Interaction of transactive response DNA binding protein 43 with nuclear factor κB in mild cognitive impairment with episodic memory deficits

Acta Neuropathol Commun. 2014 Apr 1;2:37. doi: 10.1186/2051-5960-2-37.

Abstract

Introduction: Transactive response DNA binding protein 43 (TDP-43) is detected in pathological inclusions in many cases of Alzheimer's disease (AD) and mild cognitive impairment (MCI), but its pathological role in AD and MCI remains unknown. Recently, TDP-43 was reported to contribute to pathogenesis in amyotrophic lateral sclerosis through its interaction with p65 nuclear factor κB (NF-κB) resulting in abnormal hyperactivation of this signaling pathway in motor neurons. Hence, we investigated the interaction of TDP-43 with p65 in the temporal cortex of subjects with a clinical diagnosis of MCI (n = 12) or AD (n = 12) as well as of age-matched controls with no cognitive impairment (NCI, n = 12).

Results: Immunoprecipitation and immunofluorescence approaches revealed a robust interaction of TDP-43 with p65 in the nucleus of temporal lobe neurons in four individuals with MCI (named MCI-p). These MCI-p cases exhibited high expression levels of soluble TDP-43, p65, phosphorylated p65 and low expression levels of β-amyloid 40 when compared to AD or NCI cases. The analysis of cognitive performance tests showed that MCI-p individuals presented intermediate deficits of global cognition and episodic memory between those of AD cases and of NCI cases and MCI cases with no interaction of TDP-43 with p65.

Conclusions: From these results, we propose that enhanced NF-κB activation due to TDP-43 and p65 interaction may contribute to neuronal dysfunction in MCI individuals with episodic memory deficits. Accordingly, treatment with inhibitors of NF-κB activation may be considered for MCI individuals with episodic memory deficits.

Publication types

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

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Cognitive Dysfunction / complications
  • Cognitive Dysfunction / pathology*
  • DNA-Binding Proteins / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Immunoprecipitation
  • Longitudinal Studies
  • Male
  • Memory Disorders / complications
  • Memory Disorders / pathology*
  • Peptide Fragments / metabolism
  • Statistics, Nonparametric
  • Temporal Lobe / metabolism*
  • Transcription Factor RelA / metabolism*
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • DNA-Binding Proteins
  • Peptide Fragments
  • Transcription Factor RelA
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • tau Proteins