bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interactome Analysis of Tau‐seed Isolated from AD Brains Suggests New Mechanism for Tau Aggregation and Spreading
Authors: Martinez Pablo , You Yanwen , Patel Henika , Jury Nur , Min Yuhao , Redding Javier , Huang Xiaoqing , Dutta Sayan , Mosley Amber L. , Rochet Jean‐Christophe , Zhang Jie , Ertekin‐Taner Nilüfer , Troncoso Juan C , Reeves Cristian A Lasagna 
Published: January 2025

AbstractBackgroundTau aggregates, a hallmark of Alzheimer’s disease (AD) and other tauopathies, spread throughout the brain, contributing to neurodegeneration. How this propagation occurs remains elusive. Previous research suggests that tau‐seed interactors play a crucial role. Based on this, the study aimed to identify novel tau‐seed interactors in AD brains and validate their impact in vivo.MethodAD and control brain extracts were separated in fractions by Size Exclusion Chromatography. Fractions with the highest tau seeding activity, measured using a tai‐biosensor cell line, were analyzed by mass spectrometry to identify interacting proteins. Bioinformatic tools dissected enriched pathways, identifying interactors that were validated in a Drosophila tauopathy model by genetically interfering with their homologs and assessing tau accumulation and eye degeneration.ResultsTau seeding activity was concentrated in high molecular weight fractions containing only a small portion of total tau in the AD brains. Compared to controls, AD brains revealed a distinct interactome for tau‐seeds, enriched in proteins associated with synaptic and mitochondrial pathways. Notably, Drosophila screening confirmed that several novel interactors significantly reduced tau accumulation and eye degeneration, suggesting their potential therapeutic relevance.ConclusionThis study sheds light on tau propagation mechanisms in AD by identifying novel tau‐seed interactors. These interactors, particularly those involved in synaptic and mitochondrial pathways, offer promising targets for therapeutic interventions aimed at decreasing tau spread and potentially preventing neurodegeneration in tauopathies. The findings add to the growing evidence that targeting tau‐seed interactors, like previously identified BSN, could represent a novel strategy for treating these debilitating conditions.
Amyloid Precursor Protein alters Mitochondrial function and Mitophagy
Authors: Strope Taylor A. , Hauger Brittany M , Wilkins Heather M , Schroeder Kealan 
Published: January 2025

AbstractBackgroundAmyloid Precursor Protein (APP) processing to Aβ is well understood but the function of APP is largely unknown. APP is expressed ubiquitously and localizes to mitochondria. The consequences of mitochondrial APP localization are not known. We leveraged models of altered APP mitochondrial localization to understand the relationship between APP and mitochondrial function.MethodWe have generated several isogenic iPSC lines using Crispr/Cas9 including WT APP (no gene targeting), 3M APP homozygous and hemizygous (which harbors mutations at amino acids +41, +44, and +52 (His to Asp)), APP knockdown (missing one allele), APP knockout (missing both alleles), and APP duplication. These iPSC lines were differentiated into both neurons and astrocytes. Mitochondrial localization of APP was quantified using Western blot analysis. Aβ was measured via ELISA. Mitochondrial respiratory function was analyzed using Seahorse Technology or Vmax spectrophotometric assays. Mitophagy was examined by qPCR against mitochondrial DNA content and an adenovirus expressing EGFP‐COX8. Mitochondrial biogenesis and turnover were measured using an adenoviral MitoTimer vector.Result3M APP and knockdown/knockout APP models had reduced mitochondrial APP localization while APP duplication had increased mitochondrial APP localization. Models with reduced APP localization to mitochondria had reduced Aβ production, while APP duplication had increased Aβ production. Reduced mitophagy levels and altered mitochondrial biogenesis were observed in models with reduced mitochondrial APP localization. APP duplication increased mitophagy and altered mitochondrial biogenesis. Both reduced and increased mitochondrial APP localization reduced mitochondrial respiratory function.ConclusionAPP localization to mitochondria alters mitochondrial function, mitochondrial mass, and mitophagy. Further studies are in progress to elucidate the effects of mitochondrial localization of APP on bioenergetics.
Inhibition of thrombin signaling after traumatic brain injury improves neurobehavioral dysfunction in 5xFAD mice
Authors: Iannucci Jaclyn , Arismendi Victoria , Bandopadhyay Shreya , Grammas Paula , Shapiro Lee A. 
Published: January 2025

