurch) into the murine genome. Mice were then bred to homozygosity with either the 5xFAD mouse model of amyloidosis (Abca7 and Apoe), or the PS19 mouse model of tauopathy (Apoe), and then phenotyped across multiple ages using histology, biochemistry, and single cell spatial transcriptomics and proteomics.ResultAbca7V1613M variant dramatically reduced Ab production, protected against the formation of parenchymal plaques, and against increases in cortical and plasma neurofilament light chain. ApoeR136S produced divergent effects in glial populations depending on the stimulus. In 5xFAD mice it decreased plaque number and size, and increased the microglial response to the plaques, as evidenced by upregulated disease associated gene expression and protein expression. In PS19 mice tau pathology was mildly increased, but the glia response was markedly suppressed with ApoeR136S. Plasma neurofilament light chain was reduced by ApoeR136S in 5xFAD mice but not PS19 mice.ConclusionWe highlight that the primary mechanism of ABCA7 appears to be via the production of Ab and plaques. On the other hand, APOE Christchurch dramatically effects glial responses to pathology, notably increasing microglial reactivity to plaques, but markedly suppressing their response to tauopathy.
CD14 in Salt‐Sensitive Hypertension‐Related Cognitive Impairments
Authors: Tang Chengyun , Burns Emily , Border Jane J. , Bunn David , Cantwell Cameron , Gregory Andrew , Johnson Claire , Dong Yanbin , Roman Richard J. , Mattson David L , Fan Fan 
Published: January 2025

AbstractBackgroundHypertension is a leading risk factor for the development of Alzheimer’s disease and Alzheimer’s disease‐related dementia (AD/ADRD), which is closely linked with cerebral vascular inflammation and dysfunction. We previously found that high‐salt‐treated Dahl Salt‐Sensitive (SS) rats displayed blood‐brain barrier (BBB) leakage, astrocyte activation, neurodegeneration, and cognitive impairments. CD14 functions in the Toll‐like receptor 4 (TLR4) complex to initiate proinflammatory signaling events in response to LPS. CD14 levels were elevated in the brains of human and animal AD/ADRD models. This study aims to explore the vascular contribution of CD14 to AD/ADRD.MethodThe expression of Cd14 was assessed through RT‐PCR in primary cerebral vascular smooth muscle cells (VSMCs) isolated from TgF344‐AD rats, and the results were compared to cells from control rats. The myogenic response of the middle cerebral artery (MCA) was compared between SS (SSCD14+/+), SSCD14‐/‐, and SD rats with and without the induction of hypertension with 4% NaCl diets. BBB function was detected by the leakage of injected Evans blue and fibrinogen. Brain cytokine levels were detected with Bio‐Plex Rat Cytokine 23‐Plex Assay.ResultCd14 emerged as one of the significantly upregulated top genes in high‐salt‐fed SSCD14+/+ rats, with a subsequent three‐fold increase observed specifically in cerebral VSMCs of AD compared with control rats. Hypertensive SSCD14+/+ rats exhibited an impaired myogenic response of the MCA compared to normotensive SSCD14+/+ rats and SD rats fed with both high‐ and low‐salt diets. Notably, the deletion of CD14 demonstrated a remarkable trend in enhancing the myogenic response of the MCA in female SSCD14‐/‐ rats. Furthermore, high salt‐fed 24‐week SSCD14+/+ rats displayed BBB dysfunction. An augmented pan‐cytokine panel was observed in low salt‐fed 12‐week SSCD14+/+ rats, and this effect was magnified in high salt‐fed 24‐week SSCD14+/+ rats.ConclusionThese results collectively point to the potential role of CD14 in influencing vascular and immune responses, suggesting a link between CD14, hypertension, and cerebrovascular pathologies, particularly in the context of AD. Additional investigations are warranted to delve into the underlying mechanisms and ascertain whether CD14 exhibits a sex‐specific role in AD/ADRD.
Deep learning resolves cell‐type specific transcriptomes and unveils synaptic changes associated with neurodegeneration
Authors: Berson Eloise , Perna Amalia , Phongpreecha Thanaphong , Aghaeepour Nima , Montine Thomas J. 
