bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling tau aggregation through optogenetics
Authors: Profes Marcos Schaan , Zou Lyucheng , Farrell Kurt W. , Crary John F. 
Published: January 2025

AbstractBackgroundThe molecular etiology of tau‐derived neurodegeneration remains poorly understood, reflected in the low success rate of clinical trials. Hence, aquiring a better understanding the molecular basis of tauopathies is a critical need.ObjectiveTo develop a versatile and reproducible system to study tau aggregation with high spatiotemporal control through optogenetics that will aid in investigating the differences in tau aggregation kinetics, the burden the burden of tau isoforms, and mutations and that will be suitable for high‐throughput analysis of tauopathy‐related mechanisms.MethodWe engineered an optogenetic cellular model using the CRY2 protein that when light‐activated enables spatiotemporal control over tau aggregation. A panel of CRY2‐tau constructs expressing all six neuronal isoforms and known mutations was created to assess aggregation kinetics and cellular burden due to imbalances in tau proteoforms. Tauopathy‐associated factors will be assayed with biochemistry, and challenge optogenetic tau aggregation with their overexpression and knockdown. Experiments in patient‐derived human induced pluripotent stem cell models will be performed supporting the project’s translational nature.ResultHEK293 and SH‐SY5Y cells expressing our constructs showed mCherry stable tau inclusions after light stimulation, which are not present when the backbone alone is transfected and are less frequent without light stimulus. These inclusions where positive for phosphorylation markers consistent with Alzheimer disease when assessed by immunocytochemistry. Western blotting analysis confirmed the presence of high molecular weight tau molecules consistent with dimmers and higher aggregates and live‐imaging assessments of different tau proteoforms suggest different CRY2‐tau inclusion formation kinetics.ConclusionThese data support the feasibility of generating tau aggregates with pathological features in our cellular system. This approach has the potential to enhance the screening process of possible tau aggregation modulators allowing analysis in real time of tau aggregation in a precise manner with high spatiotemporal resolution while. This model may r be amenable to drug screening.
Associations between blood‐based biomarkers of Alzheimer’s disease and rate of global and domain‐specific cognitive decline in an elderly population with 15 years of follow‐up
Authors: Laukka Erika J , Ekström Ingrid , Grande Giulia , Valletta Martina , Qiu Chengxuan , Winblad Bengt , Fredolini Claudia , Fratiglioni Laura , Vetrano Davide Liborio 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD)‐related biomarkers assessed in blood have proved to be useful for detecting dementia and cognitive impairment in the memory clinic. However, less is known about their predictive value in the long‐term and in a community‐based setting.MethodWe examined six common serum‐derived biomarkers of AD (P‐tau181, T‐tau, Aβ42/Aβ40 ratio, P‐tau181/Aβ42 ratio, Nfl, and GFAP) from the baseline assessment of the population‐based Swedish National Study on Aging and Care in Kungsholmen (SNAC‐K; n = 2071, mean age at baseline = 72 years). At baseline, participants were free from dementia and neurodegenerative disorders and their cognitive level was within normal range (Mini‐Mental State Examination score > 23). Global cognition and performance in four specific domains (i.e., episodic and semantic memory, verbal fluency, and perceptual speed) were assessed regularly with a neuropsychological test battery across up to 15 years. Associations of AD‐related serum biomarkers with rate of cognitive decline across the follow‐up period were examined with linear mixed‐effects models.ResultEffects on rate of change in all examined cognitive domains were observed for all biomarkers, except T‐tau. The strongest associations were observed for P‐tau181 (global cognition: β = ‐0.024, 95% CI: ‐0.029 to ‐0.020) and for individuals with relatively high biomarker concentrations (3rd or 4th quartile). Interactions were explored for age, sex, and APOE ԑ4‐carrier‐status.ConclusionTo summarize, this study shows that higher concentrations of blood‐based biomarkers for neurodegeneration are associated with faster rates of cognitive decline in the general elderly population.
