Amyloid beta pathology induces astrocytic pTDP-43 mislocalization and disrupts TDP-43-regulated cryptic exon transcripts.
Background: While amyloid-β (Aβ) and tau are hallmark pathologies of Alzheimer's disease (AD), TDP-43 proteinopathy is increasingly recognized as an important contributor, occurring in up to 57% of AD cases and associated with accelerated cognitive decline. TDP-43 regulates RNA splicing, and its mis...
| Publicado en: | Frontiers in Aging Neuroscience pp. 1 - 12 |
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| Autores principales: | , , , , |
| Formato: | research tables/charts Journal Article |
| Publicado: |
Frontiers Media S.A.
2026
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=193361836&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 193361836 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 16634365 BG2U jtl: Frontiers in Aging Neuroscience issn: 16634365 maglogo: N pubinfo: dt: 2026 pid: 40038 pub: Frontiers Media S.A. artinfo: ui: 193361836 193361836 193361836 10.3389/fnagi.2026.1766448 193361836 ppf: 1 ppct: 11 formats: tig: atl: Amyloid beta pathology induces astrocytic pTDP-43 mislocalization and disrupts TDP-43-regulated cryptic exon transcripts. aug: au: Rafiee, Zeinab Santiago, Jessica Andersson, Emelie Hansson, Oskar Wennström, Malin affil: Cognitive Disorder Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden sug: subj: Amyloid beta-Peptides Adverse Effects TDP-43 Proteinopathies Metabolism Animal Studies Funding Source Mice In Vitro Studies Cell Culture Techniques Descriptive Statistics Immunohistochemistry Gene Expression Data Analysis Software One-Way Analysis of Variance Post Hoc Analysis Mann-Whitney U Test RNA ab: Background: While amyloid-β (Aβ) and tau are hallmark pathologies of Alzheimer's disease (AD), TDP-43 proteinopathy is increasingly recognized as an important contributor, occurring in up to 57% of AD cases and associated with accelerated cognitive decline. TDP-43 regulates RNA splicing, and its mislocalization leads to cryptic exon inclusion and loss of canonical protein function. While neuronal TDP-43 pathology has been well studied, its role in astrocytes remains less understood. Recent findings suggest increased phosphorylated TDP-43 (pTDP-43) inclusions in astrocytic endfeet in AD and a bidirectional interaction between Aβ and TDP-43, promoting mutual aggregation. Methods: We analyzed pTDP-43 immunoreactivity (IR) in astrocytic perivascular end-feet, nuclei, and cytosol in hippocampal sections from 3-month-old and 18-month-old AppNL–F/NL–F mice and 18-month-old wild-type controls using ImageJ. In vitro , primary fetal human astrocytes were exposed to oligomeric Aβ42, and changes in cytosolic and nuclear pTDP-43 IR were quantified via ImageJ, while TDP-43 and pTDP-43 protein levels were measured using an in-house ELISA. Expression of canonical transcripts ATG4B and KALRN, involved in autophagy and synaptic support, was assessed by qPCR. Corresponding protein-level changes were evaluated using in-house ELISA. Results: Our findings demonstrate significantly higher pTDP-43 accumulations in astrocytic nuclei, cytosol, and endfeet in 18-month-old AppNL–F/NL–F mice compared to age-matched wild-type mice. Astrocytes exposed to oligomeric Aβ42 showed elevated cytosolic pTDP-43 IR and total pTDP-43 protein levels. Concurrently, expression of canonical ATG4B and KALRN transcripts was significantly reduced, which was accompanied by corresponding decreases in protein levels. Conclusion: Our findings demonstrate that pTDP-43 accumulates in astrocytic nuclei, cytosol, and endfeet in the presence of AD pathology. The observed Aβ-induced increase in cytosolic pTDP-43 and transcript disruption suggests a mechanistic link contributing to autophagy impairment and cytoskeletal changes in astrocytes, potentially exacerbating AD progression. pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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