bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of menopause in a mouse model of Alzheimer’s disease and comorbid metabolic disease
Authors: Abi‐Ghanem Charly , Salinero Abigail E , Kelly Richard D , Rybka Krystyna A , Gannon Olivia J , Belanger‐Mayer Kasey M , Thrasher Christina A , Groom Emily , Smith Rachel , Brooks Heddwen L , Zuloaga Damian G , Zuloaga Kristen L 
Published: January 2025

AbstractBackgroundAbout two‐thirds of those with Alzheimer’s disease (AD) are women, most of whom are post‐menopausal. Menopause accelerates the risk for dementia by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid‐life metabolic disease (e.g. obesity, diabetes, or prediabetes) is a well‐known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. The goal of this study was to determine the effects of menopause and high fat diet on metabolic, cognitive, and pathological outcomes in the AppNL‐F knock‐in mouse model of Alzheimer’s disease.MethodTo model menopause, we used an accelerated ovarian failure model (4‐vinylcyclohexene diepoxide, VCD). This ovary‐intact model is more clinically relevant than an ovariectomy model, as mice go through a perimenopausal period. At 3 months of age, AppNL‐F mice were administered VCD or vehicle (oil) and then placed on either a control diet (10% fat) or a high fat diet (HF; 60% fat) and maintained on the diets until 10 months of age.ResultMenopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. Menopause had independent effects on some serum metabolic health biomarkers (insulin) and synergic effects with HF diet on other markers (glucagon). An interaction between HF diet and menopause led to an impaired episodic‐like memory. When examining the underlying pathology, we did not detect any changes in amyloid levels, however, we observe changes in neurogenesis and microglia response.ConclusionMenopause and HF diet have independent and synergistic effects on metabolic, cognitive and pathological aspects of AD. This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD.
Genotype specific microbiome divergence of humanized APOE 2, 3, and 4 mice after microbiome standardization
Authors: Aries Michelle L , Cook Makayla , Perez Anna , Gasvoda Hope , Gooman Ashley , Hensley‐McBain Tiffany 
Published: January 2025

AbstractBackgroundApolipoprotein E (ApoE) is a lipid cargo binding protein that has three variants in humans, ApoE 2, 3, and 4. The ApoE 4 allele is the greatest known genetic factor for sporadic Alzheimer’s Disease. The gut microbiome (GMB) is a key essential to health, and bacterial dysbiosis can lead to poorer outcomes for disease states and an increase in microbiota and their metabolites in the peripheral. The intersection of sex, ApoE, inflammation, and gut microbiota is incompletely understood. Previous studies in humans and humanized APOE mice have demonstrated APOE‐genotype differences in the GMB. However, the vast majority of these studies used methods unable to resolve the bacteria to the genus or species level. It remains unknown if APOE genotype is a driver of GMB divergence over time and how GMB changes with age and sex in the context of APOE genotype.MethodsIn this study, humanized targeted replacement mice with either APOE 2, 3, or 4 (APOE‐TR) were purchased from JAX. Each APOE‐TR male was bred with one of the same two C57BL/6 sisters to standardize microbiomes across lines and monitor divergence based on APOE allele inheritance. Stool samples were collected from the parents at breeder set up and 6 months old and from heterozygous pups at wean, and 6 months old and will be collected every 6 months, including from the homozygous F2 generation. Stool was assessed via shallow shotgun sequencing to increase the sequencing depth and enable species and strain level taxonomic resolution.ResultsThe pup’s microbiome resembled each other at wean despite genotype. However, by 6 months old, GMB diverged based on sex and APOE genotype, with genotype‐specific alterations including changes in Lachnospiraceae (p<0.001 by PERMANOVA).ConclusionsThese are the first data demonstrating GMB divergence over time driven by APOE genotype. Studying genotype specific changes in GMB and how specific APOE‐specific bacteria impact inflammatory responses can aid in understanding and potentially treating some of the underlining diseases associated ApoE 4 allele including cardiovascular disease and Alzheimer’s Disease (AD).
ABCA7‐dependent Neuropeptide‐Y signalling is a resilience mechanism required for synaptic integrity in Alzheimer’s disease
Authors: Tayran Huseyin , Yilmaz Elanur , Bhattarai Prabesh , Min Yuhao , Wang Xue , Ma Yiyi , Nelson Nastasia , Kassara Nada , Cosacak Mehmet I , Dogru Ruya M , Reyes‐Dumeyer Dolly , Reddy Joseph S. , Qiao Min N , Flaherty Delaney , Yang Zikun , Gunasekaran Tamil Iniyan , Teich Andrew F , Vardarajan Badri N. , Tosto Giuseppe , Is Ozkan , Ertekin‐Taner Nilüfer , Mayeux Richard , Kizil Caghan 
Published: January 2025

