bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early hippocampal hyperexcitability precedes synaptic reorganization in mouse models of amyloidosis
Authors: Ray Ajit , Loghinov Iulia , Barth Alison L 
Published: January 2025

AbstractBackgroundThe failure of amyloid plaque‐reducing drugs to reverse cognitive decline in Alzheimer’s disease (AD) has suggested that treatments might be more effective in early or prodromal stages of the disease. However, the progression of synaptic and circuit changes associated with Aβ overexpression, particularly at very early ages, have not been well‐characterized. Indeed, evidence from both human and animal studies indicates that brain structure and function might be altered months to years before plaques can be detected.MethodHere we used quantitative, fluorescence‐based methods for synapse detection in CA1 pyramidal neurons (Pyr) to investigate the interaction between abnormal circuit activity, measured by Fos‐immunoreactivity (Fos‐IR), and synapse reorganization in mouse models of amyloidosis.ResultUsing a fluorescently‐tagged molecule (FAPpost) for both excitatory and inhibitory synapses, we find that Aβ overproduction is associated with early synapse gain and loss, depending on the dendritic compartment. Juvenile APP/PS1 and Tg2576 transgenic mice both show a reduction in synapses at the apical tuft of CA1 Pyr and an increase in synapse density along the apical dendrite, which receives inputs from CA3 in animals. These effects were observed at just 6 weeks of age, well before cognitive deficits and amyloid plaques can be detected. Elevated hippocampal activity precedes this reorganization, with elevated Fos‐IR in both CA3 and CA1 present at weaning.ConclusionThese data indicate that elevated Aβ may initiate abnormal activity and subsequently input‐specific synapse plasticity. Taken together, our findings indicate that sustained amyloidosis drives heterogeneous and progressive circuit‐wide abnormalities.
Shared transcriptomic similarities between mouse and C. elegans transgenic models of Alzheimer’s disease
Authors: Ryssina Vitória Vitalina Margarita , De Bastiani Marco , Pereira Flávia Suelen De Oliveira , Carello‐Collar Giovanna , Zimmer Karine Rigon , Zimmer Eduardo R. 
Published: January 2025

AbstractBackgroundThe molecular mechanisms associated with Alzheimer’s Disease (AD) have been extensively studied in mouse models (Mus musculus). However, experimental research in these models is costly and time‐consuming. In this context, the nematode Caenorhabditis elegans (C. elegans) is an interesting alternative model for studying AD. Nonetheless, whether C. elegans and mouse models of AD share transcriptomic similarities remains unclear. Thus, this study aims to investigate the transcriptomics overlap between C. elegans and M. musculus AD models.MethodWe obtained hippocampus and whole‐body transcriptomics data, respectively, from transgenic strains of AD mice (APP/PS1 and 3xTg) and C. elegans (RB809, GMC101, and CL4176) from the NCBI GEO database. The nematode strain RB809 presents a mutation in the microtubule‐associated protein homolog to human Tau. GMC101 and CL4176 strains aggregate the amyloid‐beta peptide (Aβ). We performed differential expression analysis (DEA) (FDR‐adjusted p‐value < 0.05) using the DESeq2 and Limma package to evaluate the differentially expressed genes (DEGs). Additionally, we conducted a functional enrichment analysis (FEA) to obtain Gene ontology of Biological Processes (GOBP) and Molecular Function (GOMF) terms (p‐value < 0.01).ResultThe pattern of gene expression can be visualized in Figure 1A. All nematode strains exhibited greater similarity with APP/PS1 mice compared to the 3xTg. Specifically, 94 DEGs were identified as shared between APP/PS1 mice and nematode strain RB809 (Figure 1B). Concerning GMC101 and CL4176 strains, 41 and 12 DEGs were found shared, respectively. FEA analysis revealed GOBP terms shared among models involved in similar biological processes (Figure 2). Notably, “Aβ binding”, “calcium ion homeostasis”, “neuroinflammatory response”, and “regulation of inflammatory response” (Figure 3) were identified.ConclusionOur results indicate significant overlaps in genes and biological processes associated with AD and neurodegeneration between AD nematode and mice models, highlighting the translational conservation of fundamental pathological mechanisms. The differences in expression and processes between the various strains of C. elegans and the mouse models offer a unique window to investigate specific molecular aspects of AD.
