bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral Signatures of Disease Heterogeneity
Authors: Higginbotham Lenora A 
Published: January 2025

AbstractBackgroundThere is currently an unmet need for novel accessible biomarkers that capture the complex and heterogenous pathophysiology of Alzheimer’s disease (AD). Over the past decade, the systems‐based multi‐omic approaches employed by the Accelerating Medicines Partnership in AD (AMP‐AD) have resulted in the identification of promising peripheral markers of disease heterogeneity. This scientific review will highlight these advances with a particular focus on the consortium’s successes in peripheral protein biomarker discovery in cerebrospinal fluid (CSF) and plasma.MethodsThe AMP‐AD consortium has applied a brain‐to‐biofluids approach to biomarker discovery designed to identify CSF and plasma markers that reflect the heterogeneous corticolimbic pathophysiology of AD. The successful identification of such biomarkers has relied on a combination of innovative multi‐omic techniques, sophisticated data integration strategies, and informative machine learning algorithms. Network‐based proteomic analysis has proven a powerful tool for advancing this brain‐to‐biofluids strategy.ResultsNetwork‐based proteomic analysis across hundreds of human brain tissues from AMP‐AD institutions has identified highly reproducible alterations in a variety of co‐expressed protein groups or “modules” in AD. These disease‐associated modules reflect diverse pathophysiology, including synaptic, metabolic, vascular, and inflammatory dysfunction. Integrative analyses have demonstrated that these brain‐based alterations are highly reflected in the AD CSF proteome. AMP‐AD researchers recently validated a 48‐marker brain‐derived CSF panel that can reliably predict cognitive trajectory, amyloid / tau status, and the evolution of neuroimaging markers. In a separate analysis, CSF levels of select matrisome heparin‐binding proteins originally identified in brain network studies discriminated autosomal dominant AD mutation carriers years prior to symptom onset as well or even better than traditional amyloid and tau measures. These matrisome markers have also demonstrated reliable disease‐associated alterations in heparin‐enriched plasma, highlighting their potential as AD blood‐based biomarkers. Finally, emerging research suggests the CSF and plasma marker profiles generated from these network‐based analyses can delineate biological subtypes of AD with distinct clinicopathological phenotypes.ConclusionsOver the past decade, AMP‐AD has successfully leveraged brain‐to‐biofluid multi‐omic approaches to identify and validate promising peripheral biomarkers of AD. Network‐based proteomics has proven a valuable tool in furthering these biomarker efforts and advancing precision medicine within this complex and heterogeneous disease.
Cortical thinning and Cognition in Cerebral Small Vessel Disease
Authors: Kapasi Alifiya , Lamar Melissa , Wagner Maude , Evia Arnold M , Bennett David A. , Leurgans Sue E. , Arfanakis Konstantions , Schneider Julie A. 
Published: January 2025

AbstractBackgroundEvidence is accumulating that cerebral small vessel disease may contribute to neurodegeneration. Brain arteriolosclerosis, a prominent type of small vessel disease in the aging brain, is associated with cognition. Using a previously developed published automated in‐vivo MRI classifier for arteriolosclerosis (ARTS), we examined cross‐sectionally the associations between ARTS, cortical thinning, and cognition.MethodData came from 1,023 older participants from 5 ongoing Rush Alzheimer’s Disease Center cohort studies. Participants underwent detailed annual cognitive evaluations and completed at least one in‐vivo 3T MRI scan and one cognitive evaluation during follow‐up. In addition to global cognitive measures and MRI‐derived measures for ARTS score, data including global and lobar cortical thinning composites calculated using FreeSurfer. Using the latest completed MRI scan and a close assessment of cognition, linear regression models were employed to examine the association of ARTS with cortical thinning (global and regional) and global cognition. Further, mediation analyses were used to examine whether cortical thinning mediates the relationship between ARTS and global cognition. Models were all adjusted for age, sex, education, vascular risk factors, and scanner site.ResultParticipants had an average age at 80 years (SD = 7) at last MRI scan, and 79% were women. Higher ARTS score was associated with global cortical thinning (estimate = ‐0.14; SE = 0.02, p<0.001), as well as regional cortical thinning in all four lobes (all p’s >0.017). Higher ARTS score was associated with lower global cognition (estimate = ‐0.49; SE = 0.10, p<0.001). In mediation analyses, cortical thinning accounted for 35% of the association between ARTS and global cognition.ConclusionIn vivo MRI‐derived measures for cerebral arteriolosclerosis are associated with global and lobar cortical thinning. The association between ARTS and cognition is partially mediated by cortical thinning. Findings suggest that cerebral small vessel disease may contribute to neurodegeneration and, both directly and indirectly, to subsequent cognitive impairment.
Amygdala‐predominant α‐synuclein pathology accelerates CA1 neuron loss in Alzheimer’s disease
Authors: Gawor Klara , Tomé Sandra O. , Ospitalieri Simona , Ronisz Alicja , Vandenberghe Rik , Otto Markus , von Arnim Christine , Van Damme Philip , Vandenbulcke Mathieu , Blaschko Matthew , Thal Dietmar Rudolf 
Published: January 2025

