bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Therapeutic Small Molecule Enhances γ‐Oscillations and Improves Cognition/Memory in Alzheimer’s Disease Model Mice
Authors: Wei Xiaofei , Campagna Jesus J , Jagodzinska Barbara , Wi Dongwook , Cohn Whitaker , Lee Jessica , Zhu Chunni , Huang Christine S. , Molnár László , Houser Carolyn R. , John Varghese , Mody Istvan 
Published: January 2025

AbstractBackgroundBrain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ‐oscillations (30‐120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. High temporal resolution recording methods, such as magnetoencephalography, have made it clear that Alzheimer’s disease (AD) patients, starting as early as the mild cognitive impairment (MCI) stage, have diminished γ‐oscillations even before the Aβ load takes full effect. Moreover, it has been well established that almost all AD mouse models have diminished γ‐oscillations.MethodWe describe a unique pharmacological approach meant to enhance cognitive performance and working memory in a state‐dependent manner by engaging and amplifying the brain’s endogenous γ‐oscillations through enhancing the function of parvalbumin positive interneurons (PV+INs). We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule.ResultWe anatomically and pharmacologically identified GABAARs assembled of α1β2δ subunits responsible for the tonic inhibition of PV+INs. We further demonstrated that DDL‐920, a small molecule negative allosteric modulator (NAM) of these receptors, is a potent, efficacious, and selective blocker of the tonic inhibition of PV+INs and consequently enhances γ‐oscillations both in vitro and in vivo. When orally administered twice daily for two weeks, DDL‐920 restored the cognitive/memory impairments of 3‐4‐month‐old AD model mice as measured by their performance in the Barnes maze.ConclusionOur findings indicate that the unique subunit composition of extrasynaptic GABAARs of PV+INs should be a valid target for boosting γ‐oscillations and this should be beneficial in a variety of neurological and psychiatric disorders, including AD.
NLRP3 regulates immunometabolism, impacting microglial function in Alzheimer’s disease
Authors: McManus Roisin M. , Komes Max P , Griep Angelika , Santarelli Francesco , Schwartz Stephanie , Perea Juan , Khalil Michelle‐Amirah , Schlachetzki Johannes C.M. , Bouvier David S. , Lauterbach Mario , Schmidt Susanne V. , Gomez‐Cabrero David , Tegner Jesper , Glass Christopher K. , Hiller Karsten , Latz Eicke , Heneka Michael T. 
Published: January 2025

AbstractBackgroundOur laboratory has demonstrated that the NLRP3 inflammasome has a critical role in the microglial innate immune response to Alzheimer’s disease (AD)‐related peptides, triggering the release of cleaved‐caspase‐1 and IL‐1β. NLRP3 activation was found in post‐mortem tissue from individuals with AD (Heneka et al., 2013) and in transgenic models of AD (APP/PS1 mice). However, APP/PS1 mice deficient for NLRP3 were protected from AD‐pathology and neuroinflammation. We wanted to examine the wider implications of NLRP3 deficiency and uncover other pathways and mechanisms employed by microglia to protect the brain from the buildup of Aβ.MethodSingle cell RNA sequencing (scRNAseq) and ATAC sequencing was performed on CD11b+ cells from the brains of wildtype, APP/PS1, NLRP3−/− and APP/PS1.NLRP3−/− mice. Microglia were prepared from wildtype and NLRP3−/− mice to assess metabolic function, phagocytosis and for flow cytometric analysis. Targets were investigated in the post‐mortem brain tissue of those with and without AD. In a separate experiment, APP/PS1 mice were treated with NLRP3‐targeted inhibitors.ResultScRNAseq found a unique cluster of microglia in APP/PS1.NLRP3−/− mice with pathways related to phagocytosis and glutamate metabolic signaling, with a specific increase in the glutamate transporter Slc1a3. Metabolically, NLRP3−/− microglia had increased mitochondrial and metabolic function with altered levels of the metabolite α‐ketoglutarate. NLRP3−/− microglia had greater Aβ phagocytosis than the wildtype cells, which was strictly associated with α‐ketoglutarate availability and epigenetic regulation. Importantly, we were able to replicate these findings in human cells and using NLRP3‐specific inhibitors in vitro and in vivo.ConclusionWe have identified a new mechanism where loss of NLRP3 influences glutamine/glutamate metabolism, which modulates α‐ketoglutarate to affect epigenetic regulation and gene transcription, boosting downstream phagocytic activity (McManus et al., in revision). This pathway is conserved between murine and human cells. Critically, we can mimic this effect in vivo using NLRP3‐specific pharmacological inhibition. Together, our data strengthens NLRP3 as a master‐immune regulator and an important target in the treatment of AD and dementia.
