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ApoE and TDP-43 neuropathology in two siblings with familial FTLD-motor neuron disease

Keith A Vossel1, Nga Bien-Ly, Aubrey Bernardo

  • 1Department of Neurology, University of California, San Francisco, CA, USA.

Neurocase
|April 20, 2012
PubMed

Insights

Apolipoprotein E4 (apoE4) may worsen frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) by interacting with TDP-43 and forming toxic fragments, leading to increased brain atrophy and symptoms.

Area of Science:

  • Neuroscience
  • Genetics
  • Pathology

Background:

  • Frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) involves TDP-43 protein aggregates.
  • Apolipoprotein E4 (apoE4) is linked to increased brain atrophy in FTLD, but mechanisms are unclear.

Observation:

  • Two siblings with C9ORF72-linked FTLD-MND were studied: one apoE4 homozygote and one apoE3 homozygote.
  • The apoE4 homozygote exhibited more severe cognitive-behavioral symptoms and fronto-insulo-temporal atrophy.
  • Increased apoE fragments, aggregates, and TDP-43 complexes were observed in the apoE4 homozygote's brain.

Findings:

  • Apolipoprotein E4 (apoE4) forms complexes with TDP-43.
  • These apoE-TDP-43 complexes were more abundant in the apoE4 homozygote.
  • Evidence suggests apoE4 may lead to neurotoxic apoE fragments.

Implications:

  • Apolipoprotein E4 may exacerbate FTLD-MND pathology through TDP-43 interactions and fragment formation.
  • This provides a potential mechanism for apoE4's role in FTLD progression.
  • Further research is needed to confirm these findings in a larger cohort.

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