AbstractBackgroundGenetic variations have emerged as crucial players in the etiology of Alzheimer’s disease (AD), and they serve for a better understanding of the disease mechanisms; yet the specific roles of these genetic variants remain uncertain. Animal models with reminiscent disease pathology could uncover previously uncharacterized roles of these genes. Therefore, we generated zebrafish models for AD variants to analyze the in depth molecular and biological functions of these variants.MethodUsing CRISPR/Cas9, we generated a knockout model for abca7, orthologous to human ABCA7. We performed single cell transcriptomics and analyzed the altered genes and molecular pathways in zebrafish. We leveraged data from multiethnic AD cohorts at Mayo Clinic and Columbia University, to perform genetic association studies, co‐expression analyses, in silico interaction mapping, family based variant segregation analyses and epigenetic association studies, and the functional and histological studies in zebrafish.ResultThe abca7± zebrafish reduced astroglial proliferation, synaptic integrity, and microglial response after Aβ42 toxicity. We found that the abca7 loss‐of‐function (LOF) reduced neuropeptide Y (npy) expression as well as Brain‐derived neurotrophic factor (bdnf) and Nerve growth factor receptor (ngfr). Human brain analysis showed reduced NPY in AD, regulatory interaction between NPY and BDNF, genetic variants in NPY associated with AD, and segregation of variants in ABCA7, BDNF and NGFR in families. ABCA7 variants altered the epigenetic codes in NPY, BDNF, and NGFR promoter regions. Human results paralleled with zebrafish findings to indicate an evolutionarily conserved disease mechanism through ABCA7‐NPY signalling axis. NPY administration to zebrafish rescued the phenotypes in abca7 knockout, suggesting a true biological relevance.ConclusionOur results demonstrate a previously unknown link between ABCA7 and NPY in regulation of synaptic integrity and neurogenesis in AD. We propose that ABCA7‐dependent NPY is a resilience factor in vertebrate brains, and this reserve mechanism is impaired in AD.
Uncovering hidden sensorimotor memories in mice with Alzheimer’s disease relevant pathology
Authors: Santi Andrea , Moore Sharlen , Wang Aaron , Lawlor Jennifer , Fogelson Kelly , Kuchibhotla Kishore 
Published: January 2025

AbstractBackgroundAlzheimer’s disease is a progressive form of dementia where cognitive capacities deteriorate due to neurodegeneration. Interestingly, Alzheimer’s patients exhibit cognitive fluctuations during all stages of the disease. Though it is thought that contextual factors are critical for unlocking these hidden memories, understanding the neural basis of cognitive fluctuations has been hampered due to the lack of behavioral approaches to dissociate memories from contextual‐performance. Our previous work demonstrated that interleaving reinforced with non‐reinforced (‘probe’) trials in an auditory go/no‐go discrimination task, allows us to distinguish between acquired sensorimotor memories and their contextual expression.MethodHere, we used this approach, together with two‐photon calcium imaging on behaving APP/PS1+ mice, to determine whether amyloid accumulation impacts underlying sensorimotor memories and/or contextual performance in an age dependent manner.ResultImportantly, peripheral auditory function, measured using auditory brainstem responses, was similar between WT and APP/PS1+ mice. We found that while contextual‐performance is significantly impaired in 6‐8mo APP/PS1+ mice compared to age‐matched controls, these animals have preserved sensorimotor memories. However, 12mo APP/PS1+ mice show deficits in both domains. The impairment found in the young adults was accompanied by overall network suppression, compensatory disinhibition, reduced stimulus selectivity, and aberrant behavioral encoding in neurons of the primary auditory cortex that was partially restored in probe trials. These impairments were concentrated near Aβ plaques and were recapitulated with a reinforcement learning model that accounts for contextual signal changes. Model parameters affected were those governing contextual scaling and behavioral inhibition.ConclusionThese results suggest that Aβ deposition impacts circuits involved in contextual computations before those involved in acquiring knowledge and that neural circuit interventions (modulating inhibition) may hold promise to reveal hidden memories.
Detection of differences between Amyloid‐Positive and Negative Participants based on Their Driving Behavior during On‐Ramp Merging
Authors: Danda Sai Santosh Reddy , Murphy Yi Lu , Maher Amanda Cook , Persad Carol C , Bross Jordan R , Flynn Emma , Koeppe Robert A. , Giordani Bruno 
Published: January 2025