AbstractBackgroundTraumatic brain injury (TBI) is a serious societal concern and is considered a major risk factor for the development of Alzheimer’s disease (AD) and related dementias. Identifying shared pathological mediators that contribute to the progression of AD following TBI may allow therapeutic targeting to reduce the likelihood of developing AD following TBI. Cerebrovascular dysfunction is present in both AD and TBI, and thrombin has been implicated as a mediator of cerebrovascular dysfunction and inflammation. Elevated thrombin levels and thrombin signaling following TBI have been associated with cognitive impairment. Thrombin has similarly been implicated as a pathological mediator in AD. Many of thrombin’s detrimental cellular effects have been linked to thrombin activation of protease activated receptors (PARs), including PAR‐1, which are expressed on a number of cell types in the brain and periphery, including endothelial cells, astrocytes, microglia, and neurons. Therefore, inhibiting thrombin activation of PAR‐1 may be a treatment strategy for AD pathogenesis after TBI. We hypothesize that targeting PAR‐1 activation will mitigate the TBI‐induced increase in AD pathogenesis.Methods8‐week‐old male 5xFAD mice received either our lateral fluid percussion injury (FPI) model of TBI or sham surgery. This was followed 3 hours later by inhibition of PAR‐1 activation via treatment with a selective PAR‐1 inhibitor (SCH‐79797; 25µg/kg, i.p.) or vehicle control (DMSO). Behavioral measures included digigait assessment of acute motor deficits, depression‐associated behaviors, including social interaction and burrowing, and cognitive behaviors. Mice were subsequently sacrificed and tissue was collected for analysis of AD‐associated pathology as well as cerebrovascular dysfunction.ResultsFPI causes chronic cerebrovascular alterations in 5xFAD mice. FPI was also found to induce deficits in depression‐associated behaviors in 5xFAD mice, most notably social interaction. FPI also induced hippocampal‐associated cognitive impairment in both the Y‐maze and Barnes maze. The impaired affective and cognitive behaviors were improved by SCH‐79797 treatment.ConclusionsThese findings indicate that there is chronic cerebrovascular dysfunction in 5xFAD mice that can be exacerbated by FPI and highlight the potential for targeting thrombin and related signaling processes for mitigating these effects after injury.
Enhanced microglial dynamics in the amyloid plaque microenvironment contributes to cognitive resilience in Alzheimer’s disease
Authors: Jury Nur , Redding Javier , You Yanwen , Martinez Pablo , Karahan Hande , Juarez Enrique Chimal , Johnson Travis S , Zhang Jie , Kim Jungsu , Troncoso Juan C , Reeves Cristian A Lasagna 
Published: January 2025

AbstractBackgroundAsymptomatic Alzheimer’s disease (AsymAD) refers to individuals with preserved cognition but identifiable Alzheimer’s disease (AD) brain pathology, including beta‐amyloid (Aβ) deposits, neuritic plaques and neurofibrillary tangles upon autopsy. Unlike AD cases, AsymAD exhibits low neuroinflammation and fewer soluble pathological tau species at synaptic levels. However, the link between these observations and the ability to counteract AD pathology is not fully understood. Evidence from AD mice models suggests that the plaque microenvironment significantly influences Aβ plaque‐associated tau pathogenesis. In this study, we investigated the postmortem brains of a cohort of AsymAD cases to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline.MethodWe conducted a detailed histological and biochemical analysis using postmortem brain samples from age‐matched controls (N = 13), AD (N = 19), and AsymAD subjects (N = 17). In fixed brain tissue, we performed the GeoMx whole spatial transcriptome atlas to compare the gene expression within the Aβ‐plaque microenvironment in AsymAD versus AD cases. To further explore the mechanisms insights of our findings we used human microglial cells.ResultOur findings showed that AsymAD cases exhibit an enrichment of core plaques and decreased filamentous plaque accumulation with increased surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD versus AD brains, and tau seeding activity was comparable to that in healthy brains. To further characterize the plaque niche, we used spatial transcriptomics, finding an increase in components of the actin‐based motility pathways within the microglia surrounding amyloid plaques in AsymAD brains. Ongoing mechanistic experiments in vitro aim to elucidate the role of this pathway in microglial response to Aβ.ConclusionOur findings indicate that the amyloid‐plaque microenvironment in AsymAD brains is characterized by microglia with highly efficient actin‐based cell motility mechanisms and decreased tau seeding versus that observed in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression.
Usability and Compliance of Online Cognitive Assessments in the British 1946 Birth Cohort
Authors: Giunchiglia Valentina , Cai Ziyuan , Giovane Martina Del , Street Rebecca E , Lu Kirsty , Wong Andrew , Popham Maria , Murray‐Smith Heidi , Richards Marcus , Crutch Sebastian J. , Schott Jonathan M. , Hampshire Adam 
Published: January 2025

