bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD2AP impacts Alzheimer’s disease through brain vascular function
Authors: Vandal Milene , Institoris Adam , Korin Ben , Gunn Colin , Lee Suzie , Lee Jiyeon , Bourassa Philippe , Mishra Ramesh C , Peringod Govind , Jiang Yulan , Hirai Sotaro , Belzil Camille , Reveret Louise , Tremblay Cyntia , Hashem Mada , Elias Esteban , Meilandt William , Foreman Oded , Rouse‐Girma Meron , Muruve Daniel , Nicola Wilten , Körbelin Jakob , Dunn Jeff F , Braun Andy P. , Bennett David A. A , Gordon Grant , Calon Frederic , Shaw Andrey S , Nguyen Minh Dang 
Published: December 2023

AbstractBackgroundCerebrovascular impairment is a key aspect of Alzheimer’s Disease (AD) pathogenesis. Brain vascular defects appear early in the disease process and are associated with cognitive dysfunction. CD2‐associated protein (CD2AP), a scaffolding protein involved cytoskeleton remodeling and membrane trafficking, is an important predisposing factor for the disease. The protein is enriched in brain endothelial cells (BECs) that forms the brain vessels, suggesting that CD2AP might contribute to AD cerebrovascular dysfunction.MethodIn this study, we used brain samples from AD volunteers, genetically modified mouse models, awake two‐photon microscopy and cell culture to investigate the function of CD2AP in the brain vasculature.ResultWe found that AD individuals with lower levels of brain vascular CD2AP displayed the poorest cognitive performance. Genetic depletion of CD2AP in BECs compromised memory function, cerebral blood flow and increased vessels vulnerability to amyloid‐beta. In BECs, CD2AP controlled the levels and signaling of Apolipoprotein E Receptor 2 (ApoER2) and activation of this pathway with Reelin glycoprotein in mice depleted of endothelial CD2AP mitigated the toxic effects of peptide.ConclusionIn sum, deregulation of endothelial CD2AP drives cerebrovascular dysfunction, and harnessing the biology of specific brain vessel types may offer a refined therapeutic avenue for the treatment of AD.
Free‐listing and semantic knowledge: A diagnostic tool for detecting Alzheimer’s disease?
Authors: Ulep Maileen G. , Lienard Pierre 
Published: December 2023

AbstractBackgroundA semantic memory impairment figures prominently among the manifestations of Alzheimer’s disease (AD). That impairment manifests itself relatively early in the disease trajectory with longitudinal studies showing evidence in patients with mild cognitive impairment and preclinical AD. We investigate the impact of AD on specific semantic categories integral to daily function: living kinds and artefacts.MethodWe relied on a “free‐listing task” as developed in cultural domain analysis, and assessed its relationship with other cognitive and functional tests in clinical use. We chose the written version for the elicitation of the free‐lists that we analyze here. A written format leads to the generation of longer lists than an oral elicitation. The participant pool was comprised of 19 AD patients and a control group, 15 cognitively normal age‐matched adults.ResultThe median number of items generated in each list for the patients was 12 for living things and 18 for man‐made objects, for the control group, 39 and 45, respectively. Controlling for age, education, estimate of premorbid intellectual ability, and sex, group membership (AD or control) predicts performance in the free‐listing in the two categories. Holding demographic variables constant, functional status is inversely related to the performance on free‐listing.ConclusionEven when provided the modality (written) to generate longer lists, individuals with AD still performed worse than controls. Our findings confirm previous observations identifying an impairment of semantic knowledge in AD. Free‐listing is effective at detecting this impairment. This easy‐to‐administer, cost‐effective tool could facilitate the fast preliminary characterization of AD in distinct cultural environments.
Therapeutic targeting of TREM2: A novel approach for treatment of AD?
Authors: Schlepckow Kai 
Published: December 2023