AbstractBackgroundCognitive changes affecting performance are subtle in early stages of Alzheimer’s Disease (AD) and may emerge only with more complex tasks. Driving is a highly challenging instrumental activity of daily living, requiring higher order integration of cognitive skills. For example, driving on freeway entrance ramps requires heightened cognitive engagement such as rapid responses to fast‐emerging traffic and sudden speed changes, combining sensory processing and manipulative actions. This study analyzes quantitative attributes related to driving behaviors and physiological responses during freeway on‐ramp, merging, and post‐merge stages from fixed‐course drives taken by older amyloid‐positive and amyloid‐negative participants.MethodWe analyzed data from 21 amyloid‐positive (66‐81 years old) and 21 amyloid‐negative (65‐85 years old) consensus diagnosed cognitively normal participants in the University of Michigan’s Driving and Physiological Responses study. All 42 drivers navigated the same freeway on‐ramp, recording vehicle signals, physiological signals, and videos. Focus was on the on‐ramp, divided into ROI1 (On‐Ramp), ROI2 (Acceleration Lane), and ROI3 (10 seconds after merge). Nine driving attributes, including average speed, acceleration, and physiological signals (Heart Rate, Electrodermal activity, Blood Volume Pulse, and Skin Temperature), were assessed in each ROI. Group differences between amyloid‐positive and negative individuals were analyzed via independent sample t‐tests or Mann Whitney U tests, as appropriate.ResultIn ROI1 amyloid‐positive participants exhibited higher average speeds (T = 2.15, p = 0.03) and lower speed changes (U = 103, p = 0.003) compared to amyloid‐negative participants. ROI2 analyses revealed increased speed variability (T = 2.79, p = 0.007) and average acceleration (U = 138, p = 0.04) in amyloid‐positive participants. Amyloid positive participants also trended toward traveling further distance in the ROI2 acceleration lane (T = 1.73, p = 0.09) and toward having increased average heart rate in ROI3 (U = 152, p = 0.08).ConclusionThese results offer insights into possible cognitive‐based decision‐making differences and potential physiological markers for early cognitive decline during challenging real‐world driving activities such as on‐ramp merging in persons at high risk for cognitive decline and AD. These findings deepen our understanding of the nuanced relationship between cognitive factors and driving behaviors. Future experiments aim to classify groups based on naturalistic drive on‐ramp merging using machine learning for more accurate classification.
Neuropathologic investigation of phospho‐threonine 217 provides neurobiologic insights into the intersection between amyloid‐β and tau
Authors: Murray Melissa E. 
Published: January 2025

AbstractBackgroundPosttranslational modifications of tau occurs throughout disease progression in Alzheimer’s disease (AD) and non‐AD tauopathies. Phosphorylation of tau (p‐tau) in the proline‐rich region is a common target of immunohistochemical and fluid biomarker evaluation. P‐tau217 has emerged as a highly accurate fluid biomarker in AD, however elevated levels are not observed in non‐AD tauopathies.MethodA neuropathologic overview of tau lesions immunopositive for phosphorylation at threonine 217 (pT217) in AD and non‐AD tauopathies will be provided in a didactic format with an emphasis on disease spectrum. The relevant biomarker literature with neuropathologic validation will be highlighted.ResultImmunohistochemical evaluation of pT217 in AD demonstrates immunostaining in pretangles and mature tangles, but rarely observed in ghost tangles. Neuritic pathology in AD with pT217 immunopositivity include both neuropil threads and dystrophic neurites that cluster in neuritic plaques. Lesions in non‐AD tauopathies are also immunopositive for pT217, as exampled by immunolabelling of argyrophilic grains and tufted astrocytes. Digital pathology measures of pT217 and amyloid‐β will be compared with plasma p‐tau217 levels to contextualize the relationship. Additionally, the relationship between neurotransmitter hub vulnerability will be explored to consider upstream factors that may influence soluble tau release into plasma.ConclusionNeuropathologic insights discussed through visual and quantitative comparison of insoluble phospho‐tau accumulation and soluble levels of p‐tau217 may provide neurobiologic insights into the intersection between amyloid‐β and tau in the human brain.
Defining the role of perineuronal nets in Alzheimer’s disease pathology
Authors: Barahona Rocio A. , Salgado Giovanna Rubio , Kono‐Soosaipillai Aashna R. , Green Kim N. 
Published: January 2025