AbstractBackgroundCognitive assessments are essential for detecting and monitoring cognitive changes in neurological populations. Compared to standard pen‐and‐paper tests, online cognitive tasks offer a more accessible, scalable, repeatable and cost‐effective approach to assessment. Cognitron is an online cognitive assessment platform with previously demonstrated validity and reliability (1). This study aims to derive meaningful insights into the application of online and computerized assessments in older age cohorts by examine the usability of Cognitron tasks with the MRC National Survey of Health and Development (NSHD; the 1946 British birth cohort).Method1753 members of the NSHD cohort (all aged 77) were invited to complete a battery comprising 13 Cognitron tasks, spanning multiple cognitive domains, on their home devices. Each task generated measures of accuracy and reaction time. We examined data quality, completion rates, and levels of engagement and compliance. Qualitative data from email (N = 200) and telephone (N = 78) queries were analysed to determine insights into participant experiences.Result990 members (56.47%) consented to participate in the study, of whom 813 attempted the battery (46.34%). 739/813 (90.89%) completed all cognitive tests (average completion time = 40 minutes). 8 tasks (61.53%) were completed by all participants. 4 tasks had <2% of participants incompletely engaging. One task (Choice Reaction Time) had 9% of data with signs of non‐compliance and was dropped from further analysis (Figure 1). The most common signs of non‐compliance were repetitive clicking in the same screen location, switching of browser page, accuracy scores below minimum expected (e.g. failing the simplest trials) and non‐engagement with >90% of trials (Table 1). The qualitative analysis of the reasons participants contacted the study by email or telephone identified five key themes: (1) technical issues (N = 137), (2) general queries (N = 88), (3) reasons for withdrawing (N = 72), (4) providing feedback (N = 43) and (5) subjective reports (N = 28) (Figure 2).ConclusionCognitron assessment was characterised by high completion, engagement and compliance rates in the NSHD cohort, suggesting that online cognitive assessments have potential to monitor cognitive changes in older age cohorts, including those at risk of developing dementia.Reference(1) Del Giovane, Martina, et al. (2023) EClinicalMedicine 59 https://doi.org/10.1016/j.eclinm.2023.101980
Mapping the neuroimmune landscape of Alzheimer’s disease in African Americans
Authors: Ifediora Nkechime E. , Nimmagadda Nivedita , Lee Emily , Canoll Peter D. , Schneider Julie A. , Bennett David A. , Menon Vilas , Barnes Lisa L. , Olah Marta 
Published: January 2025