AbstractBackgroundGenome‐wide association studies have revealed risk genes for developing late‐onset AD many of which are exclusively expressed by microglia in the brain. One of these microglial genes is TREM2. Studies employing mouse models of amyloid pathology have shown that TREM2 function is essential for microglia to mount a proper response to amyloid pathology. The fact that microglia exert protective effects via TREM2 at least at the early stages of amyloid deposition suggests that boosting TREM2 function pharmacologically during the early stages of AD may be a promising novel therapeutic approach.MethodWe have developed and evaluated the protective potential of agonistic anti‐TREM2 antibodies boosting TREM2 function in preclininal models of amyloid pathology and related disorders employing immunoblotting, ELISA, immunohistochemistry, scRNA‐seq, lipidomics, and TSPO‐ as well as FDG‐PET imaging.ResultOur agonistic anti‐TREM2 antibody 4D9 binds 12 amino acids N‐terminal of the ectodomain cleavage site, inhibits proteolytic TREM2 cleavage, and potently activates downstream pSYK signaling. Boosting TREM2 signaling by 4D9 leads to improved survival of macrophages, enhanced phagocytic activity of primary microglia, lower amyloid burden in an AD mouse model as well as accelerated recovery in mouse models of demyelination. In more recent work we focused on the development of a version of 4D9 with an engineered Fc part, which allows very efficient transcytosis of the antibody across the blood brain barrier (ATV:4D9; ATV: antibody transport vehicle). We demonstrate in an AD mouse model by TSPO and FDG PET imaging that a human specific version of the antibody enhances microglial activation and brain glucose metabolism, respectively.ConclusionSeveral independent studies including our own efforts have convincingly shown amelioration of amyloid pathology in preclinical models of AD upon administration of agonistic anti‐TREM2 antibodies. Together with findings demonstrating reduced cognitive decline in patients with higher levels of CSF soluble TREM2, which serves as a surrogate marker for TREM2‐dependent microglial activity, this suggests that TREM2‐boosting therapies should be actively explored in the clinical setting. In addition, our work indicates that TSPO‐ and FDG‐PET imaging may be used to assess target engagement.
Synaptic proteasome is inhibited in Alzheimer’s disease models and is associated with memory impairment in mice
Authors: Ribeiro Felipe C. , Ferreira Danielle Cozachenco , Fortuna Juliana , de Freitas Guilherme B. , Souza Jorge M , Alves‐Leon Soniza , Leite Renata Elaine Paraizo , Suemoto Claudia Kimie , Grinberg Lea T. , De Felice Fernanda G. , Lourenco Mychael V. , Ferreira Sergio T. 
Published: December 2023

AbstractBackgroundThe proteasome plays key roles in neuronal function by regulating protein turnover, quality control, and elimination of oxidized and misfolded proteins. Recent evidence indicates that proteasome activity is required for synaptic plasticity and memory, and may be altered in Alzheimer’s disease (AD).MethodHere, we investigate proteasome function and localization at synapses in AD post‐mortem brain tissue and in experimental models of AD by using western blotting, immunocytochemistry and proteasome activity assay. We also evaluated core AD‐related features upon proteasome inhibition by using DCFDA measurement, phaloidin staining, SUnSET and mice memory tasks.ResultWe found a marked increase in ubiquitinylated proteins in post‐mortem AD hippocampi compared to controls. Using human ex vivo adult cortical tissue, primary neuronal cultures, isolated synaptosomes and in vivo experiments in mice, we show that amyloid‐b oligomers (AbOs) inhibit synaptic proteasome activity and trigger a reduction in synaptic proteasome content. We further show proteasome inhibition specifically in hippocampal synaptic fractions derived from APPswePS1DE9 mice. Treatment with the proteasome inhibitor, lactacystin, induces reactive oxygen species formation and loss of dendritic spines in hippocampal neurons, inhibits hippocampal mRNA translation, and causes memory impairment in mice.ConclusionThese findings demonstrate that synaptic proteasome activity is inhibited in post‐mortem AD brain tissue and in experimental models of AD. Results further show that proteasome inhibition is associated with spine loss and memory impairment in mice, suggesting that proteasome inhibition may contribute to synaptic and memory deficits in AD.
Longitudinal Elastic Shape Analysis of Brain Subcortical Structures
Authors: Wu Yuexuan , Zhang Zhengwu , Chan Kwun Chuen Gary , Shibata Dean , Kukull Walter A. , Srivastava Anuj , Zhu Hongtu 
Published: December 2023

