Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/258921

Early candidate urine biomarkers for detecting Alzheimer’s disease before beta amyloid plaque deposition in an APP (swe)/PSEN1dE9 transgenic mouse model

Zhang, F.·Wei, J.·Li, X.·Ma, C.·Gao, Y.
View original source ↗Export metadata ↓

Abstract

Alzheimers disease (AD) is an incurable age-associated neurodegenerative disorder that is characterized by irreversible progressive cognitive deficits and extensive brain damage. The identification of candidate biomarkers before beta amyloid plaque deposition occurs is therefore of great importance for the early intervention of AD. Urine, which is not regulated by homeostatic mechanisms, theoretically accumulates changes associated with AD earlier than cerebrospinal fluid and blood. In this study, an APP (swe)/PSEN1dE9 transgenic mouse model was used to identify candidate biomarkers for early AD. Urine samples were collected from 4-, 6-, and 8-month-old transgenic mouse models, and the urinary proteomes were profiled using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The levels of 33 proteins differed significantly between wild-type and 4-month-old mice, which had not started to deposit beta amyloid plaque. Among these proteins, 16 have been associated with the mechanisms of AD, while 9 have been suggested as AD biomarkers. Our results indicated that urine proteins enable detecting AD before beta amyloid plaque deposition, which may present an opportunity for intervention.

Source connections

Explore related subjects

molecular biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Zhang, F., Wei, J., Li, X., Ma, C., Gao, Y.. 2018-02-02. Early candidate urine biomarkers for detecting Alzheimer’s disease before beta amyloid plaque deposition in an APP (swe)/PSEN1dE9 transgenic mouse model. https://doi.org/10.1101/258921

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

IER3-N-cadherin axis contributes to apoptosis resistance in dermal fibroblasts under profibrotic conditions

Background: Persistent activation and resistance to apoptosis of dermal fibroblasts contribute to pathological skin fibrosis. Immediate early response 3 (IER3) is a stress-responsive protein involved in cell survival, but its role in cutaneous fibrosis remains unclear. We investigated the functional significance of IER3 in dermal fibroblasts and its potential contribution to fibrosis. Methods: IER3 expression was examined in skin samples from patients with systemic sclerosis, keloids, and hypertrophic scars. Primary human dermal fibroblasts were stimulated with transforming growth factor-{beta}1 (TGF-{beta}1). RNA sequencing, siRNA-mediated gene silencing, quantitative PCR, and flow cytometric apoptosis assays were performed to investigate the downstream mechanisms and functional consequences of IER3 expression. Results: IER3 expression was increased in dermal fibroblasts within fibrotic skin lesions and was induced by TGF-{beta}1 independently of SMAD3 and MEK/ERK signaling. Transcriptomic analysis identified CDH2, encoding N-cadherin, as a downstream target of IER3. Moreover, TGF-{beta}1 induced CDH2 expression in a SMAD3 phosphorylation-dependent manner. IER3 knockdown attenuated TGF-{beta}1-induced CDH2 expression, whereas CDH2 knockdown did not affect IER3 expression. Furthermore, CDH2 knockdown enhanced staurosporine-induced apoptosis in TGF-{beta}1-stimulated fibroblasts, accompanied by a shift in apoptosis-related gene expression toward a pro-apoptotic profile. Conclusion: Our findings identify a previously unrecognized IER3-N-cadherin regulatory axis that may promote dermal fibroblast survival by suppressing apoptosis under profibrotic conditions. Targeting this pathway may represent a novel therapeutic strategy for persistent skin fibrosis.

molecular biology↗
bioRxiv2026

Molecular basis of Cyclin B1-CDK1 recruitment by MAD1

The interaction between Cyclin B1-CDK1 and MAD1 recruits kinase activity to the nuclear pore complex and kinetochore corona to sustain spindle assembly checkpoint (SAC) signaling. Here, we characterize a short linear motif (SLiM) within MAD1 that mediates its interaction with Cyclin B1. This SLiM peptide is specific for B-type cyclins and lacks the canonical "RxL" cyclin-binding consensus sequence, suggesting a distinct mode of cyclin recognition. Using a combination of deep mutational scanning, structural analysis by cryogenic electron microscopy, and binding affinity measurements, we define the molecular basis of the Cyclin B1-MAD1 interaction. These approaches reveal that a short MAD1 peptide binds as an -helix to the RxL-binding hydrophobic patch of Cyclin B1. The interaction employs hydrophobic contacts that overlap with those used by canonical RxL motifs, but is distinguished by additional contacts and sequence features that confer preferential recognition by B-type cyclins while excluding other cyclin types. We also show that the MAD1 motif is sufficient to confer B-type cyclin-specific substrate phosphorylation in mitotic cells. Together, these findings reveal a non-canonical, B-type cyclin-specific helical binding mode that ensures selective Cyclin B1-CDK1 recruitment at two critical stages of SAC signaling, and suggest potential strategies for selective therapeutic targeting of this interaction.

molecular biology↗
bioRxiv2026

Characterizing nascent readthrough transcripts in human cells

Termination of transcription by RNA polymerase II (RNAPII) is critical to appropriately define transcriptome and proteome identity; yet mechanisms of termination regulation are incompletely understood. Current models suggest critical roles for the exonuclease XRN2, which is posited to "torpedo" out RNAPII after degrading uncapped and RNAPII-tethered nascent transcripts and posit an allosteric model wherein elongating RNAPII loses its processivity downstream of the transcription end site (TES) via unknown mechanisms. Here, we used nascent RNA Bru-seq to interrogate transcription termination across 16 human cell lines of distinct lineages, as part of the ENCODE 4 project, to identify key regulatory modes. We find that > 75% of protein-coding genes engage in readthrough transcription under homeostatic conditions. Exposing human cells to oxidative stress or hyperosmotic conditions or splicing inhibitors cause an increase in readthrough transcripts globally. Using an auxin-inducible degradation approach we find that depletion of BRD4, MED14 or XRN2 increases the extent and pervasiveness of readthrough transcripts while depletion of SUPT16H results in shorter readthrough transcripts. Our study provides a comprehensive view of homeostatic readthrough transcripts in human cells and delineates key components regulating transcription termination.

molecular biology↗