APOE2 Exacerbates TDP-43 Related Toxicity in the Absence of Alzheimer Pathology

Axel D. Meneses, Shunsuke Koga, Zonghua Li, Justin O'Leary, Fuyao Li, Kai Chen, Aya Murakami, Wenhui Qiao, Aishe Kurti, Michael G. Heckman, Launia White, Manling Xie, Yixing Chen, Nicole A. Finch, Melina J. Lim, Marion Delenclos, Michael A. DeTure, Cynthia Linares, Nicholas B. Martin, Tadafumi C. IkezuMarka M. van Blitterswijk, Long Jun Wu, Pamela J. McLean, Rosa Rademakers, Owen A. Ross, Dennis W. Dickson, Guojun Bu, Na Zhao

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Recent evidence supports a link between increased TDP-43 burden and the presence of an APOE4 gene allele in Alzheimer's disease (AD); however, it is difficult to conclude the direct effect of APOE on TDP-43 pathology due to the presence of mixed AD pathologies. The goal of this study is to address how APOE isoforms impact TDP-43 pathology and related neurodegeneration in the absence of typical AD pathologies. Methods: We overexpressed human TDP-43 via viral transduction in humanized APOE2, APOE3, APOE4 mice, and murine Apoe-knockout (Apoe-KO) mice. Behavior tests were performed across ages. Animals were harvested at 11 months of age and TDP-43 overexpression-related neurodegeneration and gliosis were assessed. To further address the human relevance, we analyzed the association of APOE with TDP-43 pathology in 160 postmortem brains from autopsy-confirmed amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) in the Mayo Clinic Brain Bank. Results: We found that TDP-43 overexpression induced motor function deficits, neuronal loss, and gliosis in the motor cortex, especially in APOE2 mice, with much milder or absent effects in APOE3, APOE4, or Apoe-KO mice. In the motor cortex of the ALS and FTLD-MND postmortem human brains, we found that the APOE2 allele was associated with more severe TDP-43-positive dystrophic neurites. Interpretation: Our data suggest a genotype-specific effect of APOE on TDP-43 proteinopathy and neurodegeneration in the absence of AD pathology, with the strongest association seen with APOE2. ANN NEUROL 2023;93:830–843.

Original languageEnglish (US)
Pages (from-to)830-843
Number of pages14
JournalAnnals of neurology
Volume93
Issue number4
DOIs
StatePublished - Apr 2023

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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