Synergistic effects of α‐synuclein, tau, and amyloid pathology on mitophagy in dementia with Lewy bodies
Authors: Hou Xu , Richardson Tyrique , Fiesel Fabienne C , Heckman Michael G. , Koga Shunsuke , Dickson Dennis W. , Springer Wolfdieter 
Published: January 2025

AbstractBackgroundDirected by the enzyme pair PINK1 and PRKN, mitophagy is a crucial mitochondrial quality control mechanism that selectively decorates damaged mitochondria with phosphorylated ubiquitin (pS65‐Ub), facilitating their lysosomal degradation. The dynamic pS65‐Ub signal accumulates upon enhanced activation from increased mitochondrial damage or upon reduced autophagic‐lysosomal flux. Previous studies including ours demonstrated altered mitophagy and elevated pS65‐Ub levels in Parkinson’s and Alzheimer’s disease brains that also independently associated with α‐synuclein, tau, or amyloid pathology. However, their combined impact on mitophagy and organelle function remains unclear. Notably these three pathologies often coexist in susceptible brain areas of a neurodegenerative condition named dementia with Lewy bodies (DLB). We herein investigated the interactions of α‐synuclein, tau, and amyloid pathology to uncover their combined effects on mitophagy in a large DLB cohort.MethodThis study included 371 DLB autopsy brains with neurologically normal cases as controls. Immunohistochemistry for the mitophagy marker pS65‐Ub in the hippocampus and amygdala was performed and associations of pS65‐Ub levels with neuropathological measures from the same region were evaluated. Immunofluorescence co‐staining of pS65‐Ub, phospho‐α‐synuclein, and phospho‐tau was conducted to study their interactions at single‐cell level.ResultpS65‐Ub positive cells were significantly more abundant in the hippocampus and amygdala of DLB cases compared to controls. Significant associations were observed between pS65‐Ub levels with age, brain weight, Braak stage, Thal phase as well as counts of Lewy body (LB), neurofibrillary tangle (NFT), and senile plaque (SP) in both regions. Strong synergistic effects of LB and NFT pathologies on pS65‐Ub accumulation were found in the amygdala, while only additive effects of LB and SP pathologies were observed. Single‐cell analysis in the amygdala showed that most affected cells contained either LB or NFT inclusion rather than co‐residing two pathologies within the same cell. Notably, cells harboring LB pathology exhibited mainly smaller, granular pS65‐Ub deposits (type G), possibly associated with increased mitochondrial dysfunction. Conversely, those containing NFT showed larger, vacuolar pS65‐Ub deposits (type V), likely resulting from reduced lysosomal degradation.ConclusionOur study revealed complex interactions of α‐synuclein, tau, and amyloid pathology on mitophagy alteration in DLB brains, highlighting different molecular mechanisms underlying α‐synuclein‐ and tau‐associated mitophagy alterations.
Environmental Triggers for Different Behavioral Symptom Clusters
Authors: Pickering Carolyn E , Winstead Vicki , Yildiz Mustafa 
Published: January 2025

AbstractBackgroundWe have previously shown that there are 3 unique behavioral symptom clusters, or groupings of temporally related co‐occurring behavioral and psychological symptoms (BPSD) representing how an individual’s daily BPSD group together relative to their own typical BPSD manifestation across a 21‐day period. To further validate these symptom cluster concepts, we examined whether they are predicted by different environmental triggers.MethodFamily caregivers completed daily diary surveys for 8 consecutive days reporting on the physical, social and care environment in addition to their care recipients different BPSD. Guided by the unmet needs theory, progressively lowered stress threshold theory and environmental theory of BPSD, we used a generalized linear mixed model to assess the effects of different hypothesized environmental triggers on the likelihood of the previously identified symptom clusters manifesting the same day.ResultThe behavioral symptom cluster had significant 2 unique predictors, routine disruption (OR 19, p = 0.005) and skipped care that same day (OR 2, p = 0.005). The psychological‐mood symptom cluster had 5 unique predictors including daily social demands (OR 1.59, p = 0.046), participating in household chores that day (OR 0.38, p = 0.025), number of prescription medications (OR 1.03, p<.001), number of routine over‐the‐counter medications (OR 1.08, p<.001) and larger household composition size (OR 1.28, p<.001). Finally, the psychosis‐like symptom cluster was predicted by use of pain medication that same day (OR 1.51, p = 0.49).ConclusionThese findings validate that the symptom clusters are mechanistically unique concepts. The findings also highlight modifiable environmental targets that could help to prevent or reduce the occurrence of BPSD. Importantly, findings highlighted the importance of novel concepts like social demands (e.g., decision‐making that is beyond the person with dementia’s capacity) and unmanaged pain in the etiology of BPSD. The increased likelihood of the psychological‐mood cluster due to increased household size may indicate other aspects of the physical environment like noise and available space may impact BPSD.