Published: January 2025

AbstractBackgroundSingle nucleus RNA sequencing (snRNA‐seq) has revolutionized our ability to dissect transcriptional profiles in specific cell types. While nuclear sequencing enhances analysis robustness, it captures only 20‐50% of the cellular transcriptional information, limiting our comprehensive understanding of the cellular transcriptional ensemble. Therefore, we propose a computational approach to extract the cellular signal from bulk transcriptomic data from brain tissue, allowing us to investigate cell type‐specific transcriptomic programs underlying neurodegeneration.MethodWe adapted Cellformer ‐ a deep learning deconvolution model for ATAC‐seq data ‐ to RNA‐seq data. We leverage an excitotoxicity mouse model to detect cell‐type specific transcriptomic responses to injury.ResultCellformer accurately deconvoluted mouse brain bulk RNA into 9 major cell types (mean Pearson correlation of 0.97) (Figure 1A). Validation with single nucleus datasets reveals a significantly higher correlation (0.85) within the same cell type compared to different cell types (0.20) (P‐value < 1e‐6) (Figure 1B).We applied Cellformer to bulk RNAseq data obtained from both tissue and nuclei isolated from the hippocampus of the same mouse. We compared these cell‐type‐specific transcriptomic signatures between healthy mice and those exposed to a low dose of Kainic Acid (KA), a potent toxin for excitatory neurons (Figure 1C). More shared information was found between snRNA and deconvoluted RNA from nuclei compared to deconvoluted tissue (Figure 1D). Interestingly, differential expression analysis revealed a greater effect of low‐dose KA exposure on deconvoluted bulk tissue compared to nuclei, pinpointing synaptic and lysosomal signaling to excitatory neuronal cells (Figure 1E‐F).ConclusionIn this study, we introduce a computational approach utilizing the Cellformer algorithm to deconvolute bulk RNA sequencing data into cell‐type‐specific profiles, enabling in‐depth analysis of bulk RNAseq datasets. We demonstrate Cellformer’s proficiency in recovering cell‐type‐specific RNA expression patterns. By comparing deconvoluted profiles between healthy and injured hippocampi, we unveil insights previously masked by the limitations of snRNA‐seq, revealing intricate synaptic signaling dynamics. Cellformer offers the unprecedented ability to investigate extranuclear signaling in neurodegeneration.
Cognitive integrity in Non‐Demented Individuals with Alzheimer’s Disease Neuropathology is associated with preservation and remodeling of dendritic spines
Authors: Guptarak Jutatip , Scaduto Pietro , Tumurbaatar Batbayar , Jupiter Daniel , Taglialatela Giulio , Fracassi Anna 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent neurodegenerative disorder leading to dementia. The existence of individuals who remain cognitively intact despite presenting histopathological signs of AD, here referred to as “Non‐demented with AD neuropathology” (NDAN), suggests that some mechanisms are triggered to resist cognitive impairment. These individuals are distinguished by the presence of highly phagocytic microglia capable of clearing damaged synapses near plaques, mitigating further damage to axons and dendrites.MethodWe conducted a comparative analysis of dendritic spines morphology in the post‐mortem frontal cortex of NDAN individuals, AD patients, and age‐matched healthy controls. Our investigation included an in‐depth examination of synaptic structures both near and far from Aβ plaques, quantifying aspects such as dendrite length, diameter, spine density, and types. We expanded our research to investigate levels and distribution of Pin1, identified as a potential key player in the protective mechanisms against AD, influencing the regulation of dendritic spine formation and maintenance.ResultWithin 100 µm of Aβ plaques, significant synaptic toxicity was observed in all groups. However, in areas distal to plaques, NDAN exhibited significantly higher spine density than AD, suggesting the existence of a compensatory mechanism. We also measured the relative abundance of four spine types: mushroom, stubby, filopodia, and long thin, finding stubby spines to be the most common across all groups. Mushroom spines, the least dynamic, were significantly more abundant in AD compared to NDAN and control subjects. Conversely, NDAN individuals showed a higher density of more dynamic and plastic spines, such as filopodia and long thin spines, than AD. These findings suggest that the rearrangement of dynamic dendritic spines in NDAN may underlie the ability of these individuals to replace damaged synapses and preserve cognitive integrity. Furthermore, our results revealed lower expression of Pin1 in AD patients than control and NDAN groups, across regions, proximal and distal to plaques. This finding suggests that reduced Pin1 expression in AD may contribute to the compromised synaptic integrity and plasticity observed in these individuals.ConclusionThis study sheds light on the potential mechanisms allowing NDAN individuals to retain cognitive function despite AD pathology, offering insights for future therapeutic strategies.
