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

Autor: Meneses AD; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.; Clinical and Translational Science Graduate Program, Mayo Clinic, Jacksonville, Florida., Koga S; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Li Z; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., O'Leary J; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Li F; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Chen K; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Murakami A; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Qiao W; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Kurti A; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Heckman MG; Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, Florida., White L; Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, Florida., Xie M; Department of Neurology, Mayo Clinic, Rochester, Minnesota., Chen Y; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Finch NA; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Lim MJ; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Delenclos M; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., DeTure MA; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Linares C; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Martin NB; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Ikezu TC; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., van Blitterswijk MM; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida., Wu LJ; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; Neuroscience Graduate Program, Mayo Clinic, Jacksonville, Florida., McLean PJ; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.; Neuroscience Graduate Program, Mayo Clinic, Jacksonville, Florida., Rademakers R; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.; VIB Center for Molecular Neurology, Antwerp, Belgium., Ross OA; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.; Neuroscience Graduate Program, Mayo Clinic, Jacksonville, Florida., Dickson DW; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.; Neuroscience Graduate Program, Mayo Clinic, Jacksonville, Florida., Bu G; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.; Neuroscience Graduate Program, Mayo Clinic, Jacksonville, Florida., Zhao N; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.; Neuroscience Graduate Program, Mayo Clinic, Jacksonville, Florida.
Jazyk: angličtina
Zdroj: Annals of neurology [Ann Neurol] 2023 Apr; Vol. 93 (4), pp. 830-843. Date of Electronic Publication: 2023 Jan 10.
DOI: 10.1002/ana.26580
Abstrakt: 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.
(© 2022 American Neurological Association.)
Databáze: MEDLINE
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