xploring Neuromelanin Accumulation in the Locus Corelulus: Implications for Early Alzheimer’s Disease Pathology
Authors: Hassanein Leslie , Weinshenker David , Lab Weinshenker 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) is a pressing global health concern, particularly among the elderly population. Early detection and intervention are vital for effective management. Recent research has identified the Locus Corelulus (LC) as one of the initial sites of pathology in AD, characterized by the degeneration of norepinephrine (NE) producing cells, resulting in cognitive and mood disturbances. This study investigates the relationship between neuromelanin (NM) and AD pathology, focusing on its accumulation in the LC. NM, a pigment‐like substance synthesized from catecholamine neurotransmitters such as NE, has been proposed to have a neuroprotective role. However, its potential toxicity remains unexplored.MethodWe employed a novel approach involving the introduction of NM production in mice using a cre‐dependent human tyrosinase (hTyr) virus. This technique allowed us to observe significant NM accumulation in the LC and the emergence of neurodegenerative disease‐like phenotypes in mice. Our investigations extended to examining LC‐NE dependent behavior, NM accumulation, and cell death at distinct time points (1, 6, and 10 weeks).ResultOur results show a longitudinal degradation of the LC, with almost complete loss of the region at 6 weeks.ConclusionThe progressive LC loss and behavioral changes suggest NM’s involvement in AD pathogenesis. Further research is needed to explore NM‐induced neurodegeneration and its potential for early AD detection and intervention.
Polytranscriptomic risk score for Alzheimer Disease in a large diverse multi‐center brain bank study
Authors: Cieza Basilio , Yang Zikun , Reyes‐Dumeyer Dolly , Lee Annie J. , Dugger Brittany N , Jin Lee‐Way , Murray Melissa E. , Dickson Dennis W. , Pericak‐Vance Margaret A , Vance Jeffery M. , Foroud Tatiana M. , Mayeux Richard , Tosto Giuseppe 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) missing heritability remains extensive despite numerous genetic risk loci identified by genome‐wide association or sequencing studies. This has been attributed, at least partially, to mechanisms not currently investigated by traditional single‐marker/gene approaches. Polygenic Risk Scores (PRS) aggregate sparse genetic information across the genome to identify individual genetic risk profiles for disease prediction and patient risk stratification. Recent advancements have pivoted on innovative approaches utilizing OMICS data to construct such risk scores.MethodWe employed a random forest algorithm to identify a list of gene candidates from bulk RNA sequencing data in prefrontal cortex from 565 AD brain samples (non‐Hispanic Whites, n = 399; Hispanics, n = 113; African American, n = 12) across six U.S. brain banks. Subsequently, we calculated their effect size on Braak staging using regression models to construct a polytranscriptomic risk score (PTRS). We employed two distinct models: “Ethnicity‐Agnostic” Model (randomly assigning samples to training and testing samples) and “Ethnicity‐Aware” Model (assigning NHW samples to training and Hispanics to testing sample). Analysis of variance and the receiver operating characteristics area under the curve (ROC AUC) was used to evaluate PTRS’s classification performances. We validated findings using the Religious Orders Study/Memory and Aging Project study (ROS/MAP, n = 1,095).ResultWe found a significant difference in PTRS between samples with low vs. high Braak stages (≤4 vs. ≥5, p = 1*E‐04; Figure 1 upper panel). AUC was found to be 79‐81%, consistently in both Ethnicity‐Agnostic and Ethnicity‐Aware models (Figure 1 lower panel). Finally, the PTRS in ROS/MAP yielded a similar classification performance (p = 2*E‐04, AUC = 77%).Conclusioncontrary to prior studies, we developed a PTRS with optimal transferability across ethnicities. This underscores the importance of developing novel tools to stratify and harmonize large brain repositories for AD.
CRFR1‐Antagonism Ameliorates Early AD Pathology and Alters Stress‐Induced Changes in Pathology
Authors: Ellisman Maya Anne , Sarsoza Floyd , Rissman Robert A. 