Delivery of mRNA encoding an anti‐tau monoclonal antibody and engineered scFv intrabody results in functional antibody expression in neurons
Authors: Wongsodirdjo Patricia , Caruso Alayna C , Yong Alicia , Lester Madeleine , Vella Laura J , Hung Ya Hui , Nisbet Rebecca M 
Published: January 2025

AbstractBackgroundMonoclonal antibodies have emerged as a leading therapeutic agent for the treatment of disease, including Alzheimer’s disease. Such antibodies, however, are expensive and timely to produce and require frequent dosing regimens to ensure disease‐modifying effects. Synthetic in vitro‐transcribed mRNA encoding antibodies presents a promising alternative to conventional passive immunotherapy and overcomes the need to generate recombinant antibodies.MethodIn vitro‐transcribed (IVT) mRNA encoding a tau specific antibody as a full‐sized IgG and as a single chain variable fragment (scFv) was synthesised. Human neuroblastoma SH‐SY5Y cells and mouse primary hippocampal neurons were transfected with the IVT mRNA and antibody translation and ability to bind tau was assessed.ResultTransfection of mammalian cells with IVT synthesised mRNA results in the translation of a secreted tau‐specific IgG and an intracellular scFv intrabody. Importantly, both antibody formats engage tau, with the intrabody engaging tau directly within the cell cytoplasm.ConclusionIVT synthesised mRNA can be used to generate both functional full‐length IgG antibodies and scFv intrabodies targeting tau. Our study highlights the utility of mRNA as an inexpensive and versatile delivery platform for antibody therapeutics.
Amyloid β and cardiovascular risk factors promote endothelial cell apoptotic and mitochondrial stress, blood‐brain barrier dysfunction and angiogenesis impairment
Authors: Fossati Silvia 
Published: January 2025

AbstractBackgroundBrain endothelial cell (EC) stress, including that induced by vascular amyloid β (Aβ) deposits in cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD), contributes to cerebral blood flow impairment, blood brain barrier (BBB) damage, neurovascular unit dysfunction, microhemorrhages and hypoperfusion, precipitating neurodegeneration and neuroinflammation processes. Epidemiological and experimental evidence suggests that hyperhomocysteinemia (Hhcy) contributes to increasing AD risk as well as CAA pathology. However, the cellular and molecular mechanisms through which Aβ and Hhcy drive EC and BBB dysfunction, whether the molecular effects of these challenges are additive or independent, and possible therapeutic strategies, remain to be determined.MethodsOur work analyzed specific mitochondria‐ and death receptor‐mediated pathways in human cerebral microvascular ECs challenged with Aβ, high Hcy, or their combination. We also assessed the effects of these challenges, alone or combined, on the loss of BBB Resistance, junction proteins expression and structure and angiogenic activity, as well as the potential protective effects of carbonic anhydrase inhibitors.ResultsOur data demonstrates that Aβ activates death receptors 4/5 (DR4/5)‐ and mitochondria‐mediated apoptotic pathways in human cerebral microvascular ECs and promotes loss of mitochondrial respiratory function (OXPHOS). Hhcy potentiates the Aβ‐mediated activation of both the extrinsic and intrinsic mitochondria‐mediated apoptotic pathways, the loss EC barrier permeability, a deregulation of multiple junction proteins and the impairment in VEGF‐A/VEGF‐receptor signaling and angiogenic capabilities. However, Hhcy does not affect endothelial Aβ‐mediated OXPHOS impairment and metabolic defects. Carbonic anhydrase inhibitors successfully improve EC apoptotic outcomes and microvascular fitness both in vitro and in vivo.ConclusionThis data highlights new and specific molecular mechanisms that drive endothelial and BBB pathology in AD/CAA in the presence or absence of a comorbid cerebrovascular condition such as Hhcy. Moreover, we discovered a new potential therapeutic target, carbonic anhydrase, whose inhibition can revert the cerebrovascular effects of Aβ in vitro and in vivo.
