bluuebunny/crossref_metadata_2025_split huggingface dataset:
X Ray Absorption Near Edge Spectroscopy (XANES) Shows Abnormal Iron Oxidation State in Alzheimer’s Hippocampi
Authors: Tran Dean , DiGiacomo Phillip , Nirschl Jeffrey , Edwards Nicholas , Bone Sharon , Webb Samuel , Georgiadis Marios , Zeineh Michael 
Published: January 2025

AbstractBackgroundRecent studies suggest that iron and neuroinflammation are key components of Alzheimer’s Disease (AD) pathology. Ferrous Fe2+ can cause oxidative stress and cellular toxicity, but it is unknown to what extent Fe2+ is elevated in AD, in particular with the hippocampus. To answer this question, we quantified iron oxidation state in frozen human brain hippocampi.Methods22 fresh‐frozen human brain hippocampi from the Stanford Alzheimer’s Disease Research Center (high AD—n = 13, low AD—n = 7, non‐AD controls—n = 2) were imaged in beamline 7‐2 of Stanford’s Synchrotron Radiation Lightsource using X‐ray fluorescence imaging (XFI) to identify regions of interest (ROIs) with high iron concentration (Fig. 1A‐B). X‐ray absorption near‐edge structure (XANES) spectroscopy was performed on ROIs to determine the relative proportions of Fe2+ and Fe3+ in each deposit (Fig. 1B‐E). A Fischer’s exact test was performed to evaluate the association between AD stage and levels of Fe2+. Since Fe2+ proportion is a bounded measure with an excess of zeroes, a zero/one‐inflated beta (ZOIB) regression model was fitted.In addition, to interrogate the effects of tissue thawing on iron oxidation state during the hours long scan times, a cryo‐chamber kept 3 hippocampal specimens frozen while their respective deposits were being scanned. These specimens were then allowed to thaw and their same deposits rescanned. The proportion of Fe2+ between the paired frozen/thawed deposits were compared using a Wilcoxon signed‐rank test.ResultsThere was a statistically significant increase in Fe2+ in the AD specimens (p = 0.007). The ZOIB regression showed that low AD (z = 9.10, p<0.001) and high AD (z = 3.36, p = 0.001) hippocampi exhibit a significantly higher proportion of Fe2+ compared to controls.Thawed deposits showed a statistically significant lower proportion of Fe2+ compared to their frozen state (p = 0.0145).ConclusionsWe found increased Fe2+ in thawed AD hippocampi compared to controls. Additionally, the thawing of frozen iron deposits resulted in a decrease of measured Fe2+. These findings may suggest actual differences are even higher between iron oxidation state in AD hippocampi versus controls.
Mitigation of Synaptic and Memory Impairments through F‐Actin Stabilization in an Alzheimer’s Disease Mouse Model
Authors: Haseena P A , Kommaddi Reddy Peera 
Published: January 2025

AbstractBackgroundF‐actin plays crucial roles in establishment and maintenance of synapses including post synaptic density organization, facilitation of vesicle trafficking, anchoring of postsynaptic receptors, and involvement in translational machinery. Proteomic analysis of actin‐interacting proteins revealed the interaction of PSD‐95 with actin in synaptosomes from brain cortex of APP/PS1 mice. PSD‐95 functions as a critical scaffold for the assembly of neurotransmitter receptors at the synapse, playing a pivotal role in regulating synaptic strength and plasticity. PSD‐95 directly interacts with NMDA receptors, whereas its interaction with AMPA receptors occurs through an auxiliary subunit, TARPs. The disruption in PSD‐95 association with actin observed in nine‐month‐old APP/PS1 mice may contribute to the synaptic neurotransmission deficit evident in the AD mouse model. Our objective here is to stabilize the F‐actin using Jasplakinolide to examine the disrupted interaction and assess its impact on synaptic function and memory impairment.MethodsNine‐month‐old wildtype and APP/PS1 mice were injected intrathecally with vehicle or Jasplakinolide (0.5µg/mice) and contextual fear conditioning memory was assessed 24 hours later. Following behavioral analysis, synaptosomes were isolated and examined for synaptic F‐actin levels and PSD‐95‐ actin association. Additionally, primary cortical cultures were treated with Jasplakinolide and analyzed for F‐actin intensity, dendritic spine density and AMPA receptor subunit surface localization.ResultsMemory recall and PSD‐95 association with actin is dysregulated in nine‐month‐old APP/PS1 mice compared to wildtype mice. However, injection of Jasplakinolide in APP/PS1 mice rescued the memory recall deficit. Synaptic F‐actin levels and the association of PSD‐95 with actin were restored in APP/PS1 mice received the Jasplakinolide. Primary cortical neurons, DIV21, derived from APP/PS1 mice showed a significant reduction in surface localization of AMPA receptor, F‐actin levels and dendritic spine density while these molecular events are restored by stabilization of F‐actin by Jasplakinolide.ConclusionThe compelling evidence supporting the stabilization of F‐actin suggests a promising strategy for alleviating synaptic impairments in AD, as it not only restores dendritic spines but also increases the surface localization of glutamate receptors. Our findings on complex interplay between cytoskeleton dynamics and synaptic functions may provide potential therapeutic targets aimed at preserving synaptic integrity and ameliorating cognitive decline in AD.