Published: January 2025

AbstractBackgroundChronic stress has been linked to an increased risk for various health issues, including Alzheimer’s disease (AD). While novel therapies for AD have improved disease prognosis, a deeper understanding of the link between stress and AD may delineate potential novel preventative treatments. Within the stress system, corticotrophin‐releasing factor receptor 1 (CRFR1) has been shown to influence AD pathological hallmarks. Drugs targeting CRFR1 may elucidate how CRFR1 alters AD and provide a potential novel treatment approach.MethodsTo examine the effects of CRFR1‐antagonism and chronic stress on AD pathology, young WT/PSAPP mice (6‐month) underwent treatment with vehicle/R121919 alongside chronic restraint stress. Then, subjects were assessed with a series of behavioral tests measuring learning, memory, and cognitive flexibility. Additionally, brain regions were immunohistologically analyzed for plaque deposition and biochemically analyzed for various Aβ species.ResultsCRFR1‐antagonist treatment in early AD improves learning and cognitive flexibility, lowers plaque levels throughout the hippocampus and cortex, and lowers highly toxic cortical soluble Aβ oligomers while increasing insoluble Aβ monomers. Chronic restraint stress improves learning and memory, increasing plaques in the hippocampus and lowering cortical plaques while increasing insoluble cortical Aβ monomers. With CRFR1‐antagonism, stress‐induced benefits to learning are more pronounced, yet the stress effects on memory are abolished. At the same time, stress combined with CRFR1‐antagonism lowers the number of cortical plaques and insoluble cortical Aβ monomers, while increasing cortical Aβ soluble oligomers.ConclusionsCRFR1‐antagonism has the potential to improve and may be beneficial for stress‐induced AD pathogenesis in the early phases of AD.
RARE‐LacZ Mice as a Model to Study of Retinoic Acid Signaling in Alzheimer’s Disease
Authors: Hindle Ashly , Smith Shane , Hernandez Matthew , Baker Adam , Strickland Jake , Medina Jocelyn , Lawrence J. Josh 
Published: January 2025

AbstractBackgroundDisrupted balance between amyloidogenic and non‐amyloidogenic pathways leads to cognitive decline in Alzheimer’s disease (AD). Evidence suggests vitamin A (VA) supplementation favors the non‐amyloidogenic pathway through upregulation of α‐secretase. Originally used to map embryonic retinoic acid (RA) signaling, RARE‐LacZ mice possess multiple LacZ genes controlled by retinoic acid response elements (RAREs). We crossed RARE‐LacZ mice with AD mouse models to determine their suitability for quantitative studies into the effects of VA on dentate gyrus (DG) RA signaling and learning in AD.MethodsRelative LacZ gene copy ratio was determined by qPCR of LacZ in gDNA, normalized to ultra‐conserved region 329. Dietary intervention compared VA supplemented (20 IU/g) AIN‐93M to standard AIN‐93M (4 IU/g VA). Mice were tested at postnatal day (P)125 via water T‐maze (WTM, 9 simple discrimination, 9 reversal trials). PFA‐fixed sections (40µm) were immunostained for LacZ, doublecortin, and/or calbindin, confocally imaged, and analyzed using ImageJ.ResultsRARE‐lacZ mice were first crossed with C57BL/6J, ‐NJ, and CD1 mice (wildtype strains of J20, hAβ‐KI, and RARE‐LacZ mice, respectively). The relative LacZ gene copy ratio was ∼2.6:1 between RARE‐LacZ mice (N = 12) and crosses (N = 34). Values for 32/34 offspring fell within ±50% of the mean. Strain affected latency to platform on WTM during simple discrimination and reversal (N = 11‐12, p<0.05, Friedman), however total distance traveled was unaffected suggesting intact learning in all backgrounds. In WT strains, hippocampal LacZ immunoreactivity was localized to a subset of mature doublecortin‐negative, calbindin‐positive DG granule cells, appearing higher on C57BL/6J and ‐NJ than CD1 backgrounds. Offspring from J20± AD and RARE‐LacZ mice exhibited impaired learning (N = 16, p<0.05, Kolmogorov‐Smirnov). No significant difference in behavior between supplemented (20 IU/g) and standard (4 IU/g) VA was observed in AD mice. However, DG LacZ signal was completely silenced in 7/32 mice evaluated by immunostaining.ConclusionsRARE‐LacZ mice appear to have behavioral and genetic characteristics appropriate for testing VA‐mediated interventions in AD models. RA signaling is prominent in mature DG cells associated with successful reversal learning. Although reversal of AD‐related learning deficits by VA supplementation was not observed, testing AD mice on a VA deficient (0.4 IU/g) diet is planned.
