bluuebunny/crossref_metadata_2025_split huggingface dataset:
LOAD1 and LOAD2: Longitudinal characterization of mouse models carrying human‐relevant risk factors for late‐onset Alzheimer’s disease
Authors: Bernabe Cristian S , Kotredes Kevin P , Pandey Ravi S , Carter Gregory W , Sasner Michael , Oblak Adrian L , Howell Gareth R , Lamb Bruce T. , Territo Paul R ,   MODEL‐AD consortium
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia, yet the effectiveness of disease‐modifying interventions is inconclusive. Although exceptional progress in our understanding of AD neuropathology has been made via transgenic mouse models bearing familial mutations, they often fail to recapitulate the disease progression of late‐onset AD (LOAD). To address this, MODEL‐AD has developed LOAD1 and LOAD2 mouse models which carry the most common human‐relevant risk factors for AD. In‐depth, longitudinal characterization through aging will reveal useful insights to develop novel treatments for LOAD.MethodAPOEε4 and Trem2*R47H, two risk factors for LOAD, were incorporated into C57BL/6J mice to produce the double homozygous LOAD1 model, whereas LOAD2 also contains humanized amyloid‐beta (Aβ) yielding a triple homozygous model. Cohorts of LOAD1 and LOAD2 mice were aged on multiple sites to 4‐, 12‐, 18‐, and 24‐month timepoints and both sexes were characterized using behavior, PET/CT, cytokines/Aβ40‐42 immunoassays, and astrocyte and microglia immunohistochemistry.ResultAlthough aging LOAD1 and LOAD2 mice did not display significant cognitive deficits, there was a genotype‐dependent increase of plasma levels of Ab40‐Ab42. Both sexes across genotypes showed significant region‐dependent increases in brain glycolysis and tissue perfusion between 4 and 24 months. Consistent with the increased brain metabolism and perfusion neurovascular coupling phenotypes, immunopathology analyses revealed an age‐dependent increased number of astrocytes across genotypes that was restricted to cortical regions. Similarly, the total number of activated microglia was slightly elevated in cortical regions of aging mice, even though the results were only marginally significant. Lastly, aged LOAD1 mice displayed increased brain levels of the pro‐inflammatory cytokine IL‐12p70 when compared to LOAD2. Longitudinal analyses of brain and plasma cytokines are still in progress.ConclusionLOAD1 and LOAD2 PET/CT analyses revealed phenotypes which are in line with imaging profiles of patients at prodromal stages of AD. Combined with the astrogliosis, these strains are promising venues that can be used to test early disease‐modifying therapeutic targets and can also serve as platform to incorporate additional human‐relevant AD risk factors.
Exploring the neuroprotective effects of fenchone against ICV‐STZ‐induced Sporadic Alzheimer’s disease in rats: Investigating neuroinflammation, oxidative stress and mitochondrial dysfunction as potential mechanisms
Authors: Mini Mini 
Published: January 2025

AbstractBackgroundSporadic Alzheimer’s disease (sAD) is the most prevalent type of dementia, characterized by progressive neurodegeneration. Intracerebroventricular (ICV) administration of streptozotocin (STZ) serves as a model for sAD, inducing neurodegeneration through oxidative stress, apoptotic damage, mitochondrial dysfunction, and neuroinflammation. Fenchone, a monoterpenoid, has been reported to possess neuroprotective properties by attenuating oxidative stress, acetylcholinesterase activity, mitochondrial dysfunction and neuroinflammation. This study aimed to explore the neuroprotective potential of fenchone in ICV‐STZ‐induced sAD and its associated pathology in wistar rats.MethodTo assess the neuroprotective potential of fenchone (20, 40, and 80 mg/kg) and galantamine (2 mg/kg) were given orally in ICV‐STZ‐induced wistar rats for 21 days. Behavioral assessments, including locomotor activity, Morris water maze, and novel object recognition, were conducted. Subsequently, rats were sacrificed on the 21st day, hippocampus and pre‐frontal cortex were prepared for the quantification of oxidative stress, apoptotic markers, mitochondrial complex activity, acetylcholinesterase activity, and neuroinflammatory markers.ResultIn‐vivo, studies revealed that fenchone treatment ameliorated ICV‐STZ‐induced cognitive deficits in the Morris water maze and novel object recognition tests. Furthermore, fenchone arrested oxidative stress (glutathione (GSH), catalase, superoxide dismutase (SOD), and lipid peroxidation (LPO)), decreased apoptotic damage (caspase 3) and neuroinflammation (TNF‐α and IL‐6) in the cortex and hippocampus regions of the brain. Additionally, normalization of mitochondrial enzyme complexes and acetylcholinesterase activities was observed.ConclusionThis study demonstrates the neuroprotective effects of fenchone in the ICV‐STZ rat model, alleviating oxidative stress, apoptotic damage, reversing mitochondrial dysfunction, acetylcholinesterase activity, and neuroinflammation in brain.