Theta band optogenetic stimulation of the septo‐hippocampal fibres in the fornix reduces interictal spikes and rescues memory performance in hAPP‐j20 mice
Authors: Varela Eva Vico , Carmichael James Eric , Manseau Frédéric , Choi Jisoo , Etter Guillaume , Williams Sylvain 
Published: January 2025

AbstractBackgroundAltered neuronal timing and synchrony are biomarkers for Alzheimer’s disease (AD) and correlate with memory impairments. Electrical stimulation of the fornix, the main fibre bundle connecting the hippocampus to the septum, has emerged as a potential intervention to restore network synchrony and memory performance in human AD and mouse models. However, electrical stimulation is non‐specific and may partially explain why fornix stimulation in AD patients has yielded mixed results. We hypothesize that driving the specific circuits underlying rhythmicity within the fornix via optogenetics at the biologically relevant theta rhythm (5Hz) will stabilize septo‐hippocampal network timing in an AD mouse model (hAPP‐j20) to alleviate hypersynchronous interictal spikes (IS) and restore memory performance.MethodsGABAergic neurons in the septum were transfected with the excitatory opsin ChETA (or eYFP controls) in J20+/+ or J20± littermate controls. An optical fibre was placed above the fornix to limit excitation to the projection fibres and recording electrodes were placed in CA1 to measure network oscillations. 5Hz stimulation was applied continuously for 4 hours following the encoding phase of either novel‐object‐location or passive contextual avoidance memory tasks. We also combined in vivo calcium imaging with electrical recordings in CA1 to monitor network activity to determine how IS shape hippocampal cell assemblies in J20+/+ mice without fornix stimulation.ResultsInterictal spikes were present in sleep in J20+/+ mice, and at a higher rate during REM (4.78/min) compared to slow‐wave (1.76/min; n = 11, p<0.001, one‐way ANOVA). J20+eYFP controls displayed a strong negative correlation between the rate of IS and memory recall score (n = 9, r = ‐0.62, p = 0.015). 5Hz optical fornix stimulation reduced the occurrence of IS in REM both during stimulation and 4hrs post‐stimulation (n = 11, p = 0.024, repeated measures ANOVA). Continuous 4‐hour theta stimulation between the encoding and recall phases of both memory tasks rescued J20+ChETA performance to levels comparable with healthy controls while J20+eYFP mice performed at the chance level (n = 9‐10 per group, p = 0.017, two‐way mixed ANOVA).ConclusionThese data validate theta band optical stimulation as a viable method to pace the septo‐hippocampal network effectively reducing IS events and recovering memory performance in an APP mouse model.
Selective targeting free beta‐2 microglobulin as a promising therapeutic strategy for Alzheimer’s Disease
Authors: Cho Mi‐Hyang , Kim Min‐Seok , Han Seung‐Hwan , Mun Yeon‐Seon , Song Ha‐Lim , Kim Na‐Young , Shin Jung‐Su , Kim Dong‐Hou , Yoon Seung‐Yong 
Published: January 2025

AbstractBackgroundBeta‐2 microglobulin (β2m) is a component of the major histocompatibility complex class I (MHC‐I) playing a crucial role in the immune system on cell surface, but it can be separated from the MHC‐I and exist in biological fluid independently. Numerous reports have shown that β2m is a systemic pro‐aging factor impairing cognitive function, and that it is increased in the blood and CSF of patients with Alzheimer’s disease (AD). While β2m in the body fluid has been recognized as a potential factor in AD and aging, the development of therapeutic agents, especially those directly targeting β2m using antibodies, may face challenges. As β2m is a protein normally expressed in most nucleated cells as heterodimer bound to MHC‐I, targeting β2m may indeed carry a risk of compromising immune responses and leading to side effects by inhibiting MHC‐I.MethodTo develop monoclonal antibody against free β2m, not complexed to MHC‐I, the hybridoma clones were obtained from mice injected with peptides containing epitopes targeting the adjacent region where β2m binds to heavy chain, another subunit of MHC‐I. One of these antibody clones, termed ADEL‐Y03, was selected by characterizing its binding affinity and specificity for free β2m, and mass‐produced for in vivo efficacy study against AD.ResultThe ADEL‐Y03 exhibit high affinity and specificity for free β2m, but not to β2m complexed with MHC‐ I. The in vivo activity of ADEL‐Y03 in blocking free β2m was validated by recovering β2m‐induced cognitive deficit in wild type mice. In addition, intraperitoneal injection of ADEL‐Y03 reduced free β2m levels in the brain and plasma, leading to a decrease of beta‐amyloid and inflammation, hallmarks of AD pathology, in 5XFAD mice brain. In vitro study demonstrates the role of free β2m in AD pathology, and these effects were ameliorated by ADEL‐Y03.ConclusionSpecific targeting free β2m using ADEL‐Y03 antibody may be a promising approach to developing new therapies for AD without deleterious effects such as downregulating immune function of MHC‐I.
