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Basic Science and Pathogenesis.

Antonio Rocco Fusciardi1, Jonathan Mill1, Akshay Bhinge1

  • 1University of Exeter, Exeter, Devon, United Kingdom.

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Summary
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This study investigates how APOE4 and TDP43 mislocalization interact to cause neurodegeneration in Alzheimer's disease models. Findings may reveal new therapeutic targets for Alzheimer's disease progression.

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Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • APOE4 is a major genetic risk factor for Alzheimer's disease (AD).
  • TDP43 inclusions are found in 80% of severe AD cases, suggesting a role in disease progression.
  • Investigating the combined effects of APOE4 and TDP43 is crucial for understanding AD pathogenesis.

Purpose of the Study:

  • To establish a dual-hit model combining APOE4 expression and TDP43 mislocalization.
  • To assess the synergistic impact of these factors on neurodegeneration in human induced pluripotent stem cell (iPSC)-derived cortical neurons.
  • To explore potential new therapeutic strategies for Alzheimer's disease.

Main Methods:

  • Optimized generation of cortical neurons from human iPSCs using transcription factors and small molecules.
  • Overexpression of APOE4 via lentiviral vectors and induction of TDP43 mislocalization using GFP-tagged TDP43 iPSCs and nanobodies.
  • Quantification of AD biomarkers (amyloid beta, phospho-tau), neurodegeneration (cell viability assays), and epigenetic changes via ELISA, Western blotting, RNA sequencing, and comparative analysis.

Main Results:

  • Protocols for generating specific cortical neuron subtypes (layers 2-3, deeper layers) are being established.
  • Existing resources include GFP-specific nanobodies and a TDP43-GFP tagged iPSC line.
  • Lentiviral vectors for APOE4 transduction are currently being generated.

Conclusions:

  • The dual-hit model shows promise for studying synergistic neurodegeneration in AD.
  • This research could uncover novel pathways for Alzheimer's disease research and clinical intervention.
  • Understanding the interplay between APOE4 and TDP43 is vital for developing effective AD treatments.