AbstractBackgroundAfrican Americans (AA) are disproportionally burdened by Alzheimer’s disease (AD), but there is a scarcity of research focusing on understanding the neuroimmune component of AD pathogenesis in this population. It is generally accepted that microglia would be an ideal therapeutic target for AD and that genetic, lifestyle, societal and environmental factors and stressors have the potential to shape microglia phenotypes and their contribution to neurodegenerative processes. The overarching goal of the current study is to establish the population structure of microglia in older AAs and to investigate the relationship of the different microglia subsets with histopathological hallmarks of brain aging and AD in AAs.MethodWe utilized our established pipeline to isolate live microglia (and other immune cells) from human brain and investigate them at the single cell level using a multi‐omic approach employing transcriptomic, epigenetic and proteomic profiling. This approach, that has recently yielded the first map of microglia population structure in the aged human brain of NHW donors, has been supplemented with in situ investigation of microglia phenotypes and their association with AD pathology in archival tissue specimens.ResultWe isolated and profiled live microglia from the dorsolateral prefrontal cortex and the anterior watershed deep white matter of 10 AA donors from the Minority Aging Research Study (MARS). Both of these brain regions have been previously associated with cognitive decline. Using single cell RNA‐sequencing, unsupervised hierarchical clustering of the data revealed nine distinct microglia phenotypes: two homeostatic subsets and seven differentiated subsets, similarly to what we previously described in NHW donors. Intriguingly, we detected a different population structure of microglia in AA donors when compared to NHWs. To establish an in depth understanding of these findings we investigated the chromatin accessibility and proteomic profile of the different subsets as well as their relationship to histopathological traits of brain aging in AA donors.ConclusionWhile microglia in the cortex and white matter of older AA donors acquire the same functional phenotypes as microglia in the brains of NHW donors, they display a distinct population structure. Our findings underline the importance of studying the neuroimmune compartment of AD specifically in AAs.
Mitochondrial Dysfunction in Down Syndrome associated Alzheimer’s Disease
Authors: Smith Keith P , Strope Taylor A. , Hauger Brittany M , Lysaker Colton R , Shaddy‐Gouvion Cynthia , Haeri Mohammad , Head Elizabeth , Swerdlow Russell H , Wilkins Heather M 
Published: January 2025

AbstractBackgroundMitochondrial dysfunction and Aβ accumulation are hallmarks of Alzheimer’s disease (AD). However, the role of these pathologies in Down Syndrome associated Alzheimer’s Disease (DSAD) is unknown. Decades of research describe a relationship between mitochondrial function and Aβ production. Amyloid precursor protein (APP), from which Aβ is generated, is found in mitochondria. APP and Aβ alter mitochondrial function, while mitochondrial function alters Aβ production from APP. How these interactions contribute to DSAD pathology and progression are unknown. Here we interrogated the association of full‐length APP with mitochondria, mitochondrial function, and AD pathological hallmarks.MethodND (n = 10, without DS) and DS associated Alzheimer’s Disease (DSAD, n = 10) postmortem brain tissue was obtained from the University of California Irvine. A human iPSC line was purchased from WiCell with Trisomy 21 and a isogenic control line which underwent Crispr/Cas9 genome editing to remove the extra chromosome 21 copy. iPSC models were differentiated into neurons, astrocytes, and cerebral organoids using StemCell Technologies reagents and protocols. We examined mitochondrial function using a Seahorse XF analyzer. We measured full‐length APP protein levels in whole cell extracts and mitochondrial fractions via Western Blotting. We measured Aβ levels with ELISA kits from ThermoFisher.ResultDSAD postmortem brain tissue had reduced mitochondrial function regardless of sex. Full‐length APP levels were significantly higher in mitochondrial fractions in DSAD brain tissue. Full‐length APP levels in mitochondrial fractions correlated with mitochondrial function. Higher mitochondrial APP (full‐length) levels associated with lower mitochondrial function. iPSC derived models showed similar phenotypes to postmortem brain tissues, including increased mitochondrial APP levels, and decreased mitochondrial function.ConclusionWe describe a relationship between mitochondrial APP accumulation, and mitochondrial function. These data support a centralized role for mitochondrial function in APP physiology and APP may play a role in modulating mitochondrial function. Further, DSAD postmortem tissue and iPSC models show significant mitochondrial dysfunction.
Cognitive, behavioral, and quality of life outcomes in cognitively unimpaired older persons with or without sleep complaints
Authors: Guan Dylan X. , Beaudin Andrew , Smith Eric E. , Ismail Zahinoor 
Published: January 2025