Clinicopathological mismatching in a patient presenting with clinical symptoms of Parkinson’s disease
Authors: Chung Eun Joo 
Published: January 2025

AbstractBackgroundBecause of clinically overlapping parkinsonian motor symptoms, it is hard to diagnose a specific disease in atypical parkinsonism or differentiate Parkinson’s disease (PD) from atypical parkinsonism. Herein, we report the clinicopathological mismatching of an autopsy‐confirmed PSP in a patient clinically diagnosed with PD.Method Clinical historyWe reviewed the brief clinical history of a 70‐year‐old man and neurologic examination. We investigated the findings of the Mini‐mental state examination (MMSE), Clinical dementia rating (CDR), and Montreal cognitive assessment (MoCA). He performed brain magnetic resonance imaging (b‐MRI) and fluoro‐propyl‐carbomethoxy‐iodophenyl‐tropane (FP‐CIT)‐positron emission tomography (PET).AutopsyThe patient and his family gave antemortem consent for a postmortem examination. Autopsy was performed at the Inje University Brain Bank. The right brain was frozen and the left side was fixed into the 10% formalin. The fixed brain was photographed and coronally sliced at 1 cm intervals. After slicing, tissue block‐taking was done at 17 parts. Specimens were fixed with 10% buffered formalin at room temperature and embedded in paraffin. The hematoxylin‐eosin stain and immunohistochemical stains were performed.ResultThe UPDRS motor scale of off‐state was 18.5, and the HY stage of off‐state was 2.0. The first MMSE and MoCA were 28, and the CDR score was normal. The third MMSE was assessed at 76 years old, and the score was 25 which increased by 2 points compared to a year ago. These results are in the table. The b‐MRI revealed mild small vessel ischemic change in the corona radiata (CR). FP‐CIT PET revealed asymmetrically bilateral decreased FP‐CIT uptake in both the putamen and caudate nucleus. The total brain weight of this patient was 1270mg. The neuropathological findings did not show the Lewy body pathologies. Instead, PSP pathology based on the tufted astrocytes was observed.ConclusionHis clinical symptoms were initially accordant with clinical diagnostic criteria for PD. However, neuropathological findings showed PSP pathology based on the tufted astrocytes. The patient had worse Parkinsonian motor symptoms, which pathologically suggested the brainstem‐predominant PSP rather than typical or cortical‐predominant.