AbstractBackgroundIn 43‐63% of symptomatic Alzheimer’s disease (AD) patients, there is an observed accumulation of misfolded alpha‐synuclein (αSyn). Two primary αSyn subtypes have been identified based on the underlying spreading pattern of this pathology: caudo‐rostral and amygdala‐predominant. Interactions between pathological TDP‐43, Tau, and αSyn can aggravate their spread and aggregation. The amygdala might serve as an incubation hub due to its early involvement in these pathologies. Here, we tested our hypothesis that the amygdala‐predominant αSyn pathology contributes to limbic degeneration, including the hippocampus, and increases the burden of other protein aggregates.MethodsWe conducted a neuropathological analysis of 291 autopsy brains from both demented and non‐demented elderly individuals. Neuronal density in the CA1 region of the hippocampus was quantified from hematoxylin‐stained slides. We semi‐quantitatively evaluated αSyn‐pathology severity in six brain regions, stratifying cases into two spreading patterns. In 99 AD cases, we also assessed limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological changes (LATE‐NC) stages and the proportion of pTau affected neurons in CA1.ResultsWe identified an association between amygdala‐predominant αSyn, but not caudo‐rostral, with decreased neuronal density in CA1 (P‐value<0.001). AD patients with amygdala‐predominant patterns showed higher LATE‐NC stages than those without αSyn (adj. P‐value = 0.015), while those with caudo‐rostral patterns had fewer neuritic plaques (adj. P‐value = 0.023) and pTau than pure AD (adj. P‐value = 0.038). Using structural equation modeling, we found that the relationship between αSyn and CA1 cell loss is indirect, mediated through hippocampal pTau and TDP‐43.ConclusionsOur findings indicate that the amygdala‐specific αSyn pattern, but not the rostro‐caudal one, may indirectly contribute to hippocampal neurodegeneration by enhancing the aggregation and toxicity of TDP‐43 and pTau. Furthermore, our study reveals differences in neuropathological characteristics between AD patients with two spreading patterns. These findings underscore the significance of identifying co‐morbid pathologies in AD patients and the necessity for further research on distinct αSyn subtypes.
Molecular and Synaptic Signatures in Mouse Models of Late‐Onset Alzheimer’s Disease Independent of Amyloid and Tau Pathology
Authors: Oblak Adrian L 
Published: January 2025

AbstractBackgroundMODEL‐AD (Model Organism Development and Evaluation for Late‐onset AD) is developing, characterizing, and distributing novel mouse models expressing humanized, clinically relevant genetic risk factors. Models expressing human‐relevant risk genetic risk factors are expected to better phenocopy LOAD than widely used transgenic models.MethodHere, two genetic risk factors APOE4 and Trem2*R47H, were incorporated into C57BL/6J (B6) mice along with humanized amyloid‐beta to produce the LOAD2 model. LOAD2 and control mice were aged up to 24 months with some being provided in the absence or presence of normal chow or a high fat/high sugar diet (LOAD2 HFD) from two months of age. A phenotyping pipeline was employed to evaluate disease outcomes observed in human patients, including in vivo imaging, brain and blood biomarker and cytokine analyses, multi‐omics (transcriptomics and proteomics), neuropathology and behavior.ResultBy 18 months, unlike control mice (e.g., LOAD2 mice fed a control diet, CD), LOAD2 HFD mice presented subtle but significant loss of neurons in the cortex, elevated levels of insoluble AΒ42 in the brain, and increased plasma neurofilament light chain (NfL). Transcriptomics and proteomics showed changes in gene/proteins relating to a variety of disease‐relevant processes including lipid metabolism and synaptic function. In vivo imaging revealed an age‐dependent reduction in brain region volume (MRI) and neurovascular uncoupling (PET/CT). LOAD2 HFD mice also showed a learning deficit based on a Touchscreen cognitive assay.ConclusionDespite the absence of hallmark amyloid and Tau pathologies, collectively these data support the use of LOAD2 HFD mice reveal this model as important for preclinical studies that target other features of LOAD independent of amyloid and tau.
MODEL‐AD Pre‐Clinical Testing Core: A Precision Medicine Pipeline for Preclinical Testing of Alzheimer’s Disease Therapeutic Candidates
Authors: Territo Paul R 
Published: January 2025

