Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
Previous research demonstrated that genetic heterogeneity is a critical factor in modeling amyloid accumulation and other Alzheimer's disease phenotypes. However, it is unknown what mechanisms underlie these effects of genetic background on modeling tau aggregate-driven pathogenicity. In this study, we induced tau aggregation in wild-derived mice by expressing MAPT. To investigate the effect of genetic background on the action of tau aggregates, we performed RNA sequencing with brains of C57BL/6J, CAST/EiJ, PWK/PhJ, and WSB/EiJ mice (n = 64) and determined core transcriptional signature conserved in all genetic backgrounds and signature unique to wild-derived backgrounds. By measuring tau seeding activity using the cortex, we identified 19 key genes associated with tau seeding and amyloid response. Interestingly, microglial pathways were strongly associated with tau seeding activity in CAST/EiJ and PWK/PhJ backgrounds. Collectively, our study demonstrates that mouse genetic context affects tau-mediated alteration of transcriptome and tau seeding. The gene modules associated with tau seeding provide an important resource to better model tauopathy.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10443211 | PMC |
| http://dx.doi.org/10.1084/jem.20230180 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Potential diagnostic markers in Alzheimer's disease: current perspectives and future directions.
Neurodegener Dis Manag
September 2025
Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.
Alzheimer's disease (AD), the most common form of dementia, remains a leading neurodegenerative disorder that necessitates the development of diagnostic markers. While current cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers facilitate diagnostic accuracy, their invasive and pricey nature limits widespread application. Blood-based biomarkers, such as plasma Aβ42/40 and phosphorylated tau isoforms, are emerging as accessible alternatives.
View Article and Find Full Text PDFPolyserine-mediated targeting of FAF2/UBXD8 ameliorates tau aggregation.
Neuron
August 2025
Department of Biochemistry, University of Colorado, Boulder, CO, USA; Howard Hughes Medical Institute, University of Colorado, Boulder, CO, USA; BioFrontiers Institute, University of Colorado, Boulder, CO, USA. Electronic address:
Tau aggregation is a hallmark of several neurodegenerative disorders, and the gain of toxic function of misfolded tau species is linked to pathobiology. Herein, we identified proteins that limit tau aggregation when targeted to tau aggregates by polyserine domains. Polyserine targeting was most effective at mitigating tau aggregation when fused to the vasolin-containing protein (VCP) adaptor protein fas-associated factor family member 2/UBX domain-containing protein 8 (FAF2/UBXD8).
View Article and Find Full Text PDFPhosphorylation at serine 214 correlates with tau seeding activity in an age-dependent manner in two mouse models for tauopathies and is required for tau transsynaptic propagation.
J Alzheimers Dis
September 2025
Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
BackgroundTau aggregation and propagation are hallmark features of Alzheimer's disease and related tauopathies. The molecular identity and post-translational modifications that contribute to tau seeding activity remain incompletely understood.ObjectiveTo characterize the temporal dynamics of tau seeding activity and identify specific phosphorylated tau species associated with tau propagation in vivo.
View Article and Find Full Text PDFβ-Amyloid induces microglial expression of GPC4 and APOE leading to increased neuronal tau pathology and toxicity.
Mol Neurodegener
August 2025
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA.
Unlabelled: To define how Aβ pathology alters microglia function in Alzheimer’s disease, we profiled the microglia surfaceome following treatment with Aβ fibrils. Our findings reveal that Aβ-associated human microglia upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). Glial GPC4 expression exacerbates motor deficits and reduces lifespan in a amyloidosis model, implicating GPC4 in a toxic neurodegenerative program.
View Article and Find Full Text PDFStructural and functional insights into the selective inhibition of mutant tau aggregation by purpurin and oleocanthal in frontotemporal dementia.
Protein Sci
September 2025
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University and University Hospital Olomouc, Olomouc, Czech Republic.
Tau aggregation driven by microtubule-associated protein tau (MAPT) mutations is central to frontotemporal dementia pathology, yet no disease-modifying therapies effectively target mutant tau. Here, we identify purpurin (PUR) and oleocanthal (OLC) as selective inhibitors of mutant tau aggregation using peptide models spanning the R2R3 interface. Biophysical and cellular assays demonstrated that both compounds more effectively inhibit the aggregation of mutant tau peptides compared to wild-type, with PUR preferentially targeting V287I and N279K variants, and OLC showing broader inhibitory activity.
View Article and Find Full Text PDF