GSK3α levels in Alzheimer´s disease mimicking models
Authors: Pinho Beatriz , Vaz Margarida , Martins Tânia Soares , da Cruz e Silva Odete , Henriques Ana Gabriela 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by the development of amyloid plaques and neurofibrillary tangles in the brain, which contribute to synaptic dysfunction and extensive neuronal loss. Protein phosphorylation is a key event in AD pathogenesis. Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase with two isoforms, GSK3α and GSK3β. While GSK3β link with AD is well stablished, the role of GSK3α in AD is not fully understood. Few studies suggest that GSK3α can be involved in tau phosphorylation, amyloid‐beta (Aβ) production, and neuronal cell death. Hence, the objective of this study was to test GSK3α levels and its potential contribution to AD.MethodTwo AD‐mimicking models were employed, SH‐SY5Y treated with the Aβ peptide and SH‐SY5Y carrying the Swedish mutation of APP695. Cell lysates were subjected to Western Blot analysis to monitor total protein levels and phosphorylation of both GSK3 and its isoforms α and β.ResultSignificant differences in the GSK3 total levels and in specific phosphorylation sites associated with protein activation were obtained for both isoforms in AD mimicking conditions.ConclusionThis research supports that GSK3α is altered in disease conditions and offers new insights of GSK3 involvement in AD pathology. This research was supported by iBiMED UIDB/04501/2020 and UIDP/04501/2020, FCT, the COMPETE program, QREN, and the European Union. M.V. is supported by the FCT through the individual PhD grant UI/BD/151354/2021.
CCAB–Español: The California Cognitive Assessment Battery in Spanish
Authors: Jaramillo Isabella , Woods David L. , Hall Kathleen , Geraci Kristin , Blank Michael , Miranda Miranda , Ortiz‐Menchaca Alejandra , Garcia Elloise , Kahly Omar , Herron Timothy J , Williams Garrett , Johnson David K 
Published: January 2025

AbstractBackgroundBy 2060, the incidence of ADRD is predicted to increased 6‐fold in the US Hispanic population (Matthews, Xu et al. 2019). However, cognitive testing of US Hispanics is complicated by limited Spanish‐language test materials and a dearth of examiners fluent in Spanish. Here, we present preliminary results from an automated computerized battery, CCAB–Español, that administers and scores verbal and non‐verbal tests in Spanish.MethodSpanish‐language equivalents of CCAB‐English test materials were created and presented with text‐to‐speech voices in a Mexican dialect. Participants (n = 61; age 43‐79; 64% women) completed 32 tests over three days, including verbal, visual, memory, and processing speed tests, as well as demographic and psychological questionnaires. Test were administered in participants’ homes and remotely monitored by Spanish‐speaking examiners. Verbal tasks were objectively scored using Consensus Automatic Speech Recognition (CASR). Selected tests were administered twice to assess test‐retest reliability.ResultReaction times, response accuracy, error types, and speech metrics were collected and analyzed. Participant satisfaction with the battery was high, with 100% of the participants completing all days of testing. Tests demonstrated excellent test‐retest reliabilities, for example the test‐retest value for delayed recall on a story recall task was .83.ConclusionThe results from ongoing normative data collection show that CCAB‐Español is an efficient, scalable platform for the comprehensive cognitive assessment of US Spanish speakers.Matthews, K. A., W. Xu, A. H. Gaglioti, J. B. Holt, J. B. Croft, D. Mack and L. C. McGuire (2019). “Racial and ethnic estimates of Alzheimer’s disease and related dementias in the United States (2015‐2060) in adults aged ≥65 years.” Alzheimer’s & Dementia 15(1): 17‐24.