AbstractBackgroundPreclinical testing in animal models is a critical component of the drug discovery process. Over the past three decades hundreds of interventions have demonstrated preclinical efficacy for ameliorating cognitive impairments in animal models; however, none have translated to efficacy in Alzheimer’s disease (AD) clinical trials. This lack of translation suggests that there are issues with the animal models employed, the preclinical assays, and poor scientific rigor and reproducibility during execution. To overcome these limitations, the Preclinical Testing Core (PTC) of the Model Organism Development and Evaluation for Late‐onset AD (MODEL‐AD) consortium has established a rigorous screening strategy with go/no‐go decision points that permits unbiased assessments of therapeutic agents.MethodFor each compound selected for screening, a mouse model that is best matched to the drugs mechanism of action, and that has been comprehensively characterized by the MODEL‐AD consortium, will be enrolled. An initial screen evaluates drug identity, stability, formulation, pharmacokinetics (PK), and simulations to confirm appreciable brain exposure in the disease model at the pathologically relevant ages. These efforts inform on the dose regimen for long‐term studies, where secondary pharmacodynamics studies (PD) evaluates target engagement utilizing non‐invasive PET/CT and post‐mortem confirmation. Provided the compound meets the “go” criteria for these endpoints, evaluation for behavioral endpoints are conducted as well as post treatment transcriptomic and proteomic analyses.ResultValidation of this pipeline using both small molecule and biologic tool compounds including the evaluation of verubecestat, levetiracetam, and aducanumab revealed the importance of critical quality control (QC) steps when executing preclinical studies. These include confirmation of the active pharmaceutical ingredient, PK, and PD in well powered studies powered to evaluate effects of sex and conducted according to the ARRIVE guidelines.ConclusionBased on our experience executing rigorous screening strategies with QC checkpoints provide insight to the challenges of conducting translational studies in animal models. The PTC pipeline, an NIA resource, is accessible to the research community for investigators to nominate compounds for testing (https://stopadportal.synapse.org/), thus enabling unbiased studies that support clinical translation.
Interactions with regulatory antibodies modulate CHIP E3 ubiquitin ligase‐driven tau clearance
Authors: Unnikrishnan Aparna , Connelly Emily J , Chung Dong hee , Nadel Cory M , Thwin Aye , Craik Charles S , Southworth Daniel 
Published: January 2025

AbstractBackgroundThe direct and chaperone‐associated interactions of E3 ubiquitin ligase CHIP with tau in Alzheimer’s disease and other tauopathies, regulates tau turnover, by directly linking it to ubiquitination and proteasomal degradation, as well as through suppression of tau aggregation. Modulation of these CHIP‐driven tau clearance mechanisms can be an effective treatment strategy. Antigen‐binding antibody fragments (Fabs) are potent tools that can highly‐selectively engage target proteins and act as functional probes or inhibitors. Development and characterization of Fabs that target unique 3D epitopes on CHIP can help in exploring their therapeutic potential, while enabling structural characterization and providing insights into CHIP‐driven tau clearance mechanisms.MethodRecombinant Fabs were developed to conformation‐selectively bind CHIP, by bio‐panning and BLI binding assays. They were then functionally screened using SEC‐MALS, ubiquitination activity assay, binding assays, ThT fibrillation assays etc. Selected Fab interactions that potently regulated CHIP‐driven mechanisms were further characterized via Cryo‐EM high‐resolution structural studies.ResultCHIP‐Fab complexes with distinct 3D binding epitopes and different functional regulatory effects were identified and studied. High‐resolution details of these Fab interaction sites on CHIP were obtained by Cryo‐EM 3D reconstruction and molecular modeling. Fab ‘2F1’ that forms a 2:2 complex with CHIP, potently inhibits its ubiquitination activity by directly blocking the required E2‐CHIP interactions. Fab ‘H1’ that forms both 1:2 and 2:2 complexes with CHIP, significantly improves its tau aggregation suppression and reveals distinct functional conformational states of CHIP. Fab ‘2D2’ forms a 1:2 complex with CHIP, blocks CHIP‐tau interactions and stabilizes the CHIP coiled‐coil domain dimerization interface.ConclusionFunctional screening of Fabs that were generated to specifically target 3D epitopes on CHIP have revealed potent modes of CHIP functional modulation. Insights from the corresponding CHIP‐Fab complex structures help in better understanding the CHIP‐driven tau clearance mechanisms and in describing unique therapeutic target sites on CHIP.
Pathways of inhibitory interneuron dysregulation in 5XFAD mice
Authors: Chen Kevin S , Noureldein Mohamed , Rigan Diana M , Hayes John M , Savelieff Masha G , Feldman Eva L 
Published: January 2025