AbstractBackgroundChanges in sleep are common in older persons and have been linked to higher dementia risk. The link between sleep complaints and early risk markers of Alzheimer’s disease (AD), namely subjective changes in cognition and mild behavioral impairment (MBI), have not been fully explored. This study investigated associations between sleep complaints with cognitive and behavioral AD risk markers and quality of life (QoL) among cognitively unimpaired older persons. We hypothesized that older persons reporting sleep changes would also report more severe cognitive and behavioral changes, and poorer QoL.MethodParticipants (n = 1395) were from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging (CAN‐PROTECT) study. Sleep complaints were self‐reported presence or absence of sleep disruption (symptoms of insomnia or sleep‐related movement disorders), daytime sleepiness, sleep‐disordered breathing, or prolonged sleep duration. Outcomes included the Everyday Cognition (ECog‐II) scale, Mild Behavioral Impairment Checklist (MBI‐C), and Quality of Life and Function (QFS‐5) scale. Age, sex, years of education, marital status, and ethnocultural origin were balanced across exposure groups using inverse probability of treatment weighting. Negative binomial and bootstrapped linear regressions were used, as appropriate, to model sleep complaint (exposure) associations with ECog‐II and MBI‐C total scores, and QFS‐5 mean scores (outcomes).ResultParticipant characteristics are summarized in Table 1. Table 2 shows that all sleep complaints were associated with poorer everyday cognition, more severe MBI symptoms, and poorer QoL. However, excessive daytime sleepiness was generally the most strongly associated with the three outcomes with them having 1.50 (95%CI [1.40, 1.60]) and 2.29 (95%CI [2.10, 2.50]) times higher ECog‐II and MBI‐C score compared to participants without daytime sleepiness, and a 0.71 SD (95%CI [0.59, 0.82]) lower QFS‐5 mean score.ConclusionSleep complaints, even among cognitively unimpaired older persons, are linked to cognitive and behavioral risk markers of AD, as well as poorer QoL. These findings provide further evidence that sleep complaints represent modifiable risk factors or may reflect a prodrome for AD, and may contribute to overall disease burden.
The Association between measures of Sleepiness and Subjective Cognitive Decline symptoms in a diverse population of cognitively normal older Adults
Authors: Briggs Anthony Q , Betensky Rebecca A , Bernard Mark A , Masurkar Arjun V. 
Published: January 2025

AbstractBackgroundSubjective cognitive decline (SCD) is a preclinical stage of Alzheimer’s disease (AD), with correlations to cerebral amyloid and tau and accelerated cognitive decline. Studies have also revealed an association between sleep fragmentation and such AD biomarkers and cognitive decline, suggesting that cognitive function should be monitored in individuals experiencing excessive sleepiness. It is unclear if and how sleep dysfunction relates to SCD apart from AD biomarkers, as well as symptoms related to SCD and sleep dysfunction, such as depression. Furthermore, studies of SCD and sleep dysfunction have primarily focused on non‐Hispanic Whites. Hence, a better understanding of how sleep impacts preclinical AD risk in SCD is needed in more diverse cohorts. We investigated the cross‐sectional relationship between excessive sleepiness in cognitively normal older adults and SCD symptoms linked to cognitive domains in a cohort consisting of NHWs and Black/African Americans (B/AA).MethodThis retrospective cross‐sectional study included cognitively normal older participants (n = 147, age> 60 years, 61 B/AA, 86 NHW) evaluated at the NYU Alzheimer’s Disease Research Center. Participants underwent Uniform Data Set 3.0 psychometric testing to confirm normal cognition, Epworth Sleepiness Scale (ESS), Geriatric Depression Scale (GDS), and the Cognitive Change Index (CCI) as a measure of SCD. The CCI was further divided into subscores of non‐amnestic (i.e. executive) and amnestic domains (i.e. memory). Participants underwent amyloid (florbetaben) and tau (PI‐2620 or MK‐6240) PET MRI, with composite SUVR calculated by averaging key cortical regions. Multivariable linear regression models tested the association of ESS and covariates (GDS, amyloid SUVR, tau SUVR, race) to the three CCI outcome measures (total, non‐amnestic, amnestic).ResultESS (excessive sleepiness) was significantly positively associated with total CCI (p = 0.01042) as well as non‐amnestic (0.00771) and amnestic CCI subgroups (0.02583), after full covariate adjustment, as was GDS. Race did not show an independent statistically significant association.ConclusionThese results suggest that excessive sleepiness, independent of depression and amyloid and tau burdens, may be a significant contributor to SCD severity. Furthermore, these contributions impact both amnestic and non‐amnestic domains. Future studies are needed to investigate the longitudinal impact of excessive sleepiness on SCD outcomes.