Transcriptional characterization of relaxin‐3‐positive neurons in aging and Alzheimer’s disease
Authors: de Avila Camila , Nolz Jennifer , Khatri Divyanshi , Uzum Zerrin , Intorcia Anthony J , Serrano Geidy E , Beach Thomas G. , Gundlach Andrew L , Mastroeni Diego 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide and is characterized by clinical symptoms that include deficits in memory and cognition. There is an urgent need to better identify the neural networks that govern cognitive processes in humans and how they are impacted by AD pathology. The brainstem is a critical region that ‘connects’ the forebrain and the spinal cord and contains various nuclei involved in autonomic and complex functions (e.g., locus coeruleus) that are affected during the early stages of AD. In this regard, the brainstem contains the GABAergic nucleus incertus (NI), which has a demonstrated key role in rodents' contextual memory formation by directly inhibiting the hippocampus. Therefore, we mapped the human NI using the neuropeptide relaxin‐3 (RLN3), a neurochemical marker primarily expressed in GABAergic neurons of the NI. In these novel studies, we investigated the transcriptomics of the RLN3‐positive neurons in AD and controls.MethodUsing fresh‐frozen postmortem human tissue provided by the Banner Brain and Body Donation Program, Sun City, Arizona, USA, we isolated RLN3‐positive neurons from the NI of non‐demented controls (N = 6), and subsequently from AD (N = 6) age/sex‐matched subjects. After immunostaining, we will use laser‐capture microdissection to isolate RLN3‐positive neurons, followed by RNA sequencing and computational analysis.ResultSimilarly to rodents, we found that RLN3 positive neurons express relaxin/insulin‐like family peptide receptor 3 (RXFP3), GABA‐related, cholecystokinin, and corticotropin‐releasing factor type 1 receptor mRNA. In addition, RLN3 and phosphorylated tau markers, including the microtubule‐associated protein tau, mRNAs were upregulated while RXFP3 mRNA was downregulated in AD subjects compared to controls. We used RNAscope in situ hybridization as a validation method.ConclusionThese results suggest that the NI of humans and lower vertebrates share similar neurochemistry. In addition, the NI‐RLN3/RXFP3 system was dysregulated in AD, suggesting RLN3 as a potential biomarker for AD. Further studies investigating RLN3/RXFP3 mRNA changes in pre‐ and early AD are required to understand the time course of its dysregulation.
Structural and functional locus coeruleus‐norepinephrine system metrics are distinctly related to affective and stress‐related reports in the context of AD markers
Authors: Engels Nina , Patsyuk Yuliya , Ashton Nicholas J. , Janelidze Shorena , Blennow Kaj , Hansson Oskar , Zetterberg Henrik , Riphagen Joost M. , Van Egroo Maxime , Jacobs Heidi I.L. 
Published: January 2025

AbstractBackgroundThe locus coeruleus (LC)‐norepinephrine (NE) system is one of the first systems affected in Alzheimer’s Disease (AD), prior to cortical involvement. LC‐NE system dysregulation has also been associated with neuropsychiatric and stress‐related symptoms, early non‐cognitive signals of AD. This study investigates whether structural and functional LC‐NE system metrics are associated with affective and stress‐related reports among predominantly cognitively healthy adults, and whether these associations are exacerbated by AD fluid biomarkers of tau, neurodegeneration and astrocyte reactivity.MethodCross‐sectional data from 116 life‐span study participants (cognitively healthy/MCI: N = 114/2; age range = 30‐87 years; female = 53%; Table 1) who completed affective (DASS–Stress, DASS–Anxiety, HDRS) and stress‐related (MIA–Anxiety, Perceived Stress Scale (PSS), NEO PI‐R–Neuroticism, DASS–Stress) questionnaires. Plasma 3‐methoxy‐4‐hydroxyphenylethyleneglycol (MHPG) and AD‐related markers (ptau217, ptau231, NfL, or GFAP), and 7T LC‐MRI scanning were obtained. MHPG was normalized against NE. LC MRI signal intensity was obtained using an MT‐TFL sequence, standardizing LC signal to the pontine tegmentum (reference), and creating a study‐specific LC template. Bootstrapped linear regression examined associations of affective and stress‐related questionnaires with LC MRI signal intensity alone, or interacted with AD markers. Linear regressions assessed equivalent associations with MHPG instead of LC MRI signal intensity. Analyses were based on complete cases, corrected for age and sex, and FDR‐adjusted.ResultsLower LC MRI signal intensity related to higher DASS–Anxiety scores (pFDR = 0.008; Table 2/Fig. 1A). This relationship was more pronounced in individuals with higher ptau217 (pFDR = 0.002), ptau231 (p = 0.028), NfL (pFDR = 0.002) or GFAP (pFDR = 0.002; Table 2/Fig. 1B‐E). Higher MHPG was linked to higher PSS scores in individuals with elevated GFAP, while higher MHPG was associated with lower PSS in the context of lower GFAP (p = 0.029, Table 2/Fig. 1F).ConclusionThis work suggests that structural and functional LC‐NE system metrics are distinctly related to stress and affective functioning. Lower structural LC integrity is associated with worse anxiety, particularly at elevated AD pathology levels. Among individuals with elevated astrocyte reactivity, higher LC metabolism is no longer protective against stress. These findings are consistent with previous autopsy and metabolite studies, and support the importance of the LC‐NE system in neuropsychiatric symptoms as the earliest AD manifestations.