AbstractBackgroundInhibitory interneurons normally regulate neural networks underlying memory and cognition, but are disrupted in Alzheimer’s disease. Proper interneuron activity reduces amyloid‐beta, whereas hyperexcitability elevates amyloid levels. Still, the underlying pathologic processes mediating interneuron dysfunction remain unknown. Therefore, we employed a spatial transcriptomics approach to map transcriptomic profiles of interneurons in a temporal and spatial manner.MethodCoronal hemibrain sections from early stage (12 wks) and late stage (30 wks) male mice (5XFAD) underwent fluorescence in situ hybridization to identify interneuron subtypes (parvalbumin‐expressing, PV+, or somatostatin‐expressing, SST+). Slides were submitted for GeoMx DSP spatial transcriptomics (2 duplicate slides per timepoint, n = 2 5XFAD and n = 2 WT per slide). Regions of interest (ROIs) were defined in hippocampal and cortical regions (Figure 1). UV‐liberated barcodes from each ROI, restricted to PV+ or SST+ interneurons, were collected by microcapillary and sequenced by the NanoString Max/Flex nCounter system. Differentially expressed genes (DEGs) were assessed by linear mixed‐effect model and the GeoMx analysis suite, and attribution to respective time points, cell type, and anatomic region were sequentially parsed.ResultIn early‐stage disease, 1,562 DEGs were uniquely expressed by PV+ interneurons and 2,284 DEGs were uniquely expressed by SST+ interneurons. Similarly, at late‐stage disease, 2,790 DEGs were expressed by PV+ interneurons and 2,346 DEGs were uniquely expressed by SST+ interneurons (Figure 2). Focusing on the CA1 region, previously implicated as having a central role in hippocampal dysfunction, interneurons again showed unique alterations. Early‐stage PV+ interneurons in CA1 uniquely expressed 310 DEGs, with “metabolic pathways” having the most DEGs (Figure 3). By contrast, early‐stage SST+ interneurons in CA1 uniquely expressed 422 DEGs, enriched in pathways canonically linked to “amyotrophic lateral sclerosis” and “Alzheimer disease.”ConclusionThe most significant altered pathways within AD interneurons at the earliest stages of disease included neurodegeneration and metabolism pathways. Zero or few DEGs overlapped across all regions or neuronal subtypes. Thus, interneurons display distinct profiles and transcriptional changes by brain area at early‐ and late‐stage disease. These findings will inform future mechanistic experimentation, and suggest investigation into neural circuit dysfunction in AD will require consideration of anatomic subregion specificity.
Early molecular events of Autosomal Dominant Alzheimer’s Disease in marmosets with PSEN1 mutations
Authors: Bailey Lauren , Homanics Gregg E , Park Jung Eun , Schaeffer David J , Schaeffer Lauren K Hayrynen , Zhang Ting , Haber Annat , Spruce Catrina , Greenwood Anna , Murai Takeshi , Schultz Laura , Mongeau Lauren , Ha Seung‐Kwon , Oluoch Julia , Stein Brianne , Choi Sang‐Ho , Huhe Hasi , Thathiah Amantha , Strick Peter L , Carter Gregory W , Silva Afonso C , Rizzo Stacey J Sukoff 
Published: January 2025

AbstractBackgroundFundamental questions remain about the key mechanisms that initiate Alzheimer’s disease (AD) and the factors that promote its progression. Here we report the successful generation of the first genetically‐engineered marmosets that carry knock‐in (KI) point mutations in the presenilin‐1 (PSEN1) gene that can be studied from birth throughout lifespan.MethodCRISPR/Cas9 was used to generate marmosets with C410Y or A426P point mutations in PSEN1. Founders and their germline offspring are comprehensively studied longitudinally using non‐invasive measures including behavior, biomarkers, neuroimaging, and multi‐omics signatures.ResultPrior to adulthood, increases in plasma Aβ were observed in PSEN1 mutation carriers relative to non‐carriers. Analysis of brain revealed alterations in several enzyme‐substrate interactions within the gamma secretase complex prior to adulthood.ConclusionMarmosets carrying KI point mutations in PSEN1 provide the opportunity to study the earliest primate‐specific mechanisms that contribute to the molecular and cellular root causes of AD onset and progression.
Key role of ERβ in estrogenic regulation of neuronal mitochondrial function
Authors: Wang Tian , Mao Zisu , Chen Shuhua , Shang Yuan , McLean John W. , Stanton James Brett , Qi Guoyuan , Yin Fei , Brinton Roberta Diaz 
Published: January 2025