Sex differences in the impact of arterial stiffness on cerebrovascular function
Authors: Reeve Emily H , Hogan Ainsley P , Cullen Abigail E , Walker Ashley E 
Published: January 2025

AbstractBackgroundStiffening of the large arteries is a hallmark feature of vascular aging and is associated with cognitive impairment and Alzheimer’s disease pathology. Increased large artery stiffness leads to higher‐than‐normal pulse pressure in the cerebral circulation, damaging endothelial cells. It is known that short‐term exposure to stiffer large arteries causes cerebral artery endothelial dysfunction and hypoperfusion in young mice. However, the impact of long‐term exposure to large artery stiffness on cerebrovascular function is unknown. As there are known sex differences in Alzheimer’s disease risk, we sought to understand the influence of sex on the impact of large artery stiffness on cerebrovascular function.MethodWe studied an established model of greater large artery stiffness, the elastin haploinsufficient (Eln±) mouse, at young (6 months) and old (24 months) ages and compared with wildtype (Eln+/+) mice. We measured endothelium‐dependent dilation ex vivo in pre‐constricted, pressurized posterior cerebral arteries by the maximal response to acetylcholine. Nitric oxide bioavailability was determined by the acetylcholine response with and without the presence of L‐NAME, a nitric oxide synthase inhibitor. Endothelium‐independent dilation was assessed by the maximal response to sodium nitroprusside.ResultWith the sexes combined, posterior cerebral artery endothelium‐dependent dilation was better for young compared with old mice (p<0.001) and for Eln+/+ compared with Eln± mice (p = 0.03). In males, Eln+/+ mice had better posterior cerebral artery endothelium‐dependent dilation than Eln± mice at young ages (p = 0.05), but not at old ages (p = 0.35). The opposite occurred in females, as Eln+/+ mice had better posterior cerebral artery endothelium‐dependent dilation than Eln± at old ages (p = 0.04) but not at young ages (p = 0.71). Group differences in endothelium‐dependent dilation were mediated by differences in nitric oxide bioavailability. There was no effect of genotype, age, or sex on endothelium‐independent dilation.ConclusionOur results suggest males are more vulnerable at young ages, while females are more vulnerable at old ages, to the detrimental effects of large artery stiffness on cerebrovascular function. These age‐dependent differences in vulnerability could underlie sex differences in Alzheimer’s disease risk. Funded by AARG‐200675709, TL1TR002371.
Repeated infection by cytomegalovirus induces neuroinflammation and compromises BBB integrity
Authors: Barahona Natasha B , Garfinkel Lucas P , Wang Hanyun , Marcus Miayla , Subramanian Advaith , Willis Kennedy N , Harrison Mark A , Morris Sara , Zwezdaryk Kevin , Engler‐Chiurazzi Elizabeth 
Published: January 2025

AbstractBackgroundIt is well established that genetic factors are implicated in the development of Alzheimer’s disease (AD), but there is growing interest in how environmental factors like infection contribute to its progression. Recent evidence suggests that greater exposure to infections across the lifespan can potentiate the rate and severity of cognitive decline. In addition to contributing to mechanisms underlying the aggregation of Aβ fragments and phosphorylation of tau proteins, the infectious etiology of dementia may be caused by infectious agents triggering neuroinflammatory pathways and degradation of the blood‐brain barrier (BBB). To further understand neurological changes following viral infection, we investigated the effects of repeated intermittent exposure to cytomegalovirus (CMV) on neuroinflammation and BBB integrity. We hypothesized that if infection burden promotes a dementia phenotype, then mice with a higher lifetime history of intermittent viral exposure will display increased neuroinflammation and BBB permeability.MethodBeginning at 2 months of age, we exposed female Balb/c mice to murine CMV infection or mock infection every 3 months until they reached 8, 14, or 20 months of age, corresponding to 2, 4, or 6 exposures. We used immunofluorescence staining to evaluate the presence of neuroinflammatory markers GFAP and Iba‐1 and barrier permeability markers IgG, Claudin‐5, and Fibrinogen in the hippocampus and striatum, brain regions central to learning and memory function and in which dysfunction is implicated in AD.ResultAcross age groups, we saw a significant increase in astrocytic activity in the hippocampus as measured by GFAP (p< 0.05). For barrier permeability markers, IgG was increased in the hippocampus across age groups (p<0.05), while there was a decrease in claudin‐5 (p = 0.0272) and an increase in fibrinogen (p = 0.0232) at 14 m.o. Changes in striatum were modest though we identified significant increases in Iba‐1 and fibrinogen at 14 months. Measurement of markers in 20 m.o. mice are ongoing.ConclusionA history of intermittent CMV infection led to significant increases in reactive astrocytic and microglial activity in conjunction with compromised BBB integrity in the hippocampus. These results together provide a framework for how infection burden alters neurobiology and contributes to the progression of cognitive decline.