Neuronal Calcium‐Sensing Receptor Is A Druggable Target To Treat Alzheimer’s Disease
Authors: Tu Chia‐Ling , Kurisu Kota , Cheng Zhiqiang , Miller Stephanie R , Mizuma Atushi , Liu Jialing , Palop Jorge J , Grinberg Lea T. , Yenari Midori A , Chang Wenhan 
Published: January 2025

AbstractBackgroundEffective disease‐modifying regimens for Alzheimer’s Disease (AD) remain lacking due to insufficient understanding of its pathogenic drivers. It was shown previously that upregulation of the calcium‐sensing receptor (CaSR), an excitatory family C GPCR, induces neurodegeneration by interfering with the inhibitory γ‐aminobutyric acid (GABA) signaling following acute brain injuries (Ann_Clin_Transl_Neurol, 1:851‐66). Herein, we determined whether CaSR overexpression is causally associated with the AD.Method(1) Proteomic profiles of hippocampal CA1 neurons in postmortem brains of subjects at progressive AD Braak stages (0, 1, 2, 4 and 6) were compared using a NanoString GeoMx profiler. (2) Proximity ligation assays (PLA) were performed to assess interactions of neuronal CaSR with type B GABA receptors (GABAB1R and GABAB2R). (3) Y‐maze and new object recognition (NOR) tests were performed to assess the impact of neuronal ablation of the Casr gene by Camk2a‐Cre‐mediated gene recombination (Camk2aCaSRΔflox/Δflox) or pharmacological inhibition of neuronal CaSR activities by daily subcutaneous injections of a brain‐permeable calcilytic (NPS‐2143, 20 µmole/kg) on cognitive functions of aging C57/B6 mice and two mouse models of early‐onset AD, 5XFAD (MMRRC_034840‐JAX) and hAPPNL‐G‐F (Nature_Neuroscience, 5:661) mice.ResultThe abundance of CaSR protein was significantly (p<0.0001) increased from the Braak stage 2 to 4/6 (Fig. 1A, C) and positively correlated (r2 = 0.2448 ‐ 0.4655, p<0.0001) with the abundance of APP, Aβ1‐42, BACE1, PSEN1, and phospho‐tau proteins (Fig. 1E‐I) in the somas of CA1 neurons (Fig. 1B) of the human brains. PLA showed increases in heterodimerization of CaSR with the GABAB1R in human brain from the Braak 0 to 5 (Fig. 2A) and in cultured hippocampal neurons overexpressing the CaSR by lentiviruses along with reduced GABAB1R/GABAB2R heterodimerization (Fig. 2B). While the control mice showed significant (p<0.001) cognitive declines from 12 to 18/20 months of age (MOA), these defects were prevented in the age‐matched Camk2aCaSRΔflox/Δflox or NPS‐2143‐injected mice (Fig. 3A, B). Similarly, the early cognitive declines in the 5XFAD (Fig. 3C‐F) and hAPPNL‐G‐F (Fig. 3G, H) mice at 6 MOA were completely alleviated when the mice were bred into the Camk2aCaSRΔflox/Δflox background or injected with NPS‐2143.ConclusionThe neuronal CaSR is a critical driver of dementia by interfering with GABABR signaling and a druggable target to prevent or treat AD.
Serial Imaging of Murine Brain Capillary Pericyte Dynamics in Hyperglycemia
Authors: El‐Ghazawi Kareem , Eyo Ukpong , Peirce‐Cottler Shayn 
Published: January 2025

AbstractBackgroundThe microvasculature of the central nervous system (CNS), which delivers oxygen and nutrients and forms a critical barrier protecting the CNS, is deleteriously affected by both Alzheimer’s Disease (AD) and Type 2 Diabetes (T2D). Previous studies have shown pericyte dropout and vessel constriction in brain capillaries in AD, while other studies have shown pericyte bridging and dropout in retinal capillaries in T2D. T2D patients have increased risk of AD, suggesting potentially related microvascular pathological mechanisms. Pericytes are an ideal cell type to study for functional links between AD and T2D. The purpose of this study was to evaluate the effects of T2D on the dynamics of brain capillaries and pericytes.MethodMyh11‐CreERT2 ROSA floxed STOP tdTomato mice were fed a soft tamoxifen chow for 2 weeks. Cranial window surgery was performed in anesthetized mice, and mice underwent weekly serial live two‐photon imaging with retro‐orbitally injected FITC‐Dextran throughout a 3‐week period. Streptozotocin (STZ) (200mg/kg) was injected intraperitoneally, and mice were imaged 1‐week post‐injection. Z‐stack projections of brain tissue from the surface to 100mm deep (442um2 field of view) were collected, and capillary orientation and pericyte morphology were compared across timepoints and before and after STZ treatment.ResultQuantitative assessment revealed that capillaries move closer to each other 1 week after STZ injection, as indicated by a 30% reduction in the average distance between capillaries. Moreover, wherever capillaries were in contact with pericyte soma, capillary diameter was reduced by 31% post‐STZ injection compared to pre‐STZ timepoints, suggesting a constrictive role of pericytes in a hyperglycemic environment.ConclusionOur study demonstrates how live, serial two‐photon imaging of the same fields of view of the mouse cortex can reveal dynamic capillary and pericyte morphological changes in response to a hyperglycemic environment. This experimental model system can be deployed to investigate how pericytes changes over time may link microvascular changes in T2D to those in AD. Future studies will include additional analysis time points, as well as studies in 5xFAD mice, a widely used model of AD.