Blood‐Brain Barrier Dynamics in Vascular Dementia: Unravelling the Tripartite Crosstalk between the Endothelium, Pericytes, and Microglia
Authors: Montagne Axel 
Published: January 2025

AbstractBackgroundSmall vessel disease (SVD) is a disorder of the brain’s microvessels and a common cause of dementia and stroke. Evidence links normal ageing features to SVD progression, involving endothelial activation, pericyte dysfunction, BBB failure, and microglia response. Here, we aim to examine this relationship through a series of translational investigations.MethodUsing microscopy, we quantified pericyte coverage and endothelial VCAM‐1 expression in young/aged mice and control/SVD cases. Pericyte and endothelial fluid biomarkers were analysed in a mild stroke cohort, correlating with SVD MRI markers. We employed a novel AAV targeting brain endothelial cells to overexpress (OE) Vcam1, Icam1, Selp and Sele in mice, shedding light on endothelial activation’s role in pericyte and BBB dysfunctions, but also the reciprocal influences with the microglial response. Finally, we genetically manipulated brain pericytes using our novel Atp13a5‐CreER mouse model, offering insights into their biological impact on endothelial and BBB functions.ResultAged mice and SVD cases showed reduced pericyte coverage and increased VCAM‐1 expression in microvessels (<10 µm). Biomarker analyses revealed associations between PDGFRB, PDGF‐BB, ICAM‐1, VCAM‐1, and E‐selectin concentrations with specific SVD manifestations. AAV experiments highlighted correlations between endothelial activation, pericyte dysfunction, reduced brain perfusion, and BBB breakdown, with distinct immune responses observed in AAV‐Vcam1OE and AAV‐Icam1OE groups. The Atp13a5‐CreER model unveiled diverse pericyte subtypes and their pro‐inflammatory impact on capillary endothelial cells.ConclusionOur approach underscores endothelial‐pericyte crosstalk’s crucial role in dementia. Integrating post‐mortem tissues, fluid biomarkers, viral manipulations, and mouse models enriches understanding, guiding potential therapeutic interventions in vascular dementia.
Evidence for impaired clearance leading to amyloid beta (Aβ) accumulation in the Alzheimer’s eye
Authors: Wijesinghe Printha , Hosseini Amir , Campbell Matthew , Xi Jeanne , Haynes Justin R , MacKenzie Ian R , Hirsch‐Reinshagen Veronica , Hsiung Ging‐Yuek Robin , Spiller Benjamin , Wadzinski Brian E , Pham Wellington , Matsubara Joanne A 
Published: January 2025

AbstractBackgroundAn imbalance between the production and clearance of amyloid beta (Aß) has emerged as a major cause of sporadic Alzheimer’s disease (AD). Retinal wholemount studies can identify cell‐specific involvement in Aß clearance mechanisms which cannot be accomplished in the brain ex vivo.MethodsEye cross‐sections of double transgenic (Tg, APP‐PS1) and non‐carrier sibling female mice (n = 16, 4 per group) at 3‐ and 9‐ month ages were probed with antibodies 6E10 (Aβ1‐16 amino‐acid residues, soluble and insoluble species), ionized calcium‐binding adapter molecule 1 (IBA1, microglia/macrophage), glial fibrillary acidic protein (GFAP, astrocytes), glutamine synthetase (GS, Müller cells) and aquaporin‐4 (AQP4, membrane water channel) using immunofluorescence. Wholemount neuroretinas of human AD (n = 10, mean age = 76.8, 6 females) and control (n = 10, 72.5, 5 females) donor eyes were probed with antibodies 12F4 (Aß1‐42 amino‐acid residues, misfolded oligomers), IBA1, GFAP, GS, AQP4 and Ulex europaeus agglutinin (UEA‐l, vascular endothelium). Finally, a nanobody (soluble Aß oligomer against human Aβ1‐42 peptide) conjugated with near‐infrared dye (NIR‐E3) was probed with 12F4 using a nanobody staining protocol in wholemount retinas.ResultsIn eye cross‐sections, a significant increase in 6E10, IBA1, GFAP and AQP4 was found in the older vs. younger Tg mice, suggesting Aβ accumulation resulted in gliosis and AQP4 mislocalization. In contrast, a significant reduction for 6E10 in the older vs. younger non‐carrier siblings, suggests the existence of an effective Aβ clearance mechanism (e.g., macrophages and glymphatic drainage) as IBA1 and AQP4 levels were increased. In wholemount neuroretinas, macroglia degenerations (GFAP, GS and AQP4) which form the inner limiting membrane were prominent in human AD eyes, suggesting defective ocular glymphatic systems. The microglia phenotype was different from its resting stage in AD eyes, however, due to complexity of IBA1 positive resident microglia, and macrophages including monocytes, perivascular macrophages, pericytes and hyalocytes, it is difficult to define microglia phenotype, particularly activated and ameboid types between AD and control eyes. Interestingly, NIR‐E3 positive perivascular macrophages (but negative to 12F4), indicating soluble Aβ clearance were predominantly found within the blood vessels of control donor eyes.ConclusionThis study confirms the existence of different impaired clearance mechanisms in human AD eyes.