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Cited by 11Amyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatmentsTranscranial Magnetic Stimulation Studies

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

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Meneses, Axel D., Koga, Shunsuke, Li, Zonghua, O'Leary, Justin, Li, Fuyao, Chen, Kai, Murakami, Aya, Qiao, Wenhui +20 more·2023·Annals of Neurology
DOI 10.1002/ana.26580PMC PMC10471132
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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 APOE 2 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

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  • An association between the APOEε2 allele and higher levels of TDP-43-positive dystrophic neurites (but not neuronal cytoplasmic inclusions) in the motor cortex of individuals with amyotrophic lateral sclerosis and frontotemporal lobar degeneration-TDP has been reported.

    “An association between the APOEε2 allele and higher levels of TDP-43-positive dystrophic neurites (but not neuronal cytoplasmic inclusions) in the motor cortex of individuals with amyotrophic lateral sclerosis and frontotemporal lobar degeneration-TDP has been reported75.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [75]

    The Results section reports a greater motor-cortex burden of TDP-43-positive dystrophic neurites in APOE2 carriers with ALS or FTLD-MND, but no significant difference in neuronal cytoplasmic inclusions. The claim broadens the studied FTLD-MND group to FTLD-TDP generally; the reported finding does not establish that association across the broader group. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • APOE2 exacerbates TDP-43 proteinopathy.

    “Similarly, APOE2 exacerbated TDP‐43 proteinopathy,”

    From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [72]

  • A study using adeno-associated viral vectors to overexpress TDP-43 in the brains of APOE-TR mice of all three isoforms and in Apoe knockout mice revealed that APOE2-targeted replacement TDP43-overexpressing mice have greater reactive gliosis, neurodegeneration and motor impairments compared with APOE3-TR, APOE4-TR and Apoe knockout mice, which had very mild or no phenotypic alterations.

    “A study using adeno-associated viral (AAV) vectors to overexpress TDP-43 in the brains of APOE-TR mice of all three isoforms and in Apoe knockout mice revealed that, surprisingly, APOE2-targeted replacement TDP43-overexpressing mice have greater reactive gliosis, neurodegeneration and motor impairments75, compared with APOE3-TR, APOE4-TR and Apoe knockout mice, which had very mild or no phenotypic”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [75]

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References 63 · Cited by 11

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Authors
Meneses, A. D., Koga, S., Li, Z., O'Leary, J., Li, F., Chen, K., Murakami, A., Qiao, W., Kurti, A., Heckman, M. G., White, L., Xie, M., Chen, Y., Finch, N. A., Lim, M. J., Delenclos, M., DeTure, M. A., Linares, C., Martin, N. B., Ikezu, T. C., van Blitterswijk, M. M., Wu, L., McLean, P. J., Rademakers, R., Ross, O. A., Dickson, D. W., Bu, G., & Zhao, N.
Affiliations
  • Mayo Clinic (US)
  • Department of Neuroscience Mayo Clinic Jacksonville Florida
Corresponding author
  • Bu, Guojun
  • Zhao, Na
ORCID
Venue
Annals of Neurology
Publisher
Wiley
Published
2023-01-10
Volume
93
Issue
4
Pages
830-843
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
DOI
10.1002/ana.26580
PMC
PMC10471132
OpenAlex
W4312094627
Cited by
11
References
63
Citations by year
2026: 3 · 2025: 6 · 2024: 2
FWCI
1.05
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Annals of Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • Coins for Alzheimer's Research Trust
  • National Institutes of Health (RF1AG057181, U19AG069701)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
Keywords
APOE2, TDP-43, TDP-43 proteinopathy, APOE isoforms, neurodegeneration, gliosis, motor cortex, amyotrophic lateral sclerosis, dystrophic neurites, genotype-specific effects, APOE ε4, APOE3, ApoE-deficient mice, motor impairment
MeSH terms
Alzheimer Disease, Amyotrophic Lateral Sclerosis, Animals, Apolipoproteins E, DNA-Binding Proteins, Gliosis, Humans, Motor Neuron Disease, Mice, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2, Frontotemporal Lobar Degeneration, Frontotemporal Dementia

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