AbstractBackgroundEstrogen is a master regulator of the bioenergetic system in the female brain, exerting broad control over metabolic processes from glucose transport to glycolysis, mitochondrial respiration, and ATP generation. The loss of estrogen during the perimenopausal transition is associated with decline in brain glucose metabolism and mitochondrial function which can contribute to the two‐fold greater lifetime risk of Alzheimer’s disease in postmenopausal women. While both ERα and ERβ have been reported to mediate E2 regulation of brain bioenergetic function, their cell‐type specific contribution to bioenergetic homeostasis has yet to be elucidated.MethodHerein, we investigated the role of ERα and ERβ in E2 regulation of neuronal bioenergetics. We developed novel conditional estrogen receptor α and β knock‐down rat models by inserting two loxP sites upstream and downstream of exon 3 of Esr1 or Esr2 allele using Crispr/Cas9‐mediated genome engineering technique. Our novel ERαlox and ERβlox rat models enable inducible and brain cell‐type and region specific ERα and ERβ knockdown without disrupting normal development of estrogen dependent organs and systems. Using these models, ERα and ERβ dependent regulation on neuronal mitochondrial function was investigated in vivo and in vitro. Further, unbiased transcriptomic analysis was conducted to delineate ERα and ERβ specific signaling pathways modulating neuronal bioenergetic function.ResultERβ significantly regulated E2 activation of neuronal mitochondrial oxidative phosphorylation in vivo. Selective knockdown of neuronal ERβ resulted in significant decrease in hippocampal mitochondrial respiration and impaired OXPHOS complex activity. In contrast, ERα knockdown did not impact hippocampal mitochondrial respiration nor mitochondrial OXPHOS complex activity. These results were confirmed in primary embryonic ERα and ERβ knockdown neurons. Mechanistic investigation further revealed ERβ dependent transcriptomic regulation of TCA and OXPHOS genes. Importantly, ERβ knockdown resulted in increased UCP2 expression and decreased AKT and ERK signaling, leading to increased proton leak and decreased mitochondrial respiration.ConclusionERβ exerts a pivotal role in maintaining neuronal mitochondrial function and bioenergetic homeostasis in female brain. Selectively activating ERβ could provide a precision medicine strategy to promote brain function in menopausal women while inhibiting breast tissue proliferation.
Caregiver, Parent with At‐Risk Children
Authors: Steel Tanya 
Published: January 2025

AbstractMy beloved husband, Robert Steel, died at 58 from MAPT FTD, a disease that stretches back through his family’s generations. Before we married he told me his father died of early‐onset Alzheimers and he was terrified he would inherit that disease. In his early 50s he began exhihibiting symptoms that I attributed to stress–his work as a respected high school teacher began to slip, he began to lose the ability to have a visual map in his head, he began to repeat stories, his behavior became more compulsive, forgot how he was related to a favorite cousin. He had to leave the teaching profession and I had to support our family, with my identical twins soon headed to college.I took him to a reputed neurologist who said perhaps he was depressed. This diagnosis was repeated with other dementia specialists. One day he got into a car accident and left the scene, something that was the opposite of his character. From that day he seemed in a fog and almost unreachable. It was then that I got him diagnosed by Columbia Presbyterian’s Dr. Karen Marder, an FTD specialist. His Behavorial Variant FTD caused by the MAPT gene has likely affected many generations before him, many of whom died fairly young and often of mysterious circumstances.Since that time, I have led a support group for AFTD, begun a book for caregivers of dementia patients, and become a founding member of Cure MAPT FTD. With my three decades of experience on television, panels, public speaking including four speeches at The White House with Mrs. Michelle Obama alongside, I am committed to using my communication skills to help cure this insidious disease. I will speak from the caregiver’s vantage point, discussing the difficulty FTD specifically presents for caregivers and patients–from finances to safety–what clinicians can do to better support both constituents, the frustration in the lack of MAPT‐specific trials, the importance in spreading awareness to thus help others gain quicker diagnosis, and the decision to not yet test my sons.