Abstract
TDP-43 proteinopathy, initially associated with ALS and FTD, is also found in 30–60% of Alzheimer’s disease (AD) cases and correlates with worsened cognition and neurodegeneration. A major component of this proteinopathy is depletion of this RNA-binding protein from the nucleus, which compromises repression of non-conserved cryptic exons in neurodegenerative diseases. To test whether nuclear depletion of TDP-43 may contribute to the pathogenesis of AD cases with TDP-43 proteinopathy, we examined the impact of depletion of TDP-43 in populations of neurons vulnerable in AD, and on neurodegeneration in an AD-linked context. Here, we show that some populations of pyramidal neurons that are selectively vulnerable in AD are also vulnerable to TDP-43 depletion in mice, while other forebrain neurons appear spared. Moreover, TDP-43 depletion in forebrain neurons of an AD mouse model exacerbates neurodegeneration, and correlates with increased prefibrillar oligomeric Aβ and decreased Aβ plaque burden. These findings support a role for nuclear depletion of TDP-43 in the pathogenesis of AD and provide strong rationale for developing novel therapeutics to alleviate the depletion of TDP-43 and functional antemortem biomarkers associated with its nuclear loss.
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This work was supported in part by the Johns Hopkins University School of Medicine Neuropathology Frederick J. Pelda Alzheimer’s Research Fund, the Robert Packard Center for ALS Research, the Amyotrophic Lateral Sclerosis Association, National Institute of Health grants R01-NS095969 and R01-NS079348, and the Johns Hopkins Alzheimer’s Disease Research Center (P50AG05146). The authors wish to thank Venette Nehus and Barbara Smith for technical assistance.
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Johns Hopkins University School of Medicine Neuropathology Frederick J. Pelda Alzheimer’s Research Fund, the Robert Packard Center for ALS Research, the Amyotrophic Lateral Sclerosis Association, National Institute of Health grants R01-NS095969 and R01-NS079348, and the Johns Hopkins Alzheimer’s Disease Research Center (P50AG05146).
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LaClair, K.D., Donde, A., Ling, J.P. et al. Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration in an Alzheimer’s mouse model. Acta Neuropathol 132, 859–873 (2016). https://doi.org/10.1007/s00401-016-1637-y
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DOI: https://doi.org/10.1007/s00401-016-1637-y