AbstractBackgroundCondensed extracellular matrix structures called perineuronal nets (PNNs) preferentially enwrap the soma and stabilize proximal synapses of parvalbumin‐expressing inhibitory neurons in the cortex, serving as a protective barrier against neurotoxins. While PNN structural integrity declines in the healthy aging brain, this reduction is exacerbated in Alzheimer’s disease (AD). In the 5xFAD mouse model of amyloidosis, the elimination of microglia prevents reductions in PNN, suggesting microglia are responsible for the over‐degradation of PNNs observed in AD. Additionally, microglial elimination before plaque onset impairs plaque formation, suggesting microglia are critical for plaque development. We observe that plaque formation is inhibited in areas of PNN deposition, and therefore postulate that PNNs are protective against plaque accumulation and synaptic/neuronal damage.MethodsExpression of aggrecan protein (ACAN) is required for PNN formation, therefore we crossed ACAN floxed mice with Nestin‐Cre and 5xFAD to selectively prevent PNN production from all neurons. Mouse brains were harvested for the following 4 groups: wild‐type (WT) control, WT PNN knockout (KO), 5xFAD control, and 5xFAD PNN KO at 4 months and 8 months of age with n = 4‐6 per sex per group. One hemisphere was processed for immunohistochemistry and the other hemisphere for spatial transcriptomics.ResultsAt the 8‐month timepoint, immunohistochemical quantification of AmyloGlo+ plaques shows a significant increase in both total plaque volume and total plaque number in the cortex of the 5xFAD PNN KO group compared to the 5xFAD control group. Notably, plaque pathology spread to the upper cortical layers normally occupied by PNNs. Additionally, we know that the microglial response to plaques is important for protecting against dystrophic neurites and preventing the spread of tau pathology. Therefore, we investigated the microglia and plaque interaction and found that the absence of PNNs impairs the microglial response to plaques, suggesting that the ECM composition is integral to proper microglial sensing and responses.ConclusionsIncreases in plaque load and an impaired microglial response to plaques by 8 months in the PNN KO group suggest PNNs protect against plaque accumulation and appear to be essential for proper microglial response to plaques.
Systems genetic dissection of Alzheimer’s disease brain gene expression networks
Authors: Zhao Pinghan , Fadel Omar El , Le Anh , Mangleburg Carl Grant , Wu Timothy , Dhindsa Justin , Amoh Bismark K , Marella Aditi Sai , Li Yarong , Seyfried Nicholas T , Levey Allan I. , Liu Zhandong , Al‐Ramahi Ismael , Botas Juan , Shulman Joshua M 
Published: January 2025

AbstractBackgroundIn Alzheimer’s disease (AD), changes in the brain transcriptome are hypothesized to mediate the impact of neuropathology on cognition. Gene expression profiling from postmortem brain tissue is a promising approach to identify causal pathways; however, there are challenges to definitively resolve the upstream pathologic triggers along with the downstream consequences for AD clinical manifestations.MethodWe have functionally dissected 30 AD‐associated gene coexpression modules using a cross‐species strategy in Drosophila melanogaster models. First, integrating longitudinal RNA‐sequencing and fly behavioral phenotyping, we interrogated unique and shared transcriptional responses to amyloid beta (Aβ) plaques, tau neurofibrillary tangles, and/or aging, along with potential links to progressive neuronal dysfunction. In order to confirm causal modules and pinpoint AD network drivers, we next performed systematic in vivo genetic manipulations of 357 conserved, prioritized targets to identify modifiers of Aβ‐ and/or tau‐induced neurodegeneration. We subsequently partitioned candidate causal subnetworks, which were further validated based on human or Drosophila genetic evidence.ResultOur results highlight hundreds of conserved, differentially expressed genes mapping to AD regulatory networks. Our systematic screening identified 144 tau/Aβ modifiers. We discovered an up‐regulated, causal network that is significantly enriched for both AD risk variants and markers of immunity / inflammation, and which promotes Aβ and tau‐mediated neurodegeneration based on fly genetic manipulations in neurons. By contrast, a promising synaptic regulatory network is strongly downregulated in human AD and is enriched for loss‐of‐function suppressors of Aβ/tau, consistent with a potential compensatory response to glutamatergic excitotoxic brain injury.Conclusionour cross‐species, systems genetic approach establishes a putative causal chain linking AD pathology, large‐scale gene expression perturbations, and ultimately, neurodegeneration.
Microtubule‐Associated Protein Tau (MAPT) in non‐transgenic and transgenic P301S mouse lenses
Authors: Moncaster Juliet A , Minaeva Olga , Goldstein Lee E 
Published: January 2025