AbstractBackgroundOver the past 30 years, MRI has become a ubiquitous tool for accurately visualizing the development of the brain’s subcortical structures. However, the quantification of subcortical structures is still in its infancy due to challenges in shape extraction, representation, and modeling.MethodA simple and efficient framework of longitudinal elastic shape analysis (LESA) is developed for subcortical structures. By employing the elastic shape analysis of static surfaces using the square root normal field (SRNF) representations, we computed shape summaries of surfaces and represented the complex subcortical structures using a small number of basis functions. Further, we statistically modeled the sparse longitudinal data to predict the spatial‐temporal shape changes of subcortical structures. We also conducted the temporal registration using the square‐root velocity function (SRVF) framework to quantify the accelerated aging of Alzheimer’s disease (AD).ResultWe applied LESA to analyze longitudinal neuroimaging data sets and showcased its wide applications in estimating continuous shape trajectories, building life‐span growth patterns, and comparing shape differences among different groups. Using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) data, we found that from 60 to 90 years old, the AD group always had the largest left ventricle (LV) surface area and the smallest left hippocampus (LHC) surface area, followed by the MCI and NC groups. The enlargement of LV and the atrophy of LHC had different speeds among different groups. Most of the shape‐changing differences between the AD and NC groups were visible in the anterior and posterior ends of LV. The atrophy of LHC happened mainly at the posterior end with aging. The AD group had the sharpest posterior end, and the NC group deformed the least with aging. Compared with the NC group, the AD group showed an average accelerated enlargement of 2.91 years and accelerated shape change of 2.76 years in LV; an average accelerated atrophy of 2.56 years and accelerated shape change of 2.59 years in LHC. By constructing the life‐span growth trajectories, we observed increases in shape changes’ speed in both LV and LHC after 60 years old.ConclusionAD can significantly speed up the shape change of ventricle and hippocampus compared with normal aging.
Neutrophil extracellular traps in amyloid pathology & glymphatic impairment
Authors: Braun Molly , Sevao Mathew , Gino Elizabeth , Keil Samantha A , Pedersen Taylor J , Jang Jay , Swierz Justyna , Sanderson Keith , Jansson Deidre , Iliff Jeffrey J 
Published: December 2023

AbstractBackgroundActivated neutrophils eject neutrophil extracellular traps (NETs) consisting of web‐like structures of DNA, histones, and granular proteins. Neutrophils traffic into the brain in Alzheimer’s disease (AD) and along with NETs are associated with amyloid beta (Aβ) plaques. However, whether NETs may impair glymphatic clearance of Aβ has never been examined. The glymphatic system is a network of perivascular pathways that provides a pathway for solutes to be cleared from the brain interstitium. Impairment of glymphatic function promotes Aβ plaque deposition. We proposed that NETs may decrease glymphatic exchange by impairing perivascular and interstitial fluid movement, resulting in impaired Aβ clearance.Method5XFAD mice with amyloid pathology were crossed with Pad4−/− mice lacking the ability to form NETs, generating 5XFAD mice lacking NET formation. Barnes maze, spontaneous alternation Y maze, and open field behavioral tests were performed on 5XFAD+Pad4+/+ and 5XFAD+Pad4−/− mice at 4 months old. The following week, tracer was intracisternally injected into the CSF and dynamic transcranial imaging was performed to measure tracer movement over the cortical surface. Brains were then collected after 45 minutes. Tracer influx was quantified in these brain slices and the tissue was stained for amyloid beta, GFAP, Iba1, and neutrophil markers.ResultPad4 gene deletion in a 5XFAD mouse model of amyloid pathology improved tracer influx, decreased amyloid burden, and improved cognitive function.ConclusionNETs promote glymphatic impairment, amyloid accumulation, and cognitive impairment in a mouse model of amyloid pathology. These studies highlight the important role that neutrophils and NETs play in the pathology of AD and may be a novel therapeutic target.
Etiological contributions of adolescent binge alcohol on onset of Alzheimer’s disease‐associated basal forebrain neuropathology in 5xFAD mice and post‐mortem human AUD brain
Authors: Vetreno Ryan P. , Coleman Leon G. , Crews Fulton Timm 
Published: December 2023