Investigating Intranasal Olfactory Mucosa Progenitor Cells Administration in Compensating Hippocampal Atrophy in Alzheimer Disease: A Novel Perspective
Authors: Walid Mohammad , Ismail Youssef A. , El‐Satar Youssef M. Abd , Mohamed Hazim , Haitham Youssef 
Published: January 2025

AbstractBackgroundThe olfactory mucosa cells are capable of lifelong neurogenesis providing a viable source of progenitor cells. Olfactory mucosa progenitor cells (OMPCs) have alleviated several cerebral ischemia/reperfusion damage markers. OMPCs are safely obtainable from the upper nasal cavity. The aim is to investigate the potential of administering the OMPCs to achieve neurogenesis in regions of hippocampal atrophy in Alzheimer’s disease (AD)MethodWe reviewed database searches through December 2023 in MEDLINE, PsycINFO, and the Cochrane Central Register of Controlled Trials, and additional searches for ongoing trials through ClinicalTrials.gov and Current Controlled Trials (ISRCTN Register).ResultBased on a trial conducted to assess the homing capacity of human OPMCs applied intranasally, the OPMCs migrated to the sites of soma atrophy and axonal swelling. Mapping the position of the applied cells, the mean distance (+SD) from OMPCs to regions of axonal damage indicated B‐APP+ (the same marker in CA1 hippocampal atrophy in AD) was 71.8+60.3 µm; OMPCs to atrophic cell bodies indicated p‐c‐jun+ (the same marker in CA2 hippocampal atrophy in AD) was 188.7 + 320 µm; OMPCs to random sites was 3929.3 + 2636.3 µm. Another trial was conducted on mice to confirm whether the OMPCs also exhibit high capacity of neurogenesis. The presence of relay neurons derived from the OMPCs differentiation was evident and traced by the Wheat germ agglutinin (WGA) expression in the injured regions in the spinal cords of the subjects. Based on the analysis of evidence and reviewing the literature related to the pathogenesis and markers of AD hippocampal atrophy, human OMPCs intranasal administration have high homing capacity which make them have a strong potential to safely migrate to the site of axonal damage (B‐APP+ region) and sites of soma atrophy (p‐c‐jun+ region) in hippocampus of AD patients. At the site of homing, OMPCs differentiate into trans‐synaptic relay neurons, expressing WGA protein, which reconstructs the neural pathways in the site of atrophy not only by acting as a scaffold, but also by differentiating into relay‐neuronsConclusionOMPCs intranasal administration is a novel technique which may have potential to restore neural pathways in subjects with AD presenting with hippocampal atrophy.
Optimizing Ultrasensitive RT‐QuiC assay on AD tau seed‐monomer reactions
Authors: Chen Junle , Lee Virginia M.‐Y. , Xu Hong 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is pathologically defined by the presence of extracellular Aβ plaque and intracellular tau inclusions. Emerging evidence shows that tau aggregates contain pathogenic bioactivities of templating monomeric tau into filamentous fibrils and propagating through cells. Based on these findings, assays have been developed to detect minute amounts of pathogenic tau in human samples. With great potential, it remains unclear about the sensitivity and fidelity of tau fibrillization due to the presence of pathogenic tau species.MethodsTo that end, our study focuses on optimizing the Real‐Time Quaking‐Induced Conversion (RT‐QuiC) assay for its potential of detecting and amplifying insoluble tau seeds derived from AD patient. To this end, we utilized recombinant tau monomers t306 and k12, 2R and 3R tau peptide respectively known for their rapid fibrillization and high amplification signals in previous studies. More specifically, we optimized the RT‐QuiC assay using both crude and purified brain lysates from AD and control cases.ResultsThe specificity of the RT‐QuiC assay were successfully reproduced by multiple cases of AD and control brain lysates. Moreover, we tested the RT‐QuiC assay with purified AD tau seeds and assessed the sensitivity of the assays based on the amount of insoluble tau. To further interrogate the system, we also evaluated the impact of reaction buffer on the ThT‐based measurement of tau fibrillization. Our results show that the original RT‐QuiC assay can sensitively detect insoluble AD tau seeds at the nM level in our hands. The optimized RT‐QuiC assay could differentiate better between AD‐seeded reactions and controls with an improved sensitivity up to fM level, with a better separation between AD and control and faster reaction rate. The assay showed a clear dose‐dependent response till pM range.ConclusionUpon optimization, the RT‐QuiC assay is both ultrasensitive and specific to AD tau fibrillization. Our findings offer insights into the fibrillization mechanism of tau aggregates and expand our understanding of pathogenic tau seeds in AD. By optimizing the assay to more accessible patient samples in the future, namely CSF and plasma, the RT‐QuiC can serve as a potent diagnostic tool for AD tau progressions.