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Amyloid beta pathology induces astrocytic pTDP-43 mislocalization and disrupts TDP-43-regulated cryptic exon
Zeinab Rafiee1, Jessica Santiago1, Emelie Andersson2
1Cognitive Disorder Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
Frontiers in Aging Neuroscience
|May 1, 2026
Summary
Phosphorylated TDP-43 (pTDP-43) accumulates in astrocytes in Alzheimer's disease (AD) models, driven by amyloid-beta (Aβ). This impairs astrocyte function, potentially worsening AD progression.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Alzheimer's disease (AD) involves amyloid-beta (Aβ) and tau pathologies, with TDP-43 proteinopathy increasingly recognized as a significant contributor.
- TDP-43 dysfunction, particularly its mislocalization, disrupts RNA splicing and protein function, impacting neuronal health.
- While neuronal TDP-43 pathology is studied, its role in astrocytes, including phosphorylated TDP-43 (pTDP-43) in endfeet and its interaction with Aβ, is less understood.
Purpose of the Study:
- To investigate the accumulation and impact of phosphorylated TDP-43 (pTDP-43) in astrocytes within an Alzheimer's disease (AD) mouse model.
- To explore the direct effects of amyloid-beta (Aβ) on pTDP-43 localization and expression in primary human astrocytes.
- To assess the consequences of Aβ and pTDP-43 on the expression of key astrocytic transcripts involved in autophagy and synaptic support.
Main Methods:
- Quantified pTDP-43 immunoreactivity in astrocytic endfeet, nuclei, and cytosol in AppNL-F/NL-F mice and wild-type controls using ImageJ.
- Exposed primary human fetal astrocytes to oligomeric Aβ42 in vitro to measure changes in pTDP-43 via ImageJ and ELISA.
- Assessed expression levels of ATG4B and KALRN transcripts by qPCR and their corresponding protein levels by ELISA.
Main Results:
- Significantly elevated pTDP-43 accumulation was observed in astrocytic nuclei, cytosol, and endfeet in aged AppNL-F/NL-F mice compared to wild-type controls.
- Exposure to oligomeric Aβ42 increased cytosolic pTDP-43 immunoreactivity and total pTDP-43 protein levels in astrocytes.
- Canonical transcripts ATG4B and KALRN showed significantly reduced expression, with corresponding protein level decreases, following Aβ exposure.
Conclusions:
- pTDP-43 accumulates in astrocytes (nuclei, cytosol, endfeet) in the presence of AD pathology.
- Aβ-induced pTDP-43 increase in astrocytes contributes to disruptions in autophagy and cytoskeletal regulation.
- These astrocytic changes mediated by pTDP-43 and Aβ may exacerbate Alzheimer's disease progression.
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