AbstractBackgroundWe previously discovered that Aβ accumulates in the cortical/supranuclear region of the lens in people with Alzheimer’s Disease (AD) (Goldstein et al., 2003) and Down Syndrome (DS; (Moncaster et al., 2010). We also demonstrated Aβ in the Tg2576 APP Swedish mutation AD mouse model (Moncaster et al., 2022). Another protein that is involved in AD is Microtubule‐Associated Protein Tau (MAPT). Tau is expressed in the brain and becomes hyperphosphorylated in AD eventually forming neurofibrillary tangles. Tau has previously been reported to be expressed in the mouse lens (Bai et al., 2007; Zhao et al., 2013) but the results vary depending on the mouse model and antibodies used. Here we investigated whether tau protein was expressed in non‐transgenic mouse lenses and in a transgenic tau mutant (P301S) and whether there was a cataract phenotype.MethodP301S tau mutant transgenic and non‐transgenic mice were bred and maintained at Boston University. Breeder mice were purchased from The Jackson Laboratory, Bar Harbor, ME. Male and Female transgenic and non‐transgenic mice were sacrificed throughout their lifespan at ages 3‐12 months. Mice were perfused with phosphate buffered saline, lenses were isolated and then imaged under two different sources of light using a Nikon camera and a custom‐adapted Zeiss stereophotomicroscope. Lenses were then snap frozen and analyzed by Western using a panel of tau antibodies.ResultP301S transgenic and non‐transgenic mouse lenses all expressed tau during their lifespan when analyzed by Western blot. P301S transgenic lenses demonstrated an additional higher molecular weight band compared to the non‐transgenic mice. No cataract phenotype was observed in transgenic or non‐transgenic mouse lenses.ConclusionThere was no overt difference in lens phenotype between the P301S transgenic and non‐transgenic mice. However, the banding pattern observed by Western blot for P301S transgenic mice compared to non‐transgenic was different. Our data suggest the P301S tau mutation affects tau processing but does not result in a cataract phenotype. Based on our current and previous results, the data suggests that Aβ may play a more significant role than tau in lens pathology in AD.
Characterizing Ligands that have Immunomodulatory potential at the Choroid Plexus in Neurodegenerative Disease
Authors: Bakshi Bhavya , Rosenbalm Katelyn , Tiemeyer Michael 
Published: January 2025

AbstractBackgroundInflammatory cells play a key role in the pathophysiology of AD and other neurodegenerative disorders. Glycans are known to mediate inflammatory cell activation and migration yet very little is understood about the expression of glycans, glycoproteins, and other glycoconjugates at the CP which serves as a gateway for peripheral immune cells into the brain. In a familial AD mouse model, we observed increased expression of Siglec‐F‐recognized glycans on CP epithelial cells. Siglec‐F is part of the Siglecs family, that modulate the immune responses by binding sialylated glycans.MethodTo explore Siglec interactions with CP cells, we explored glycomics and glycoproteomics in CP papilloma cells (HIBCPP), which mimic the CP environment. We collected proteins secreted from HIBCPP cells and performed western blot analysis using Siglec‐Fc recombinant proteins to identify counter‐receptors. Secreted glycoproteins carrying Siglec‐F and ‐9 (the human functional orthologue of mouse Siglec‐F) ligands were observed at molecular weights that were similar to ligands harvested from choroid plexus organoid lysates. To characterize the nature of the glycans on the secreted counter‐receptors, we used specific endo‐glycosidases to digest the glycoproteins and performed biorthogonal analysis.ResultAnalysis revealed keratan sulfate ligands for Siglec‐9 and Siglec‐F. Proteomics identified Galectin‐3 binding protein (Gal‐3BP) as a major carrier whose function in CP and CNS biology is unknown. In cancer and viral infections, Gal‐3BP has been shown to modulate immune and inflammatory responses, indicating that it may serve similar immunomodulatory effects in the CNS and at the CP via specific glycan‐mediated interactions at cell surfaces.ConclusionThe identification of Gal‐3BP and the glycans it carries as Siglec counter‐receptors creates new opportunities to explore the potential inflammatory role of glycans in neurodegenerative diseases like AD.