Biology subjects

Abel, E.

Publications and source records attributed to Abel, E..

4 recordsLinked to original sources

bioRxiv2025

Independent Generation of Amyloid-β via Novel APP Transcripts

The amyloid precursor protein (APP) is processed by multiple enzymes to generate biologically active peptides, including amyloid-{beta} (A{beta}), which aggregates to form the hallmark pathology of Alzheimers disease (AD). A{beta} is produced through an initial {beta}-secretase cleavage of APP, generating a 99-amino acid C-terminal fragment (APP-C99). Subsequent cleavage of APP-C99 by {gamma}-secretase produces A{beta} peptides of varying lengths. To better understand the transcriptional regulation of A{beta} production, we employed long-read RNA sequencing and identified previously unannotated transcripts encoding APP-C99 with an additional methionine residue (APP-C100), generated independently of {beta}-secretase cleavage. These transcripts are expressed separately from full-length APP, and we observed that cells lacking full-length APP can still produce A{beta} through these shorter isoforms. Importantly, mass spectrometry analysis of cerebrospinal fluid (CSF) revealed peptides consistent with the methionine-extended A{beta} species, supporting the in vivo translation of these transcripts. Our findings reveal an alternative pathway for A{beta} generation and aggregation, highlighting a potential new target for modulating A{beta} accumulation in AD.

neuroscience↗

bioRxiv2024

Single-Stranded DNA with Internal Base Modifications Mediates Highly Efficient Gene Insertion in Primary Cells

Single-stranded DNA (ssDNA) templates along with Cas9 have been used for gene insertion but suffer from low efficiency. Here, we show that ssDNA with chemical modifications in 10-17% of internal bases (eDNA) is compatible with the homologous recombination machinery. Moreover, eDNA templates improve gene insertion by 2-3 fold compared to unmodified and end-modified ssDNA in airway basal stem cells (ABCs), hematopoietic stem and progenitor cells (HSPCs), T-cells and endothelial cells. Over 50% of alleles showed gene insertion in three clinically relevant loci (CFTR, HBB, and CCR5) in ABCs using eDNA and up to 70% of alleles showed gene insertion in the HBB locus in HSPCs. This level of correction is therapeutically relevant and is comparable to adeno-associated virus-based templates. Knocking out TREX1 nuclease improved gene insertion using unmodified ssDNA but not eDNA suggesting that chemical modifications inhibit TREX1. This approach can be used for therapeutic applications and biological modeling.

molecular biology↗

bioRxiv2021

Plasma amyloid beta ratios in autosomal dominant Alzheimers disease: the influence of genotype

In-vitro studies of autosomal dominant Alzheimers disease (ADAD) implicate longer A{beta} peptides in pathogenesis, however less is known about the behaviour of ADAD mutations in-vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from ADAD family members who were at-risk of inheriting a mutation or were already symptomatic. We tested for differences in plasma A{beta}42:38, 38:40 and 42:40 ratios between Presenilin1 (PSEN1) and Amyloid Precursor Protein (APP) carriers. We examined the relationship between plasma and in-vitro models of A{beta} processing and, among PSEN1 carriers, tested for associations with parental age at onset (AAO). 39 participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma A{beta} between APP and PSEN1: higher A{beta}42:38 in PSEN1 versus APP (p<0.001) and non-carriers (p<0.001); higher A{beta}38:40 in APP versus PSEN1 (p<0.001) and non-carriers (p<0.001), while A{beta}42:40 was higher in APP and PSEN1 compared to non-carriers (both p<0.001). A{beta} profiles were reasonably consistent in plasma and cell lines. Within PSEN1, sex-adjusted models demonstrated negative associations between (i)A{beta}42:40 (ii)A{beta}42:38 and parental AAO. In-vivo differences in A{beta} processing between APP and PSEN1 provide insights into ADAD pathophysiology which can inform therapy development.

neuroscience↗

bioRxiv2017

HNF1A is a Novel Oncogene and Central Regulator of Pancreatic Cancer Stem Cells

The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, PCSC depletion, and downregulation of OCT4 expression. Conversely, HNF1A overexpression increased PCSC numbers and tumorsphere formation in pancreatic cancer cells and drove PDA cell growth. Importantly, depletion of HNF1A in primary tumor xenografts impaired tumor growth and depleted PCSCs in vivo. Finally, we established an HNF1A-dependent gene signature in PDA cells that significantly correlated with reduced survivability in patients. These findings identify HNF1A as a central transcriptional regulator of the PCSC state and novel oncogene in pancreatic ductal adenocarcinoma.

cancer biology↗