A new pipeline for converting neuroimaging data into computational models of ISF/CSF processes
Authors: Elbert Donald L. 
Published: January 2025

AbstractBackgroundA multitude of high‐quality imaging modalities exist that provide structural data at unprecedented levels of detail. Tissue ultrastructure greatly influences the rate of transport of proteins and other molecules that contribute to neurodegeneration. However, our ability to model flow and diffusion processes in the brain lags behind the quality of the neuroimaging data. Here, a new framework will be presented for converting neuroimaging data into computational fluid dynamics (CFD) models in a scalable manner suitable for high performance computing. TEM data from the Allen Institute will illustrate its capabilities.MethodsSegmented TEM images were downloaded from the MicronsExplorer public storage cache. Segmented image stack volumes (4 × 4 × 4 µm) were converted into surface meshes using the Lewiner Marching Cubes algorithm. Convection and diffusion along the surface of individual cells was modeled. After each timestep mass was allowed to exchange between neighboring cells, implemented on a high performance computing cluster using the MPI protocol on 40 or more computing cores. Multiple volumes were analyzed simultaneously, with updates of the flux between cells in different volumes occurring at each time step. These steps were performed with new custom CFD code written in C and Julia.ResultsSegmented z‐stacks of TEM data from the MICrONS Explorer website were downloaded in 4 × 4 × 4 µm blocks, which typically contain ≈500 distinct cells (Fig. 1A&B). The meshing algorithm leads to perfect matching between adjacent cells (Fig. 1C). The convection‐diffusion equations are solved, modeling flow/diffusion of solutes between cells (Fig. 1D&E). Equations are solved for all ≈500 distinct cells in parallel, with concentrations at matching faces re‐balanced at each time step (Fig. 2A&B). A manager‐worker MPI model allows for solution on an arbitrary number of cores (Fig. 2C). The interfaces between cell surfaces across volumes are also perfectly matched, allowing for adjustment of the flux of mass between volumes at each timestep (Fig. 2D).ConclusionsA new modeling framework is described for solution of transport equations on high performance computing clusters for any imaging modality that produces segmented z‐stacked images.
Older African Americans with Type 2 Diabetes have Lower Frontal and Medial Temporal Lobe Cognitive Function
Authors: Napoleon Darian A. , Fausto Bernadette A. , Piaszczynska Wiktoria , Tawe Fanyu Hercules , Budak Miray , Malin Steven K. , Fitzgerald‐Bocarsly Patricia , Gluck Mark A. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is sometimes characterized as “type 3 diabetes” because hyperglycemia impairs cognitive function, particularly in the medial temporal lobe (MTL) and prefrontal regions1,2. Further, both AD and type 2 diabetes (T2D) disproportionately impact African Americans. Although people with T2D are generally suggested to have lower episodic memory and executive function, limited data exist in older African Americans. Thus, we examined the effect of T2D on frontal and MTL cognitive functions in older African Americans.MethodEighty‐four older cognitively unimpaired African Americans (70.88±6.31y; 74% female) were recruited from the Pathways to Healthy Aging in African Americans study at Rutgers University–Newark. Individuals were categorized as having T2D using HbA1c (≥6.5%; n = 48) or non‐T2D (≤6.4%; n = 36). Participants completed a cognitive battery of frontal and MTL cognitive tasks: motor speed of processing (Trail Making Test–Part A); set‐shifting (Trail Making Test–Part B); and generalization of prior learning (Concurrent Discrimination and Transfer Task). ANCOVAs were used to examine differences between groups on cognitive performance with age, sex, and education as covariates.ResultParticipants with T2D demonstrated poorer motor speed of processing (p = 0.046, η2p = 0.05) and set‐shifting performance (p = 0.05; η2p = 0.047) than those without T2D. Moreover, participants with T2D demonstrated lower generalization of prior learning accuracy (p = 0.05; η2p = 0.047).ConclusionT2D lowers frontal and MTL function in cognitively unimpaired older African Americans with when compared to those without diabetes. Further investigation into the overlapping pathologies of AD and T2D are warranted to optimize interventions aimed at prevention of AD in older adults.