AbstractBackgroundHeavy alcohol use is an etiological factor for development of dementia and may contribute to onset of Alzheimer’s disease (AD). Both alcohol use disorder (AUD) and AD share common underlying neuropathology, including basal forebrain cholinergic neuron degeneration and proinflammatory neuroimmune activation, and evidence suggest these systems are particularly sensitive to adolescent alcohol exposure. Using the 5xFAD mouse model of AD, we tested the hypothesis that adolescent intermittent ethanol (AIE), which models human adolescent binge drinking, would accelerate onset of AD‐associated pathology in the adult basal forebrain.MethodIn Experiment 1, non‐transgenic and 5xFAD male and female mice received AIE treatment (5.0 g/kg, i.g. 2‐days on/2‐days off; postnatal day [P]30 – P55) and basal forebrain tissue collected for immunohistochemistry and gene expression analysis on P100. In Experiment 2, 5xFAD female mice received AIE treatment as described above followed by glycyrrhizic acid (GA; 150 mg/L), a high mobility group box 1 (HMGB1) inhibitor, in drinking water from P56 – P100. At study conclusion, basal forebrain tissue was collected for immunohistochemistry and gene expression analysis on P100. In Experiment 3, AD‐associated neuropathology was assessed in the post‐mortem human basal forebrain of individuals with AUD relative to age‐matched moderate drinking CONs.ResultIn Experiment 1, AIE accelerated loss of basal forebrain cholinergic neurons and heterogeneous nuclear ribonucleoprotein (hnRNP) expression in 5xFAD females, but not males, relative to age‐matched 5xFAD CONs. This was accompanied by a female‐specific accelerated accumulation of plaque markers (e.g., Aβ1‐42, Thioflavin‐S, HMGB1) as well as microglial activation and proinflammatory neuroimmune signaling genes (e.g., HMGB1, RAGE) in the adult basal forebrain. In Experiment 2, post‐AIE treatment with the HMGB1 inhibitor GA reversed AIE‐induced accelerated loss of cholinergic neurons, accumulation of plaque markers, and upregulation of microglial activation markers and proinflammatory signaling molecules. In Experiment 3, AUD individuals exhibited decreased cholinergic and hnRNP markers and increased Aβ1‐42 immunoreactivity as well as cholinergic neuron co‐expression with Aβ1‐42 that negatively correlated with an adolescent age of drinking onset.ConclusionThese data reveal that adolescent binge ethanol exposure may be an etiological factor contributing to onset of AD‐associated neuropathology in the adult basal forebrain through HMGB1‐neuroimmune signaling.
Altered circadian rhythms effects on anxiety, locomotor activity, serotonin and nitric oxide levels in the prefrontal cortex of juvenile and adult rats
Authors: Obajuluwa Adejoke Olukayode , Lech James Chrystopher , Afolabi Olakunle Bamikole , Obajuluwa Tiwalola Madoc , Babafemi Laoye John , Edem Edem Ekpenyong 
Published: December 2023

AbstractBackgroundDementia and Alzheimer’s disease (AD) can be exacerbated by irregular sleep‐wake cycles, and age may be a risk factor. This study compared behavioral responses such as anxiety, motor coordination, and locomotion to altered circadian rhythms and serotonin, nitric oxide (NO), and malondialdehyde (MDA) levels in the prefrontal cortex of juvenile and adult rats.MethodA total of thirty female Wistar rats were grouped into three (n = 5) in the following juvenile (30‐45 days old) and adult (90‐120 days old) groups: (A) Control (12L:12D cycle),(B) 24‐hour LED light exposure(12L:12L cycle) and (C) 24‐hour dark cycle (12D:12D cycle). Experimental rats were kept in the stated cycle conditions using natural lighting, LED lighting, and a dark room, respectively, for 60 days. Data were analyzed using a two‐way ANOVA (GraphPad Prism 9), and statistical significance was measured at p<0.05.ResultFindings from the study revealed progressive weight loss in the sleep‐deprived juvenile (12L:12L) rats compared to adults (p<0.05) in the same and other groups. Also, anxiety‐like indices such as longer duration of time in the dark area of the light‐dark box, avoidance of open arm entries on the elevated plus maze, reduced line crossing activity in the open field box, etc. were markedly higher in the juvenile rats from the 12L:12L and 12D:12D groups respectively. When juvenile and adult 12L:12L and 12D:12D cycle rats data were compared to controls, severe depletion of serotonin (p<0.0001) and nitric oxide (p<0.01) levels were observed, while age‐dependent MDA levels were revealed across all groups.ConclusionA bi‐directional relationship was observed between age and circadian disruption effects with more severe outcomes in juveniles compared to adults and this hold interesting implications for the study of the biological clock mechanisms underlying anxiety, mood and sleep disorders in living systems.
Feasibility of Using Wearable Actigraphy for Behavioural Monitoring in Care Home Residents Living with Moderate to Severe Alzheimer’s Disease and Agitation
Authors: Guu Ta‐Wei , Aarsland Dag , Ffytche Dominic H 
Published: December 2023

