Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration in an Alzheimer's mouse model

Acta Neuropathol. 2016 Dec;132(6):859-873. doi: 10.1007/s00401-016-1637-y. Epub 2016 Oct 26.


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.

Keywords: Alzheimer’s disease; Forebrain; Nuclear depletion; TDP-43; β-Amyloid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications*
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Autophagy / genetics
  • Cognition Disorders / etiology
  • Cognition Disorders / genetics
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Neurodegenerative Diseases / etiology*
  • Plaque, Amyloid* / etiology
  • Plaque, Amyloid* / genetics
  • Plaque, Amyloid* / pathology
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism
  • Prosencephalon / pathology
  • Tamoxifen / therapeutic use


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Antineoplastic Agents, Hormonal
  • DNA-Binding Proteins
  • Presenilin-1
  • TDP-43 protein, mouse
  • Tamoxifen