Defining the Problem History Heterogeneity in Patients with Alzheimer’s Disease: A Data‐Driven Approach
Authors: Mansel Clayton , Townley Ryan A , Honea Robyn A , Sardiu Mihaela E , Veatch Olivia J 
Published: January 2025

AbstractBackgroundThe medical and social history of patients with Alzheimer’s Disease is heterogeneous with many interacting genetic and environmental factors contributing to an individual’s risk. Moreover, a maternal family history (mFH) is a key risk factor for AD—raising the risk for disease onset by as much as nine times. However, a proportion of individuals do not have a complete knowledge of their family history. Determining which problem history profiles are common among individuals with a mFH of AD may help identify these high‐risk patients. Mitochondria are inherited matrilineally and certain haplogroups have been linked to an increased risk for AD. Subgrouping AD patients based on problem and family history using novel methods such as unsupervised machine learning (ML) may provide key insights into the pathogenesis of AD and could augment future clinical trial enrollment.MethodIn this cross‐sectional study of longitudinal clinical data from the National Alzheimer’s Disease Coordinating Centers (NACC), we used agglomerative hierarchical clustering on principle components to group subjects based on self‐reported medical history and substance use history. A total of 2,754 individuals who did not have AD at their initial visit but later developed AD were included in the final analysis. Secondarily, we tested whether these clusters were associated with a mFH of AD, mitochondrial haplogroup, APOE genotype, and various demographic factors.ResultThe final dataset had a mean age of 76±8.2 years and was 44.9% (n = 1,237) male, 84.9% (n = 2,337) white, 94.4% (n = 2,601) non‐Hispanic, and had 15.7±6.0 years of education. Three distinct problem history clusters were identified: minimal problem history (n = 1,380), substance use history (n = 1,038), and cardiovascular problem history (n = 336). The cardiovascular problem history cluster had a significantly lower proportion of subjects with a mFH of AD and an E4/E4 APOE genotype.ConclusionIn this study, three distinct problem history subgroups were identified. The cardiovascular problem history cluster was not associated with an E4/E4 APOE genotype or a maternal family history of AD, indicating that this subgroup of patients may require further study to determine how to best stratify their risk of AD.
In‐situ glial cell‐surface proteomics for normal brain aging
Authors: Burns Madeline P 
Published: January 2025

AbstractBackgroundDuring aging, we observe several changes in the brain that render it more vulnerable to a variety of age‐related neurodegenerative diseases, including Alzheimer’s Disease. Glia‐neuron interactions mediate brain development and physiology via cell‐surface proteins at the cell‐surface interface, and dysregulation of these interactions is considered one of the hallmarks of brain aging. Due to the critical role glial cells play in neuroplasticity, immune function, and homeostasis, dysregulation of glial cell‐surface proteins is hypothesized to contribute to neurodegeneration. However, it remains technically difficult to profile glial cell‐surface proteomes from intact brains, which is necessary to preserve important neuron‐glia global dynamics.MethodRecently, we employed a state‐of‐the‐art in‐situ cell‐surface proteomics technique to profile how glial cell‐surface proteomes change during normal brain aging in young and old flies.ResultIn total, we identified 872 glial cell‐surface proteins, and found that while most up‐regulated genes were associated with cell localization and transport, most down‐regulated genes were associated with neural development, circuit organization, and neuroplasticity. Based on our proteomic profiles, we selected 48 candidate genes for further screening (based on which were most up‐ or down‐regulated). Currently, we are conducting several gain‐of‐function/loss‐of‐function genetic screens to investigate the effects of each candidate gene on lifespan, using the repo‐GS/UAS binary system, and have selected two candidate genes of interest to investigate further.ConclusionWe have found that some of the most differentially expressed genes were associated with neural development and wiring molecules not previously thought to be particularly active in glia.