Indigenous Peruvians’ knowledge and awareness of dementia, risk and protective factors, and barriers to risk reduction
Authors: Caipa Maritza Pintado , Booi Laura , Farina Francesca R 
Published: January 2025

AbstractBackgroundEmerging evidence suggests that Indigenous peoples may have disproportionately high rates of Alzheimer’s disease and related dementias (ADRD). However, there is a lack of data on Indigenous peoples’ knowledge and awareness of ADRD, especially in low‐ and middle‐income countries. Our aim was to investigate knowledge and awareness of ADRD, risk and protective factors, and barriers towards risk reduction in a remote Peruvian adult population.MethodAdults living in Amazonian, Andean highland, coastal Peruvian regions completed a pen and paper survey about dementia knowledge, risk and protective factors, and barriers to risk reduction. Data were analyzed using descriptive statistics.ResultParticipants were 133 young adults (98 female; 1 non‐binary; mean age = 28.6 ± 6.4 years). Most participants identified as mixed race (i.e., Indigenous and European ancestry; 62.4%) or Quechua (28.6%). Six percent of the sample identified as White. Most participants lived in rural areas (60.2%). One third of participants were unemployed and half rated their socioeconomic status as low. Nearly one fifth of participants (18‐20%) reported not having electricity or a bathroom in their house, and one third (37.6%) did not have running water. Most participants (71.4%) said violence was a problem in their community. Half of participants (52.6%) said they were fearful about developing dementia. On average, participants recognized 5 of the 12 modifiable risk factors from the 2020 Lancet Commission on Dementia Prevention. The most endorsed factors were head injury (60.2%), social isolation (52.6%), and depression (51.1%). The least recognized factors were diet (9%) and air pollution (18%). The biggest barriers to risk reduction were lack of knowledge (63.9%), lack of money (55.6%), and pre‐existing health problems (49.6%).ConclusionPeruvian adults living in remote areas have moderate knowledge dementia risk factors but identify multiple barriers to risk reduction. Findings are among the first to explore dementia knowledge in Amazonian, Andean highland and coastal regions of Peru.
Systematic Review and Meta‐Analysis of the Efficacy of BIIB080 (IONIS‐MAPTRx): The First Gene Therapy for Patients with Alzheimer’s Disease
Authors: Mahmoud Abdalla Ahmed , Ramadan Hamza Mohamed 
Published: January 2025

AbstractObjectiveThis systematic review aims to evaluate the impact of tau synthesis reduction on tau biomarkers in patients receiving BIIB080 (IONIS‐MAPTRx) treatment for mild Alzheimer’s disease (AD).BackgroundAlzheimer’s disease is characterized by the accumulation of tau protein aggregates in the brain, leading to cognitive decline. Tau pathology, including abnormal phosphorylation and aggregation of tau protein, is closely associated with disease progression. BIIB080 is a novel therapeutic agent designed to target tau synthesis, potentially modifying the course of AD by reducing tau pathology.MethodsA comprehensive search was conducted across major scientific databases: Scopus, ScienceDirect, ClinicalKey, Cochrane, Clarivate, and PubMed for relevant studies and clinical trials. Inclusion criteria encompassed studies evaluating the effect of BIIB080 on tau biomarkers in patients with mild AD. Forty‐nine studies and two clinical trials were identified for screening.ResultsOut of 102 evaluated participants, 46 with moderate AD were included; their mean age was 65.8 years (SD 5.70). BIIB080 demonstrated good tolerability and induced a dose‐dependent decrease in cerebrospinal fluid (CSF) total tau (t‐tau) and phosphorylated tau 181 (p‐tau181) throughout the mild AD stage. Significant reductions in t‐tau (56%; 95% CI, 50% to 62%) and p‐tau181 (51%; 95% CI, 38% to 63%) in CSF were observed in the two higher‐dose cohorts. This decline continued or was maintained during the long‐term extension phase with quarterly dosage. At week 25, tau positron emission tomography (PET) imaging showed less buildup in 13 subjects compared to placebo. By week 100, reductions from baseline were evident across all assessed regions (n = 12), with the most pronounced reductions observed in the temporal composite (‐0.71 standardized uptake value ratio; 95% CI, ‐1.40 to ‐0.02). A moderate correlation was noted between model‐predicted cumulative CSF drug exposure and tau PET change.ConclusionBIIB080, as a tau synthesis reduction drug, demonstrated promising results on tau biomarkers in individuals with moderate AD, along with favorable tolerability. These findings suggest its potential as a therapeutic intervention to target tau pathology and alter the course of AD. Further research is warranted to establish its clinical effectiveness and long‐term safety profile.
