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

Jean-Pierre Julien,Julie A Schneider,David A Bennett,Cyntia Tremblay,Frederic Calon,Yasuyuki Ohta

doi:10.1186/2051-5960-2-37

Abstract

IntroductionTransactive 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).ResultsImmunoprecipitation 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.ConclusionsFrom 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.

Highlights

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
(See figure on previous page.) Figure 3 TDP-43 colocalizes with p65 in the neuronal cells from the temporal cortex of individuals with MCI-p. a-d Sections from the temporal cortex of MCI-p (a, Subjects 8 and 15), MCI without the interaction of TDP-43 with p65 in coimmunoprecipitation experiments (Figure 1B, C; MCI-n, b, Subjects 6 and 12), AD (c, Subject 2) or no cognitive impairment (NCI) (d, Subjects 7 and 21) showing the interaction of TDP-43 with p65 (Figure 1B,C; AD-p or NCI-p) were incubated with anti-TDP-43 and anti-p65 antibodies and subsequently with corresponding Alexa 488 and 633 antibodies, and imaged by confocal laser microscopy
Based on data generated in the amyotrophic lateral sclerosis (ALS) field [23], these results suggest that inhibitors of nuclear factor κB (NF-κB) activation should be considered for treatment of MCI subtype with episodic memory deficits to prevent the developing AD and that potential therapeutic window would lie before their progression to AD

Summary

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. 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). Transactive response DNA binding protein 43 (TDP-43) has been implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusion (FTLD-U) [1,2,3,4]. The pathological involvement of TDP-43 in MCI remains poorly understood

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