The mTOR‐4E‐BP1 axis controls microglia inflammatory and neurodegenerative responses
Authors: Bermudez Sara , Choi Junghyun , Kim Sunghoon , Vogel Jacob W. , Mahmood Niaz , Zhu Vivian Yuchan , Yaqubi Moein L , Stratton Jo Anne , Hansson Oskar , Valles Argel Aguilar , Healy Luke M , Sonenberg Nahum 
Published: January 2025

AbstractBackgroundActivation of the mTOR pathway is pivotal for microglia to induce and sustain neuroprotective functions (Ulland et al., 2017; Wang et al., 2022). mTOR complex 1 (mTORC1) inhibits the translation repressors, eukaryotic translation Initiation Factor 4E (eIF4E)‐Binding Proteins (4E‐BPs), via phosphorylation, which causes their release from eIF4E to promote mRNA translation (Hay and Sonenberg, 2004). mTORC1 promotes mitochondrial biogenesis via inhibition of 4E‐BPs, by preferentially stimulating the translation of mitochondria‐related mRNAs (Gandin et al., 2016; Morita et al., 2013). We investigated the mechanisms at the intersection of 4E‐BP‐dependent translational regulation and metabolism in microglial response to soluble Aβ.MethodWe carried out immunoblot analysis to investigate the phosphorylation status of 4E‐BP1, the isoform most abundant in microglia, following exposure to Ab. We manipulated the mTOR pathway by knocking out the downstream effectors, 4E‐BPs, to alleviate translation suppression in microglia in vitro and in vivo. We crossed the microglia‐specific 4E‐BPs knockout mouse with a RiboTag mouse to pull‐down ribosome‐bound mRNAs, providing a genome‐wide pool of actively translating mRNAs in the absence or presence of 4E‐BPs. Finally, we examined the relationship between 4E‐BP1 levels and neuroinflammation markers in cerebrospinal fluid (CSF) of AD patients.ResultWe showed that 4E‐BP1 is inhibited acutely upon exposure to soluble Ab, which is dependent on Spleen Tyrosine Kinase (SYK) activation upstream of mTORC1, but is reduced upon chronic exposure. Furthermore, 4E‐BP1 expression is induced during prolonged exposure to Ab. The deletion of 4E‐BPs in microglia in vitro leads to an increase in mitochondrial mass and reliance on oxidative phosphorylation while decreasing expression of pro‐inflammatory mediators and cell death upon exposure to Ab. We observed that increased levels of 4E‐BP1 in the CSF of patients with Aβ pathology are associated with higher neurodegeneration (Nfl) in the presence of microglial activation.ConclusionWe demonstrate that mTORC1 signaling critically impacts microglia physiology and promotes neuroprotective functions via 4E‐BP1 inhibition. 4E‐BP1 activity in microglia engenders a dysfunctional or detrimental state that may lead to increased neurodegeneration. Therefore, 4E‐BP1 is an attractive target for microglia modulation in AD.
Targeting HDAC6 for chemotherapy‐induced neurotoxicity and Alzheimer’s disease
Authors: Ma Jiacheng , Goodwani Sunil , McReynolds Morgan , Huichalaf Claudia H , Buggia‐Prevot Virginie , Acton Paul , Kavelaars Annemieke , Heijnen Cobi J , Ray William J 
Published: January 2025

AbstractBackgroundChemotherapy‐induced cognitive impairment (CICI) is a commonly reported neurotoxic side effect of chemotherapy, occurring in up to 75% cancer patients. Connections between chemo‐treatment and increased risk of dementia have been reported. Mechanistically, chemotherapy treatment contributes to an accelerated aging phenotype in the brain through induction of pathogenic tau, disruption of neuronal integrity, reactive gliosis and neuroinflammation. Our work identified histone deacetylase 6 (HDAC6) as a potential therapeutic target against CICI. The primary substrates of HDAC6 include non‐histone cytoplasmic substrates, such as the microtubule protein α‐tubulin. Inhibition of HDAC6 has been shown to improve axonal transport of mitochondria and preserve axonal bioenergetics, the disruption of which are key factors contributing to cognitive impairment associated with chemotherapy and Alzheimer’s disease (AD). Therefore, inhibition of HDAC6 may provide benefits against chemotherapy‐induced neurotoxicity and Alzheimer’s disease.MethodCICI was established in mice with two cycles of cisplatin treatment. A brain‐penetrant HDAC6 inhibitor was then administered for two weeks. Behavioral testing, immunohistochemistry and biochemical approaches were taken to determine the effect of HDAC6 inhibition on cognitive function, synaptic mitochondrial function, synaptic integrity and tau pathology. To determine the therapeutic potential of targeting HDAC6 for AD, we crossed the Tg4510 tauopathy mouse model with HDAC6 knockout mice and evaluated behavioral changes and markers of neurodegeneration including NeuN staining and plasma neurofilament‐light.ResultHDAC6 inhibition normalizes cisplatin‐induced cognitive impairments, restores microtubule stability and reverses tau phosphorylation, leading to normalization of synaptic mitochondrial function and synaptic integrity in CICI. These data suggest that short‐term treatment with a brain‐penetrant HDAC6 inhibitor is sufficient to achieve prolonged reversal of functional deficits induced by chemotherapeutics. In the context of AD, short‐term treatment with the HDAC6 inhibitor did not provide benefits in the Tg4510 tauopathy mouse model. However, knockout of HDAC6 in Tg4510 mice reverses the hyperactive behavioral phenotype, preserves neuronal integrity and reduces plasma neurofilament‐light level up to 6‐month of age.ConclusionHDAC6 inhibition has great therapeutic potential for both chemotherapy‐induced neurotoxicity and AD.