AbstractBackgroundMeasuring and monitoring behaviour is difficult in people living with later stage Alzheimer’s disease and specific behavioural symptoms such as agitation and aggression (AA). Currently, subjective information given by these patients is highly susceptible to inaccurate recall, clinicians rely on answers provided by care givers, which can be biased and lack fine‐grain temporal detail. Although actigraphy watches have been useful tools for research, little is known about the feasibility of their use in agitated dementia participants and on the factors influencing watch compliance.MethodPeople diagnosed with Alzheimer’s disease and significant AA symptoms living in care homes were asked to wear an actigraphy watch (GENEactiv Original) for 4 consecutive weeks. Demographic data, Functional Assessment Staging Tool (FAST) score, behavioural symptom pattern and severity were recorded using the Neuropsychiatric Inventory Nursing Home Version (NPI‐NH). Watch‐recorded wearing time and activity data were used to evaluate adherence. Care home staff were interviewed to explore factors influencing watch wearing by participants and to develop solutions to improve compliance.ResultWe recruited 28 participants (14 female) and found wearing the watch feasible overall. No statistical compliance difference was found between different groups based on age, FAST score, agitation pattern or severity; however, a significant gender difference was found with male participants being more adherent (Table). Participants were more compliant in weeks 3‐4, and first week adherence predicted overall adherence (Figure). Factors influencing compliance include the design and appearance of the watch, previous watch wearing habit, and the perceived purpose of the study. Using documents easily readable to participants and care givers to facilitate understanding of the study and to communicate challenging clinical scenarios appeared to enhance adherence.ConclusionWearing an actigraphy watch for behavioural monitoring was feasible for moderate to severe Alzheimer’s disease patients with AA symptoms in care home settings. Gender‐specific design and appearance should be considered when selecting the actigraphy watch. For dementia studies planning to use an actigraphy watch, compliance can be improved by incorporating a short lead‐in phase to establish a watch wearing routine and by providing reader‐friendly documents about the watch purpose to communicate with participants and care givers.
Neuroimmune proteins can differentiate between distinct neurodegenerative diseases
Authors: Cherry Jonathan D , Baucom Zachary H. , Eppich Kaleb G , Kirsch Daniel A , Dixon Erin R , Tripodis Yorghos , Bieniek Kevin F , Farrell Kurt W. , Whitney Kristen R. , Uretsky Madeline , Crary John F. , Dickson Dennis W. , McKee Ann C. 
Published: December 2023

AbstractBackgroundAlthough we have greatly increased our ability to identify the presence of neurodegenerative pathology during life, additional techniques and targets are still needed to increase diagnostic specificity. Recently, it has become evident that the neuroinflammatory response might be tailored towards distinct diseases resulting in disease specific “neuroinflammatory signatures”. Therefore, a detailed comparison of neuroinflammatory molecules present among distinct neurodegenerative diseases could provide novel information of disease specific therapeutic targets or differential biomarkers.MethodTo better examine potential neuroinflammatory signatures, a 71 immune‐related protein multiplex ELISA panel was utilized to analyze anterior cingulate grey matter from 127 individuals neuropathologically diagnosed with Alzheimer’s disease (AD), but chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD). A partial least square regression analysis was used for unbiased clustering and identifying proteins that were distinctly correlated with each disease correcting for age and gender. Receiver operator characteristic and binary logistic regression analyses were then used to examine the ability of each candidate protein to distinguish diseases. Validation in postmortem cerebrospinal fluid (CSF) from 15 AD and 14 CTE cases was performed to determine if candidate proteins could act as possible biomarkers. Finally, histology was performed using candidate proteins to visualize cell type expression for better understanding of potential mechanistic pathways.ResultFive clusters of neuroimmune proteins were identified and compared to determine if clusters were specific to distinct disease. Each cluster was found to correlate with either CTE, AD, PSP, CBD, or AGD. When examining which proteins were the strongest driver of each cluster, it was observed the most distinctive protein for CTE was CCL21, AD was FLT3L, and PSP was IL13. Individual proteins that were specific to CBD and AGD were not observed. CCL21 was observed to be elevated in CTE CSF compared to AD, further validating the use as possible biomarkers.ConclusionOverall, these results highlight that different neuroinflammatory responses might underlie unique mechanisms in related neurodegenerative pathologies. Additionally, the use of distinct neuroinflammatory signatures could help differentiate between neuropathologies and act as novel biomarker candidate to increase specificity for in‐life diagnoses.