bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Roles of Human Tau Isoforms in the Modulation of Inflammation and Development of Neuropathology
Authors: Spencer Brian , Ngolab Jennifer , Schueler Aaron , Sung Daniel , Rissman Robert A 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most common tauopathy and characterized by the progressive accumulation of Aß and tau. Tau is expressed in two major isoforms containing either 3 or 4 c‐terminal repeats labeled as 3R and 4R tau. While these two isoforms occur in roughly equimolar ratios in AD, most research focus and mouse models of tau center only the 4Rtau protein and not 3Rtau. We recently generated a 3Rtau transgenic mouse to model Pick’s disease which is characterized by the preferential accumulation of 3Rtau. To generate a more human representative model of AD tauopathy and understand specific tau isoform‐mediated neurodegeneration, we generated a transgenic mouse line expressing both 4Rtau and 3Rtau and determined how this impacted the timing and severity of neuropathological and behavioral changes.Method3Rtau‐tg and 4Rtau‐tg mice were crossed to generate 3R/4Rtau‐tg bigenic mice. At 3, 6, and 9 months of age, mice were assessed for learning and memory (Morris water maze), cognitive ability and depression (nesting) and hyperactivity (open field). After behavior assessment, mice were sacrificed, and brains were analyzed by IHC for tau accumulation, neuronal loss, and gliosis. Frozen brains were also analyzed for tau protein accumulation by immunoblot and RNA expression by qPCR.Result3R/4Rtau bigenic mice expressed increased tau and phosphorylated tau in the hippocampus and cortex compared to 3R or 4R transgenic cohorts as early as 3 months of age. In addition to increased tau pathology, increased astrogliosis and microglia was seen in the bigenic mouse compared to single transgenic tau mice. Finally, the bigenic mouse had significantly greater behavioral deficits compared to either 3Rtau or 4Rtau‐tg mice in spatial learning and memory as well as reduced nest building indicative of depression and/or cognitive deficits.ConclusionThis new mouse model of tauopathy better recapitulates the pattern, severity and accumulation of tau and associated neuropathology and behavioral changes observed in human tauopathies such as AD and FTD. This new model should supplant existing single transgenic tau models for validation of therapeutic targets and investigations of novel therapies for ADRD.
Molecular Characterization of Knock‐In Mouse Models Harboring Genetic Risk Factors for Late‐Onset Alzheimer’s Disease
Authors: Carter Gregory W 
Published: January 2025

AbstractBackgroundDetermining the precise genetic mechanisms that contribute to LOAD, both in coding and noncoding variants, will enable a deeper understanding of pathogenesis and advance preclinical models for the testing of targeted therapeutics.MethodsWe have introduced candidate genetic variants in the EPHA1, BIN1, CD2AP, SCIMP, KLOTHO, PTK2B, ADAMTS4, IL1RAP, IL34, and PTPRB loci into a sensitized mouse model already harboring humanized amyloid‐beta, APOE4, and Trem2.R47H alleles knocked in to a C57BL/6J background. Variants were selected based on predicted function, cross‐species conservation, increased risk of LOAD, and allele frequency. Coding variants were chosen in PTPRB, IL34, and KLOTHO while promoter and/or enhancer variants were modeled for the remaining loci. Genome editing with CRISPR‐Cas9 was performed and mouse cohorts were aged to four and 12 months. Homogenized brain hemispheres were assayed from both male and female mice with RNA‐seq. Transcriptomic changes were compared to postmortem human brain data to determine disease relevance.ResultsTranscriptomic effects from these genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts, particularly when signatures were partitioned into Alzheimer’s relevant biodomains. By 12 months of age, PTPRB*D57N mice exhibited neuroimmune signatures that correlate with postmortem LOAD cases relative to controls. A noncoding variant in the EPHA1 region primarily altered apoptotic processes, potentially driven by expression changes in CASP2 at the locus. The BIN1 promoter variant exhibited both neuroimmune and oligodendrocyte‐related changes that correlated with LOAD modules. These changes were more pronounced with age, supporting their role in age‐related dementia.ConclusionsWe have characterized in vivo signatures of nine genetic candidates for LOAD, identifying alterations in specific LOAD‐related pathways in each variant on a sensitized genetic background. These results provide animal models for preclinical testing of therapeutics designed to correct specific molecular alterations that contribute to LOAD pathology and progression.
