ArticleBrain : a journal of neurology2023
Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease.
Article in Brain : a journal of neurology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 30 citations in OpenAlex.
- ZL006 Treatment Reduces Inflammation, Oxidative Stress, and Brain AβInternational journal of molecular sciences · 2026Article
- Loss of presenilin 2 function age-dependently increases susceptibility to kainate-induced acute seizures and blunts hippocampal kainate-type glutamate receptor expression.Experimental neurology · 2026Article
- Allele-specific splicing modulates protein isoforms and Alzheimer's risk.bioRxiv : the preprint server for biology · 2026Article
- Alternative Splicing: Molecular Mechanisms, Biological Functions, Diseases, and Potential Therapeutic Targets.MedComm · 2025Review
- Integrated machine learning identifies biomarkers for bilirubin-induced Alzheimer's disease-like lesions in neonates and adults.Scientific reports · 2025Article
- Loss of presenilin 2 function age-dependently increases susceptibility to kainate-induced acute seizures and blunts hippocampal kainate-type glutamate receptor expression.bioRxiv : the preprint server for biology · 2025Article
- Presence of Alzheimer's disease variants in circular RNA ofJournal of Alzheimer's disease : JAD · 2025Article
- Vanadyl sulfate restores memory impairment in streptozotocin-induced rat model of sporadic alzheimer's disease by repressing FoxO1 gene expression.Scientific reports · 2025Article
- Intron Retention and Alzheimer's Disease (AD): A Review of Regulation Genes Implicated in AD.Genes · 2025Review
- White matter dysfunction in Alzheimer's disease is associated with disease-related transcriptomic signatures.Communications biology · 2025Article
- Let-7 Family as a Mediator of Exercise on Alzheimer's Disease.Cellular and molecular neurobiology · 2025Review
- Large-scale transcriptomic analyses of major depressive disorder reveal convergent dysregulation of synaptic pathways in excitatory neurons.Nature communications · 2025Article
- Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes.Molecular neurodegeneration · 2025Article
- Mapping medically relevant RNA isoform diversity in the aged human frontal cortex with deep long-read RNA-seq.Nature biotechnology · 2025Article
- Integration of phytochemical profiling and computational approaches to evaluate the neuroprotective potential ofBiotechnology reports (Amsterdam, Netherlands) · 2025Article
- The curious case of a heterozygous loss-of-functionMolecular neurodegeneration advances · 2025Article
- Altered expression of Presenilin2 impacts endolysosomal homeostasis and synapse function in Alzheimer's disease-relevant brain circuits.Nature communications · 2024Article
- Alzheimer's Disease as Type 3 Diabetes: Understanding the Link and Implications.International journal of molecular sciences · 2024Review
- Detecting haplotype-specific transcript variation in long reads with FLAIR2.Genome biology · 2024Article
- Using deep long-read RNAseq in Alzheimer's disease brain to assess medical relevance of RNA isoform diversity.bioRxiv : the preprint server for biology · 2023Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Alzheimer's disease is the most common neurodegenerative disease, characterized by dementia and premature death. Early-onset familial Alzheimer's disease is caused in part by pathogenic variants in presenilin 1 (PSEN1) and presenilin 2 (PSEN2), and alternative splicing of these two genes has been implicated in both familial and sporadic Alzheimer's disease. Here, we leveraged targeted isoform-sequencing to characterize thousands of complete PSEN1 and PSEN2 transcripts in the prefrontal cortex of individuals with sporadic Alzheimer's disease, familial Alzheimer's disease (carrying PSEN1 and PSEN2 variants), and controls. Our results reveal alternative splicing patterns of PSEN2 specific to sporadic Alzheimer's disease, including a human-specific cryptic exon present in intron 9 of PSEN2 as well as a 77 bp intron retention product before exon 6 that are both significantly elevated in sporadic Alzheimer's disease samples, alongside a significantly lower percentage of canonical full-length PSEN2 transcripts versus familial Alzheimer's disease samples and controls. Both alternatively spliced products are predicted to generate a prematurely truncated PSEN2 protein and were corroborated in an independent cerebellum RNA-sequencing dataset. In addition, our data in PSEN variant carriers is consistent with the hypothesis that PSEN1 and PSEN2 variants need to produce full-length but variant proteins to contribute to the onset of Alzheimer's disease, although intriguingly there were far fewer full-length transcripts carrying pathogenic alleles versus wild-type alleles in PSEN2 variant carriers. Finally, we identify frequent RNA editing at Alu elements present in an extended 3' untranslated region in PSEN2. Overall, this work expands the understanding of PSEN1 and PSEN2 variants in Alzheimer's disease, shows that transcript differences in PSEN2 may play a role in sporadic Alzheimer's disease, and suggests novel mechanisms of Alzheimer's disease pathogenesis.
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