β‐amyloid impaired mitochondrial proteostasis through the impact on LONP1
Authors: Wang Wenzhang 
Published: January 2025

AbstractBackgroundMitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Mitochondrial proteostasis regulated by chaperones and proteases in each compartment of mitochondria is critical for mitochondrial function, and it is suspected that mitochondrial proteostasis deficits may be involved in mitochondrial dysfunction in AD.MethodAn unbiased screening of intraneuronal Aβ42 protein‐interactome was perfumed in AD cell culture. Mitochondrial protease activity and mitochondria functions were investigated in AD models in vitro and in vivo, while cognitive behaviors of AD transgenic mice were analyzed by memory capacity tests.ResultWe identified LONP1, an ATP‐dependent protease in the matrix, as a top Aβ42 interacting mitochondrial protein through and found significantly decreased LONP1 expression and extensive mitochondrial proteostasis deficits in AD experimental models both in vitro and in vivo, as well as in the brain of AD patients. Impaired METTL3‐m6A signaling contributed at least in part to Aβ42‐induced LONP1 reduction. Moreover, Aβ42 interaction with LONP1 impaired the assembly and protease activity of LONP1 both in vitro and in vivo. Importantly, LONP1 knockdown caused mitochondrial proteostasis deficits and dysfunction in neurons, while restored expression of LONP1 in neurons expressing intracellular Aβ and in the brain of CRND8 APP transgenic mice rescued Aβ‐induced mitochondrial deficits and cognitive deficits.ConclusionThese results demonstrated a critical role of LONP1 in disturbed mitochondrial proteostasis and mitochondrial dysfunction in AD and revealed a novel mechanism underlying intracellular Aβ42‐induced mitochondrial toxicity through its impact on LONP1 and mitochondrial proteostasis.
Distinct Methylomic Signatures Emerge in the Prefrontal Cortex Following Amyloid‐Beta Immunisation, with Altered Expression Patterns in Astrocytes
Authors: MacBean Lachlan Ford , Smith Adam , Boche Delphine , Lunnon Katie 
Published: January 2025

AbstractBackgroundPost‐mortem neuropathological examinations following the first active immunotherapy strategy (AN‐1792, Elan Pharmaceuticals, 2000) for Alzheimer’s disease (AD) have evidenced amyloid‐β (Aβ) plaque clearance and increased microglial phagocytic activity in immunised individuals. This study characterises the epigenetic profiles of individuals who underwent Aβ immunotherapy with the aim of discovering novel therapeutic targets and biomarkers.MethodDNA and RNA was isolated from post‐mortem prefrontal cortex tissue of immunised cases (n = 14) who received varying doses (ug) and number of doses during the trial period. DNA methylation was quantified using methylation arrays and the raw intensity values processed and normalised for subsequent statistical analysis to identify differentially methylated positions (DMPs) across the genome associated with Aβ immunotherapy. Additional analyses included cell enrichment analysis of the top most differentially expressed genes.ResultAfter correcting for common known variables (age, sex, cell type composition) and batch effects, a DMP located within CUGBP Elav‐like family member 2 (CUGBP2) at the genome‐wide significance level (P < 9.00E−08) was associated with Aβ immunisation. 10 DMRs were further associated with immunisation, with nine regions consisting of ≥ 3 CpG sites and having a Sidak‐corrected P < 0.05. In addition, a similar model performed on the RNA‐sequencing data showed no overlap with the aforementioned DMRs, but did exhibit significant gene expression alterations associated with astrocytes.ConclusionIndicating better inflammatory markers can help inform of effective preventative care strategies for elders. This study provides evidence for altered epigenetic processes in the pathophysiology of AD and identifies novel processes specific to Aβ immunotherapy. The next step for this project includes analysing genotyping data to identify potential methylation quantitative trait loci and further our understanding of the relationship between single nucleotide polymorphisms and methylation changes.