Effects of APOE ε4 on novel blood biomarkers of amyloid‐β pathology and inflammation in midlife adults at risk of Alzheimer’s disease
Authors: Bechke Emily , Park Kyoung Shin , Wideman Laurie , Anderson Travis , Goldenstein Samantha J , Slutsky‐Ganesh Alexis B , Armstrong Brittany D , Etnier Jennifer L 
Published: January 2025

AbstractBackgroundIn APOE ε4 allele carriers at increased risk for Alzheimer’s disease (AD), midlife (age 40‐65 years) is a critical window when amyloid‐β (Aβ) pathology could progress without overt cognitive decline, but AD‐related biomarkers may be present. Blood measures of phosphorylated tau at Thr217 (p‐tau217) indicate aggregated Aβ pathology in the preclinical stage of AD, whereas ApoE protein levels are associated with the clearance of Aβ. C‐reactive protein (CRP) and serum amyloid A (SAA) are acute phase reactants within the inflammatory pathway, but SAA is also related to ApoE levels and Aβ clearance. This study aims to investigate the cross‐sectional effects of APOE ε4 carriage on blood biomarkers of Aβ pathology (p‐tau217 and ApoE) and inflammation (CRP and SAA) in midlife adults at risk of AD.MethodBaseline data from an ongoing clinical trial (NIH R01AG058919) were analyzed. Participants (n = 75, age = 57±6.15 years) were cognitively normal, middle‐aged adults with a family history of AD. APOE ε4 carriage was determined from passive drool saliva samples. Fasting samples were collected, centrifuged at 2,000 g for 12 min at 4°C and 0.5 ml of serum/plasma was aliquoted into tubes and frozen at 80°C. All biomarkers were measured using electro‐chemiluminescence immunoassays. After winsorizing at z = 2‐2.5, analyses of covariance compared the biomarkers between APOE ε4 carriers (n = 31) and non‐carriers (n = 44) with age, sex, education, and BMI as covariates.ResultAfter covariate adjustments, APOE ε4 carriage was associated with all serum/plasma biomarkers. APOE ε4 carriers had higher p‐tau217 (p = 0.05), lower ApoE (p<0.0001), lower CRP (p<0.05), and lower SAA (p<0.05) compared with non‐carriers.ConclusionBlood biomarkers of greater Aβ aggregation and less systemic inflammation were found in cognitively normal, APOE ε4 carriers in midlife. This data suggests that even in midlife adults at risk for AD due to APOE ε4 carriage, blood biomarkers provide crucial information about early changes in Aβ pathology and provide a potential conduit for maximizing brain health by pinpointing optimal timing for interventions that mitigate risk of progression to AD. The content of this abstract is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
DNA damage and senescence in the aging and Alzheimer’s disease cortex are not uniformly distributed
Authors: Herrup Karl , Gutta Gnanesh , Mehta Jay , Kingston Rody , Ma Fulin 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) has a typical age of onset exceeding 65 years. The age‐dependency of the condition led us to track the appearance of DNA damage in the frontal cortex of individuals who died with a diagnosis of AD. The focus on DNA damage was motivated by evidence that increasing levels of irreparable DNA damage are a major driver of the aging process. This connection between aging and genomic integrity is compelling because DNA damage has also been identified as a possible cause of cellular senescence. The number of senescent cells increase with ages, and their senescence‐associated secreted products likely contribute to age‐related illnesses.MethodImmunocytochemistry was performed on 12 µm sections of brain tissue from prefrontal cortex (BA9). We tracked DNA damage with 53BP1 or 𝛾‐H2AX and cellular senescence with p16 or p27 immunostaining. Embryonic mouse cortical neurons were cultured for 14 days in vitro before exposure to etoposide to induce DNA damage. Cell counts and labeling intensity were measured using QuPath.ResultDNA damage was significantly increased in the BA9 region of the AD cortex compared to the unaffected controls (UC). In the AD but not UC cases, the density of cells with DNA damage increased with distance from the pia mater up to approximately layer V then decreased in deeper areas. This pattern of DNA damage was overlaid with the pattern of cellular senescence, which also increased with cortical depth. On a cell‐by‐cell basis, we found that the intensity of the two markers was tightly linked in the AD, but not the UC brain. To test whether DNA damage was a causal factor in the emergence of senescence, we used etoposide treatment to damage the DNA of cultured mouse primary neurons but found no change in the expression of senescence‐associated markers.ConclusionOur work suggests that DNA damage and cellular senescence are increased in the AD brain, and increasingly coupled. We propose that in vivo the relationship between the two age‐related processes is more complex than previously thought.