Microbiota‐Microglia Interactions Modulate Beta‐Amyloid Levels
Authors: Cox Laura M 
Published: January 2025

AbstractBackgroundThe gut microbiota and microglia play critical roles in Alzheimer’s disease (AD), and more information is needed on how specific bacteria affect brain immunity in AD. We found that Bacteroides increased in aging Tg2576 mice and correlated with amyloid‐beta (Aβ) plaques and hypothesized that Bacteroides worsens AD pathology by modulating microglia. Bacteroides is also elevated in AD patients and correlates with cerebrospinal fluid levels of Aβ and tau.MethodTo test the effect of B. fragilis on Aβ plaques and microglia, we administered Bacteroides fragilis to APP/PS1‐21 mice, assessed plaques by immunohistochemistry, and investigated microglial transcriptional responses on FAC sorted microglia by RNAseq. To determine whether B. fragilis suppressed microglial uptake, we also administered B. fragilis to aged WT mice for two months, then injected fluorescently labeled human Aβ1‐42 peptides to the brain and measured FITC‐Aβ by flow cytometry.ResultWe found that B. fragilis increased Aβ plaques in female mice, modulated cortical gene expression involved in amyloid processing, and down regulated expression of microglial genes involved in phagocytosis and protein degradation. To investigate microglial phagocytic function, we administered B. fragilis to aged WT female and male mice for 2 months, injected fluorescently labeled human Aβ1‐42 peptides to the brain, and found that B. fragilis suppressed uptake of Aβ in both male and female mice. Depleting murine Bacteroidota with metronidazole decreased amyloid load in aged 5xFAD mice, and activated microglial pathways related to phagocytosis, cytokine signaling, and lysosomal degradation.ConclusionTaken together, these data suggest that bacteria in the Bacteroidota phylum contribute to AD pathogenesis by suppressing microglia phagocytic function, leading to impaired Aβ clearance and accumulation of plaques.
NCRAD: Academic Biorepository to Support Standardization and Efficacy of Clinical Research Biospecimens for the Advancement of AD/ADRD Research
Authors: Snoddy Casey , Faber Kelley M. , Lacy Kaci , Jackson Jacqueline M , Foroud Tatiana M. 
Published: January 2025

AbstractBackgroundNCRAD is a National Institute on Aging (NIA) cooperative grant, awarded to Indiana University since 1990, whose purpose is to serve as a biorepository for AD/ADRD researchers. With 74 participating across 150 unique institutions, NCRAD links specimens to clinical research data. NCRAD maintains over 2 million aliquots from more than 126,000 research participants spanning a wide range of AD/ADRD related phenotypes as well as healthy controls.MethodTo ensure standardization and uniformity, NCRAD develops a manual of procedures specific to each study protocol that includes detailed pictures, schematics, and flow charts for each sample type collected. NCRAD conducts web‐based training for site staff and provides supplemental training videos to ensureResearchers receiving samples from NCRAD agree to share the data generated from the samples. Since its inception, NCRAD has distributed over 410,000 samples to more than 200 researchers. NCRAD biospecimens and data have been reported in more than 850 publications.ResultNCRAD’s mission is to maintain uniformity in collection and processing of samples sites involved in each study. Centralized biobanking and broad sharing of biospecimens has accelerated research discovery.ConclusionUsing standardized biospecimen collection, processing, shipping, storage, and distribution procedures established at NCRAD, in conjunction with attention to detail, strict compliance with regulations, and oversight from the NIA, has resulted in a biorepository with highest quality samples available to researchers investigating the etiology, early detection and therapeutic development for AD/ADRD.
