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Loss of TDP-43 splicing repression occurs early in the aging population and is associated with Alzheimer’s disease neuropathologic changes and cognitive decline

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Abstract

LATE-NC, the neuropathologic changes of limbic-predominant age-related TAR DNA-binding protein 43 kDa (TDP-43) encephalopathy are frequently associated with Alzheimer’s disease (AD) and cognitive impairment in older adults. The association of TDP-43 proteinopathy with AD neuropathologic changes (ADNC) and its impact on specific cognitive domains are not fully understood and whether loss of TDP-43 function occurs early in the aging brain remains unknown. Here, using a large set of autopsies from the Baltimore Longitudinal Study of Aging (BLSA) and another younger cohort, we were able to study brains from subjects 21–109 years of age. Examination of these brains show that loss of TDP-43 splicing repression, as judged by TDP-43 nuclear clearance and expression of a cryptic exon in HDGFL2, first occurs during the 6th decade, preceding by a decade the appearance of TDP-43+ neuronal cytoplasmic inclusions (NCIs). We corroborated this observation using a monoclonal antibody to demonstrate a cryptic exon-encoded neoepitope within HDGFL2 in neurons exhibiting nuclear clearance of TDP-43. TDP-43 nuclear clearance is associated with increased burden of tau pathology. Age at death, female sex, high CERAD neuritic plaque score, and high Braak neurofibrillary stage significantly increase the odds of LATE-NC. Faster rates of cognitive decline on verbal memory (California Verbal Learning Test immediate recall), visuospatial ability (Card Rotations Test), mental status (MMSE) and semantic fluency (Category Fluency Test) were associated with LATE-NC. Notably, the effects of LATE-NC on verbal memory and visuospatial ability are independent of ADNC. However, the effects of TDP-43 nuclear clearance in absence of NCI on the longitudinal trajectories and levels of cognitive measures are not significant. These results establish that loss of TDP-43 splicing repression is an early event occurring in the aging population during the development of TDP-43 proteinopathy and is associated with increased tau pathology. Furthermore, LATE-NC correlates with high levels of ADNC but also has an impact on specific memory and visuospatial functions in aging that is independent of AD.

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Data availability

All data are included in the manuscript and supplementary data. Individual demographic, clinical, and pathologic data of the participants are available from the authors upon reasonable request, due to privacy protection policies.

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Acknowledgements

We would like to thank all the BLSA participants and families that contributed to brain donation. This study was supported in part by the Intramural Research Program, National Institute on Aging, NIH, the NINDS, NIH Grant R01NS095969 and The Johns Hopkins Alzheimer’s Disease Research Center NIH Grant P30AG066507.

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Authors and Affiliations

  1. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Koping Chang, Jonathan P. Ling, Javier Redding-Ochoa, Ling Li, Tatiana Pylyukh, Alexander Barrett, Katherine E. Irwin, Philip C. Wong & Juan C. Troncoso

  2. Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, 100225, Taiwan

    Koping Chang

  3. Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA

    Yang An & Susan M. Resnick

  4. Office of the Chief Medical Examiner, State of Maryland, Baltimore, MD, 21223, USA

    Ling Li & Stephanie A. Dean

  5. Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Ling Li & Thomas G. Blanchard

  6. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Katherine E. Irwin & Philip C. Wong

  7. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Abhay Moghekar & Juan C. Troncoso

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  1. Koping Chang
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Contributions

KC, JPL, PCW and JCT contributed to the study conception and design. LL and SAD performed autopsies of young cohort subjects. TGB supervised brain consent process. KC, JR, and JCT performed pathologic data collection and analysis. TP and AB performed tissue slide preparation and immunohistochemistry. KC performed immunofluorescent staining, confocal imaging, and RNA in situ hybridization. JPL, PCW, and KI developed and produced the monoclonal antibody targeting the cryptic exon encoded neoepitope in HDGFL2. YA, AM, and SR provided clinical data. YA performed statistical analyses. JPL, PCW, AM, SR, and JCT supervised the project. The first draft of the manuscript was written by KC. All authors reviewed and commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Juan C. Troncoso.

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Conflict of interest

The authors declare no competing interests.

Ethics approval

This study involving human participants was in accordance with the ethical standards of the institutional and national research committees and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the JHM Institutional Review Boards (IRB00101384), Institutional Review Board of the National Institutes of Health (03AG0325), and Maryland Department of Health Institutional Review Board (#05-58).

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Informed consent was obtained from all individual participants included in the study.

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Chang, K., Ling, J.P., Redding-Ochoa, J. et al. Loss of TDP-43 splicing repression occurs early in the aging population and is associated with Alzheimer’s disease neuropathologic changes and cognitive decline. Acta Neuropathol 147, 4 (2024). https://doi.org/10.1007/s00401-023-02653-2

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