Pre‐clinical development of AVB‐101, an AAV gene therapy treatment for frontotemporal dementia with progranulin mutations
Authors: Lee Youn Bok , Miranda Carlos J , Allison Joseph , Kaliszewska Aleksandra , Bekele Yalem , Hosseini Paniz , Joubert Romain , Walker Zoe , Furtado Joana , Gumus McQuinn , Fernandes Alinda , Brock Olivier , Bouchard Page , Bloom Alex , Lee Do Young , Shaw Christopher E 
Published: January 2025

AbstractBackgroundFrontotemporal dementia (FTD) presents with a change in personality, behaviour and language and is the second most common cause of young‐onset dementia after Alzheimer’s disease. Loss of function mutations in GRN, encoding progranulin (PGRN), causes FTD in the heterozygous state, accounting for 5‐10% of all FTD cases. PGRN is essential for normal lysosomal function and neuronal survival. The PGRN reduction observed in FTD‐GRN patients leads to lysosomal dysfunction, associated with the mis‐accumulation of neuronal TDP‐43 and exaggerated microglial reactivity that accelerates neurodegeneration. FTD‐GRN represents a serious condition with significant unmet needs. AVB‐101 is being developed as a one‐time treatment for FTD‐GRN administered bilaterally into the thalamus (ITM) by convection‐enhanced delivery using a stereotaxic neurosurgical procedure.MethodsAVB‐101, a recombinant AAV9 vector, was designed to minimise vector dose and to restrict PGRN expression to neurons by engineering a cassette that includes (i) a codon‐optimised GRN sequence, (ii) PGRN expression enhancers and (iii) a neuron‐specific promoter. In vitro experimental testing of the construct was initially conducted in neuronal cultures. Efficacy studies were conducted in Grn knockout mice. Biodistribution studies were conducted first in sheep to optimize the route of administration and extended to non‐human primates (NHPs) to assess the safety and tolerability of AVB‐101.ResultsAVB‐101 induces robust levels of PGRN expression in neurons when tested in vitro. In vivo, AVB‐101: (a) can suppress neuronal lipofuscinosis even at the lowest dose tested in Grn null mice; (b) in sheep resulted in dose‐dependent and widespread cortical and basal ganglia PGRN expression even at doses lower than commonly used with direct cerebrospinal fluid delivery modalities; (c) results in no expression of PGRN outside the CNS regardless of the animal model used; (d) in NHPs was well tolerated, with no mortality or clinically evident adverse effects; (e) in sheep and NHP drives PGRN expression to human‐equivalent physiological levels in the temporal and frontal lobes, which are the cortical regions most severely affected in FTD‐GRN.ConclusionsThe preclinical data suggest that intrathalamic infusion of AVB‐101 constitutes a novel and promising approach to supplement PGRN in the CNS, supporting the clinical development of AVB‐101 for FTD‐GRN.