Analysis of neurovascular unit after voluntary physical exercise in a transgenic mouse of Alzheimer’s disease
Authors: Andrade José de Jesús , Orta‐Salazar Erika , Díaz‐Cintra Sofia , Soto‐Rojas Luis Oskar 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) stands out as the most prevalent neurodegenerative condition globally, marked by a progressive cognitive decline. Its distinctive histopathological features include neurofibrillary tangles composed of Tau protein aggregates and amyloid beta (Aβ) aggregates forming neuritic plaques in the parenchyma and cerebral amyloid angiopathy (CAA) in blood vessels. Intriguingly, it has been hypothesized that CAA induces alterations in the cells comprising the neurovascular unit (NVU), exacerbating the disease’s symptoms. Currently, effective treatments for AD remain elusive. The triple transgenic mouse model for AD (3xTg‐AD), harboring three mutations associated with familial AD (PS1M146V, APPSWE, and tauP301L), is widely employed to investigate molecular mechanisms and assess therapeutic strategies. One promising non‐pharmacological approach is physical exercise, a planned, repetitive, and regulated physical activity. However, its impact on the cerebrovascular system remains unclear. This study aims to analyze the effect of physical exercise on the NVU in the 3xTg‐AD model.MethodA total of 40 ten‐month‐old female mice, including 3xTg‐AD (n = 20) and non‐Tg (n = 20), were equally divided into exercise and sedentary groups. A voluntary physical exercise intervention spanning three months, with a frequency of five times a week, was implemented. Subsequently, we evaluated cognitive functions, CAA, and NVU morphostructure through histological assaysResultOur results demonstrate that 3xTg‐AD mice develop vascular amyloid deposits, correlating with NVU alterations and cognitive deficits. Intriguingly, voluntary physical exercise reduces CAA and amyloid plaques, coinciding with improvements in cognitive abilities and NVU component integrity.ConclusionThe intervention with voluntary physical exercise holds promise for enhancing vascular system stability and reducing CAA in symptomatic stages of AD, presenting a potential therapeutic avenue for individuals affected by the disease.
Functional impairment in a dementia‐free sample associated with a higher risk of Mild Behavioral Impairment
Authors: Mortby Moyra E , Ismail Zahinoor , Anstey Kaarin J. 
Published: January 2025

AbstractBackgroundMild Behavioral Impairment (MBI) and functional ability are two non‐cognitive markers of dementia. To date, little is known about the impact of functional ability on the clinical manifestation of MBI. Using data from the Australian population‐based PATH Through Life Study we examined the impact of functional ability on MBI. We hypothesized that poorer functional ability in a dementia‐free sample (with at most Mild Cognitive Impairment; MCI) would be associated with a higher likelihood of MBI.Method1377 dementia‐free participants (52% male; aged 72‐79; 847 cognitively healthy, 397 cognitively normal, but‐at‐risk (i.e., subjective cognitive decline), 133 MCI) were included. Functional ability was assessed using the Bayer Activities of Daily Living scale (B‐ADL), which comprises 25 items assessed by an informant. Items are scored 1‐10 with higher scores indicating poorer functional ability. Presence and absence of MBI and its five domains (decreased motivation, affect dysregulation, impulse dyscontrol, social inappropriateness, abnormal perception/thought content) were approximated using a previously published transformation algorithm, which utilizes items from the Neuropsychiatric Inventory assessed at a single study visit. Binomial logistic regression analyses were conducted to examine risk of MBI associated with functional impairment. Models controlled for Mini Mental State Exam scores (MMSE) and self‐reported gender (male/female).ResultAdjusted logistic regression (MMSE and gender) showed that a one‐unit increase on the B‐ADL was associated with a 2.27‐fold greater risk of MBI (95% CI 1.962‐2.624; p<.001). Similarly, for all 5 MBI domains, a one‐unit increase of B‐ADL was associated with greater risk of all domains: decreased motivation (B = 2.26; 95% CI 1.898‐2.684; p<.001), affect dysregulation (B = 2.02; 95% CI 1.763‐2.306; p<.001), impulse dyscontrol (B = 2.01; 95% CI 1.756‐2.301; p<.001), social inappropriateness (B = 2.01; 95% CI 1.707‐2.378; p<.001), and abnormal perception/thought content (B = 1.82; 95% CI 1.417‐2.335; p<.001).ConclusionThis study is amongst the first to identify a higher risk of MBI associated with functional ability in dementia‐free older adults. These findings highlight the importance of early monitoring of changes in functional ability and behaviour, even prior to the onset of cognitive symptomatology. They also provide further evidence of the clinical utility of functional ability and MBI as early markers of dementia.