Journal
ACTA NEUROPATHOLOGICA
Volume 132, Issue 6, Pages 859-873Publisher
SPRINGER
DOI: 10.1007/s00401-016-1637-y
Keywords
TDP-43; Alzheimer's disease; beta-Amyloid; Nuclear depletion; Forebrain
Categories
Funding
- Johns Hopkins University School of Medicine Neuropathology Frederick J. Pelda Alzheimer's Research Fund
- Robert Packard Center for ALS Research
- Amyotrophic Lateral Sclerosis Association
- National Institute of Health [R01-NS095969, R01-NS079348]
- Johns Hopkins Alzheimer's Disease Research Center [P50AG05146]
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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 A beta and decreased A beta 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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