Computational search for the interactors of alternatively spliced TREM2 isoforms
Authors: Liang Junyi , Menon Aditya Aditya , Tomco Taylor , Bekris Lynn M. ,   Group of GMI staff Dr. Lynn Bekris
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) hallmarks are amyloid plaques and tau tangles. APOE and TREM2 are the strongest genetic risk factors for AD. Triggering receptor expressed on myeloid cells 2 (TREM2) is increasingly recognized to play a central role in amyloid beta clearance and microglia activation in AD. TREM2 has several described ligands, including amyloid beta, apoE and tau. It is known that canonical full‐length TREM2 interacts with DAP12 which in turn activates downstream pathways. One study describes TREM2 interaction with TMEM59 as a regulator TMEM59 protein degradation through cell membrane protein–protein interaction. Three TREM2 alternative splicing isoforms have been described. Little is known about protein–protein interactions with all of three of these TREM2 isoforms. The hypothesis of our study is that full‐length TREM2 and its alternative splicing isoforms interact with other undescribed proteins. The aim of this study was to perform a systematic computational search for new interactors of different TREM2 isoforms by employing several state‐of‐the‐art structural bioinformatics tools, from initial large‐scale screening to identify a one‐on‐one corroborative simulation and fine visualization.MethodProteinPrompt software random forest method was used to scan mega libraries in the Homo sapien proteome to identify potential interactors of TREM2 isoforms. The top 5 predictions from ProteinPrompt were simulated in PEPPI, in order to verify the authenticity of the interactions. The TREM2 isoforms and their newfound interactors, identified by ProteinPrompt and validated by PEPPI, were then built into heterodimeric complex in AlphaFold Multimer.ResultsCD9, a cell surface glycoprotein involved in cell‐cell adhesion and migration, was identified as a new interactor for two TREM2 isoforms. CALM, a calcium binding protein involved in calcium metabolism, was identified as a new interactor for a third TREM2 isoform.ConclusionThe predicted interaction of CD9 or CALM with TREM2 isoforms suggests a possible role of TREM2 in cell adhesion and calcium regulation. Both cell adhesion and calcium regulation are two biological systems previously implicated in Alzheimer’s disease.
Positive Carrier for MAPT
Authors: Jacobs Linde L ,   Cure MAPT FTD
Published: January 2025

AbstractDementia was a condition I was aware of from a very young age as I witnessed my grandmother decline, and my mother step into the role as a caregiver, health care director and power of attorney. I was taught the foundation for this process by direct observation of my mother’s actions. One aspect of caregiving that isn’t teachable is the emotional pain, anguish, sadness and guilt that often accompanies that role. My mother started exhibiting symptoms of FTD in 2010, right as I was graduating college. Despite having a family history, it took 8 harrowing years to receive a correct diagnosis and genetic testing. It was then confirmed that my family possesses the MAPT mutation causing bvFTD. My mother passed away in 2021 at the age of 62. Shortly after her passing, I learned that I was a positive carrier for the MAPT gene as well.This started a new mission by using my past experience, to change the present, in hopes for a future. Currently, my future is not a guarantee, but I will not wait for the next 10 years hoping for a cure by staying quiet. Instead, I am using this time of waiting to use my voice and failed experiences with my mother, to motivate change, understanding and awareness for FTD. Further, I am using the knowledge of my genetic status to engage with the scientists and researchers to help in ways I am capable of driving progress forward. Being honest about the psychosocial implications genetic testing has on a person is that this test doesn’t have to render them useless, but use it to propel them forward. I look toward the future with hope knowing that the community fighting this disease is doing everything they can to find a solution. If there isn’t light at the end of my tunnel, I hope the light of the journey I led will burn so bright with persistence, strength and perseverance that my daughters will have the resilience to survive another generation of caregiving. All while they await their unpromised future because of genetic MAPT FTD.