Neuropathological Mapping of Synaptic Vesicle Protein 2A in Human Brains: Ground Truth for PET Interpretation in Neurodegenerative Diseases
Authors: Bavarsad Mahsa Shanaki , Spina Salvatore , Seeley William , Rabinovici Gil D. , Grinberg Lea T. 
Published: January 2025

AbstractBackgroundSynaptic loss, a key indicator of cognitive decline in neurodegenerative diseases, lacks a clinical biomarker, but emerging PET‐scan tracers targeting synaptic vesicle protein 2A (SV2A) show promise. The current understanding of regional changes in neurodegenerative disorders and the distribution of SV2A in the human brain is quite limited. This knowledge gap presents challenges when assessing the feasibility of using SV2A tracers in therapeutic applications. To assess the potential of SV2A tracers in diagnosis and therapy monitoring and enhance SV2A PET data interpretation, we quantified SV2A and synaptophysin (SYP) density in postmortem human brain tissue. We included subjects with different neurodegenerative conditions and healthy controls (CT) and mapped five susceptible regions.MethodHistological slides (8µm) of 28 cases (Table 1) underwent immunohistochemistry SV2A and synaptophysin. Slides were scanned using a calibrated Zeiss Axioscan. Synaptic density was quantified using the Zen software in 40 cortical ROIs (20 white & 20 gray matter) per area/case. Values were normalized by white matter intensity. Moreover, we used frozen tissue from a subset of the same cases and areas to perform Western blot (WB) using the same antibodies against SV2A and (SYP), plus Beta‐actin. Intensity values were measured by using Image J software.ResultThe immunohistochemical analysis revealed decreased SV2A density across all diseases, exhibiting distinctive regional and disease‐specific patterns (Fig. 1). However, the correlation between SV2A and synaptophysin density was weak (Fig. 1). Western blot analysis similarity showed a distinctive reduction of SV2A with regional and disease‐specific patterns. The correlation with synaptophysin was moderate (Fig. 2).ConclusionIn conclusion, our findings demonstrate reduced SV2A density and protein levels in disease categories corresponding to specific regional vulnerabilities, corroborating SV2A as a reliable marker of brain tissue integrity. Nevertheless, the observed correlation between SV2A and synaptophysin changes was less robust than anticipated, prompting questioning into whether SV2A changes accurately reflect synaptophysin alterations. Additional studies comparing the utility of both markers in predicting clinical decline, metabolic shifts, and the progression of neurodegeneration are warranted.
Temporal dynamics of microglial neuroprotection during chronic Aß ‐treatment in human iPSC‐derived 3D neurospheres
Authors: Wendt Stefan , Lin Ada J. , Ebert Sarah , Brennan Declan , Cai Wenji , Macvicar Brian , Nygaard Haakon B. 
Published: January 2025

AbstractBackgroundMurine models of Alzheimer’s Disease (AD) have resulted in numerous discoveries leading to a better understanding of AD pathogenesis but results poorly translated to novel treatment options. Over the past years, iPSC‐derived human neuronal cultures have been developed to better model AD in vitro. One key hallmark of AD is the presence of insoluble Aß plaques in the brain. To model this microenvironment a 3D tissue culture is needed to successfully study the complex neuron‐glia‐Aß interaction. Here we present human iPSC‐derived 3D neurospheres for modelling severe amyloidosis through chronic Aß application.MethodNeurospheres were formed from iPSC‐derived neuronal progenitor cells and expanded, differentiated and maintained for 60 days. Microglia were added to readily populate the tissue for the last 10 days of culture. Oligomeric Aß42 (∼35 nM) was added to the media chronically for 3 or 5 weeks. Neuronal activity was measured using GCAmP6f live imaging. Aß induced oxidative stress was quantified by using roGFP. Single nuclei RNA sequencing (NucSeq) was performed to obtain transcriptional data.ResultNeurospheres, consisting of neurons and astrocytes, display robust synchronized neuronal activity. Aß treatment induces the formation of plaque‐like aggregates in the tissue within days. We found dysregulated neuronal activity and oxidative stress after 2‐3 weeks while severe neuronal loss can be observed after 4‐5 weeks. Infiltrating microglia display high phagocytic activity towards Aß and successfully reduced extracellular Aß deposits, loss of neuronal activity and oxidative stress when added early during the Aß treatment. Microglia transferred late during Ab exposure ameliorated neuronal death but fail to recover neuronal function or reduce oxidative stress at this time point. NucSeq allows identifying the transcriptional profile of each cell type and will be used to study cell type specific changes after Aß exposure with or without microglia.ConclusionWe here present a human 3D cell culture model allowing the formation of neurospheres and a chronic Aß stimulation protocol to mimic amyloidosis as a novel human AD in vitro model. Transplanting microglia at different time points during culture allows to study the temporal dynamics of neuroprotective properties of microglia presenting a unique novel approach to reveal new potential therapeutic pathways.
Higher Gene Expression Of Dynein Heavy Chains In The Dorsolateral Prefrontal Cortex Predict Lower Neuropathology Burden And Better Cognitive Outcomes In Individuals With Alzheimer’s Disease
Authors: Lucero Esteban M , Brunetti Tonya , Chial Heidi J , Potter Huntington , Gignoux Chris 
Published: January 2025

AbstractBackgroundMotor proteins play a key role in neuronal functions and morphology that are important for learning and memory. We have previously reported that increased expression KIF11/Kinesin‐5 overrides Aß‐mediated effects on dendritic spine density and long‐term potentiation in a mouse model of Alzheimer’s disease (AD), effectively maintaining cognitive function in the face of Aß pathology. Here, we evaluated the association of key AD phenotypes with mRNA expression levels of a select set of Dynein motor proteinsMethodWe utilized measurements of gene expression, AD neuropathology burden, and cognition provided by the ROS/MAP study to determine whether an association exists between AD phenotypes and expression of genes for cytoplasmic and axonemal dynein heavy chains. Neuropathology burden was determined through immunohistochemistry. Z‐scores from the raw scores of 19 cognitive tests were used to determine global cognition. Neuropathology burden and global cognition measurements were provided by Rush Alzheimer’s Disease Center. Measurements of gene expression in the dorsolateral prefrontal cortex (DLPFC) (n = 634) were determined through an established RNAseq analysis pipeline (Logsdon et al., 2019, syn8456638;syn8456629) and made available to us through the Accelerating Medicines Partnership in Alzheimer’s Disease Target Discovery and Preclinical Validation knowledge portal (syn3219045). Associations of gene expression with neuropathology and cognition were determined through multiple linear regression and mixed effects models covarying for age, sex, education, and post‐mortem intervalResultIn participants with AD (CERAD score > 2), higher gene expression levels of DYNC1H1 and DNAH1 in the DLPFC predicted better cognitive performance longitudinally (p = 0.03 and p = 0.00197, respectively) and at the last visit prior to death (p = 8.701e‐05 and p = 3.571e‐05, respectively). Higher expression of DYNC1H1 and DNAH1 were also associated with lower amyloid pathology (p = 0.0001257 and p = 2.356e‐07, respectively) and tau tangles (p = 2.356e‐07 and p = 2.659e‐09, respectively)ConclusionOur finding that AD participants with higher expression levels of DYC1H1 and DNAH1 show reduced cognitive decline and decreased AD pathology suggest a potential beneficial effect of these motor proteins on AD progression. Based on the functions of these motor proteins, these findings warrant further studies to identify potential mechanisms underlying this association. Potential mechanisms include facilitation of higher rates of phagocytosis or neuronal lysosomal degradation of Aß