Connection between APOE4 and tau is mediated via amyloid‐beta and Alzheimer’s co‐pathologies in human autopsy brains
Authors: Gawor Klara , Verrept Sam , Laureyssen Celeste , Tomé Sandra O. , Vandenberghe Rik , Vandenbulcke Mathieu , Van Damme Philip , von Arnim Christina , Otto Markus , Ghebremedhin Estifanos , Ronisz Alicja , Ospitalieri Simona , Blaschko Matthew , Van Dongen Jasper , Sleegers Kristel , Thal Dietmar Rudolf 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) brains commonly exhibit various co‐morbid pathologies, with cerebral amyloid angiopathy (CAA) being the most prevalent, affecting 70‐90% of patients. CAA can be restricted to medium and large vessels or extend to capillaries. Additionally, AD patients often show pathologies involving phosphorylated‐TDP‐43 (pTDP‐43) and alpha‐synuclein (αSyn), typically demonstrating an amygdala‐predominant subtype. The apolipoprotein E ε4 allele (APOE ε4) is a major genetic risk factor for Amyloid Beta (Aβ) pathology, but uncertainties remain regarding its impact on phosphorylated‐tau (pTau) and pTDP‐43.MethodsTo address this knowledge gap, we conducted a neuropathological examination of 237 brains, including 89 AD patients. We assessed pTau stages, Aβ phases, capillary involvement in CAA, and the presence of pTDP‐43 in the hippocampus. We also examined αSyn in the medulla oblongata, identifying the amygdala‐predominant variant using additional staining. APOE genotyping was performed on all individuals from frozen or paraffin‐embedded brain tissue.ResultsOur structural‐equation model revealed interrelationships among AD‐related neuropathologies, APOE, and age. We confirmed previous findings on substantial influence of the APOE ε4 allele on Aβ levels. We also identified an equally robust effect on capillary CAA, even after adjusting for the impact of Aβ on this pathology. Amygdala‐predominant αSyn was also affected by the presence of an APOE ε4 allele. Significant associations were observed between pTau and all measured pathologies. Importantly, after accounting for interactions, APOE ε4 showed no effect on pTau and pTDP‐43.ConclusionsOur study suggests that APOE ε4 primary influence on pathological Tau is likely mediated through associations with Aβ, capillary CAA, and amygdala‐predominant αSyn. Similar conclusions might hold for APOE ε4 and p‐TDP‐43, although further confirmation with a larger sample size is needed. Despite indications from animal models, our results suggest that the impact of APOE ε4 on pTau in the human brain may be minimal, linked to its high interconnection with other brain pathologies.
Targeting protein O‐Glcnacylation to rescue cognitive defects and Alzheimer‐like signatures in a mouse model of down syndrome
Authors: Domenico Fabio Di , Lanzillotta Chiara , Prestia Francesca , Tramutola Antonella , Barone Eugenio , Perluigi Marzia 
Published: January 2025

AbstractBackgroundDisturbances of protein O‐GlcNAcylation have pointed out as a possible link between altered brain metabolism and cognitive decline. We previously demonstrated the disruption of O‐GlcNAcylation homeostasis, as an effect of altered OGT and OGA regulatory mechanism, and we confirmed the relevance of O‐GlcNAcylation in the appearance of Alzheimer disease hallmarks in the brain of a murine model of Down syndrome (DS). Furthermore, we provide evidence for the neuroprotective effects of brain‐targeted OGA inhibition (Thiamet G). The primary objective of this study is to provide evidence for the neuroprotective effects of brain‐targeted OGA inhibition (Thiamet G) by analyzing mice cognition and molecular pathways associated with Alzheimer‐like neurodegenenration.MethodThe neuroprotective effects of Thiamet G was evaluated in DS mice by analyzing mice performances in the novel object recognition and Y maze tests. Furthermore we analyzed by immunochemical methods APP and tau modification, and by proteomic approach using ESI‐MS/MS technique, we identified brain proteins whose O‐GlcNAcylation levels resulted significantly modulated by the treatment.ResultData supported the beneficial effect Thiamet G in DS mice hippocampus. The rescue of OGA activity was able to restore protein O‐GlcNAcylation, rescue cognitive impairments and reduce AD‐related hallmarks. In particular, the recovery of O‐GlcNAcylation was associated with the modulation of protein specific O‐GlcNAc levels occurring to several components of neuronal architecture, stress response mechanisms and energy production.ConclusionOur work emphasizes the central role of altered protein O‐GlcNAcylation in DS neuropathology and lays the foundations to consider the rescue of protein O‐GlcNAcylation as a valuable therapeutic strategy to reduce the alterations of brain metabolism and the development of AD‐hallmarks.
Will I get dementia? – Symptoms and worries of individuals affected by subjective cognitive decline
Authors: Kiene Franziska , Hildebrandt Helmut , Roheger Mandy 
Published: January 2025

AbstractBackgroundSubjective cognitive decline (SCD) is a condition, where individuals report persistent decline of cognitive abilities, even though this decline is not detectable by neuropsychological screenings. Individuals with SCD are at a higher risk of suffering from mild cognitive impairment (MCI) and Alzheimer’s disease (AD) in the future. It is important to better understand SCD to develop prevention measures, before a transition from a possible preclinical stage to MCI and AD.MethodTo get an insight into SCD symptomatology, focus group discussions with individuals affected by SCD were conducted. A comprehensive neuropsychological assessment was done beforehand. Focus groups were audio‐recorded, transcribed and analyzed with MAXQDA. Content analysis was performed using inductive and deductive approaches.Result4 group discussions with 16 participants in total (11 female, 5 male) were conducted. Although, a decline was reported for each cognitive domain (attention, memory, orientation, visuocognition, speech, executive functioning, learning), participants especially reported a decline of abilities typically impaired in AD: word‐finding, episodic memory and orientation, with declining word‐finding being amongst the first noticed symptoms, most frequently expressed and heavily affecting, as it leads to social withdrawal due to difficulties in conversations. Participants also frequently mentioned a declining prospective memory, short term memory and working memory. Individuals with SCD are especially concerned about a progression of decline and suffering from AD in the future. 9 participants already sought medical help due to SCD.ConclusionSCD as a possible preclinical stage of AD needs to be further researched. Although, individuals with SCD are experiencing impairments in their everyday life, they are not receiving support within the German health care system, as often no objectifiable cognitive impairments are detected by simple screening tools. Therefore, results of this study will be used to develop a questionnaire for measuring SCD. The aim is to develop an ambulatory SCD questionnaire to categorize the subjective feeling of cognitive decline and to identify subjects which should be assessed thoroughly.
Atherosclerosis in carotid arteries associated with cerebrovascular lesions
Authors: Pontes Beatriz Carvalho , Leite Renata Elaine Paraizo , Farias‐Itao Daniela Souza , Barbosa Maria Eduarda , Braga Maria Eduarda , Yahagi‐Estevam Maristella , Paes Vitor Ribeiro , Justo Alberto Fernando Oliveira , Pasqualucci Carlos Augusto , Grinberg Lea T. , Nitrini Ricardo , Jacob‐Filho Wilson , Suemoto Claudia Kimie 
Published: January 2025

AbstractBackgroundThe atherosclerotic plaque in carotid arteries has been associated with dementia. Clinic radiological studies in older adults suggest that the composition of atherosclerotic plaque in the carotid artery can predict vascular dementia (VD) or mixed dementia. The proposed study aims to assess components of atherosclerotic plaques in the carotid arteries, particularly concerning cerebrovascular lesions using racially diverse autopsy samples.MethodWe used data from the Biobank for Aging Studies at the University of São Paulo Medical School. We included participants aged 50 years or older at the time of death with a post‐mortem interval of less than 24 hours and a next of kin who had at least weekly contact with the deceased (n = 505). The plaque composition was evaluated using the Atherosclerotic Plaque Analyzer (APA) software. Cerebrovascular lesions included lacunar infarcts, hyaline arteriolosclerosis, and cerebral amyloid angiopathy evaluated microscopically in 13 samples areas. Logistic regression models adjusted for sociodemographic and clinical variables were used to investigate the associations between plaque composition and cerebrovascular deceased.ResultsAfter the exclusions for missing data, 193 participants were included (mean age 79.4±10.0 years, 51.3% were women, and 61% were White) (Table 1). A higher percentage of lipid deposition in the plaque was associated with higher odds of cerebral amyloid angiopathy (OR = 1.01, 95% CI = 1.03; 1.27, p = 0.007). We found no association between the other plaque components and cerebrovascular diseases (Table 3).ConclusionIn an autopsy study, the deposition of lipids in the carotid atheroma plaque was associated with cerebral amyloid angiopathy. Further autopsy studies in larger samples are needed to confirm our findings.