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

Ohta Y, Tremblay C, Schneider JA, Bennett DA, Calon F, Julien JP - Acta Neuropathol Commun (2014)

Bottom Line: 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.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Research Centre of Institut universitaire en santé mentale de Québec, Québec, QC, Canada. jean-pierre.julien@fmed.ulaval.ca.

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.

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MCI-p individuals presented intermediate deficits of episodic memory between those of AD cases and of NCI cases and MCI-n cases. Left graph shows statistical comparisons of episodic memory scores between NCI, MCI-n, MCI-p and AD using Kruskal-Wallis test followed by Dunn multiple comparisons test. Right graph shows statistical comparison of same scores between MCI-n and MCI-p using Mann–Whitney test. Number of Subjects 8, 15, 17 and 23 is written beside each blot in right graph.
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Figure 4: MCI-p individuals presented intermediate deficits of episodic memory between those of AD cases and of NCI cases and MCI-n cases. Left graph shows statistical comparisons of episodic memory scores between NCI, MCI-n, MCI-p and AD using Kruskal-Wallis test followed by Dunn multiple comparisons test. Right graph shows statistical comparison of same scores between MCI-n and MCI-p using Mann–Whitney test. Number of Subjects 8, 15, 17 and 23 is written beside each blot in right graph.

Mentions: In secondary analyses, we evaluated the clinical and neuropathological features that distinguish individuals with MCI-p from the others. We analyzed the cognitive data and the concentrations of Aβ and tau of study participants (Table 1). Interestingly, the global cognition and episodic memory scores, the clinical hallmark of AD, were more impaired in AD compared to NCI and MCI-n, with MCI-p showing intermediate deficits. In the comparison of episodic memory scores between MCI-p and MCI-n, episodic memory scores of 3 individuals with MCI-p (Subjects 15, 17 and 23) were more impaired compared to all MCI-n subjects (Figure 4). Although a deficit of episodic memory in subject 8 was mild, deficits of episodic memory in some individuals of AD were also mild. By contrast, perceptual speed scores were lower in AD compared to NCI and MCI-p, with MCI-n showing intermediate deficits (Table 1). These analyses suggest that interaction of TDP-43 with p65 in neurons of temporal lobe occurred in a majority of MCI showing mild episodic memory deficits. The accumulation of Aβ42 and phosphorylated tau in the cerebral cortex was more prominent in AD compared to only NCI and the accumulation of insoluble tau in AD was higher than both NCI and MCI-p, whereas the accumulation of soluble and insoluble Aβ40 was lower in MCI-p, especially in subject 8 (98.2, 6.4, respectively) and 17 (65.0, 5.5, respectively), compared to NCI, MCI-n and AD (not significant). In CERAD, Braak and Regan score, the scores of individuals with MCI-p and MCI-n were intermediate level between AD and NCI. In the neuropathological score of hippocampal atrophy, the severity of the individuals with MCI-p was similar to AD compared to NCI and MCI-n (not significant). The accumulation of TDP-43 and p65, and the presence of phosphorylated p65 in TBS-soluble fraction were superior in MCI-p compared to NCI, MCI-n and AD.


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

Ohta Y, Tremblay C, Schneider JA, Bennett DA, Calon F, Julien JP - Acta Neuropathol Commun (2014)

MCI-p individuals presented intermediate deficits of episodic memory between those of AD cases and of NCI cases and MCI-n cases. Left graph shows statistical comparisons of episodic memory scores between NCI, MCI-n, MCI-p and AD using Kruskal-Wallis test followed by Dunn multiple comparisons test. Right graph shows statistical comparison of same scores between MCI-n and MCI-p using Mann–Whitney test. Number of Subjects 8, 15, 17 and 23 is written beside each blot in right graph.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4230634&req=5

Figure 4: MCI-p individuals presented intermediate deficits of episodic memory between those of AD cases and of NCI cases and MCI-n cases. Left graph shows statistical comparisons of episodic memory scores between NCI, MCI-n, MCI-p and AD using Kruskal-Wallis test followed by Dunn multiple comparisons test. Right graph shows statistical comparison of same scores between MCI-n and MCI-p using Mann–Whitney test. Number of Subjects 8, 15, 17 and 23 is written beside each blot in right graph.
Mentions: In secondary analyses, we evaluated the clinical and neuropathological features that distinguish individuals with MCI-p from the others. We analyzed the cognitive data and the concentrations of Aβ and tau of study participants (Table 1). Interestingly, the global cognition and episodic memory scores, the clinical hallmark of AD, were more impaired in AD compared to NCI and MCI-n, with MCI-p showing intermediate deficits. In the comparison of episodic memory scores between MCI-p and MCI-n, episodic memory scores of 3 individuals with MCI-p (Subjects 15, 17 and 23) were more impaired compared to all MCI-n subjects (Figure 4). Although a deficit of episodic memory in subject 8 was mild, deficits of episodic memory in some individuals of AD were also mild. By contrast, perceptual speed scores were lower in AD compared to NCI and MCI-p, with MCI-n showing intermediate deficits (Table 1). These analyses suggest that interaction of TDP-43 with p65 in neurons of temporal lobe occurred in a majority of MCI showing mild episodic memory deficits. The accumulation of Aβ42 and phosphorylated tau in the cerebral cortex was more prominent in AD compared to only NCI and the accumulation of insoluble tau in AD was higher than both NCI and MCI-p, whereas the accumulation of soluble and insoluble Aβ40 was lower in MCI-p, especially in subject 8 (98.2, 6.4, respectively) and 17 (65.0, 5.5, respectively), compared to NCI, MCI-n and AD (not significant). In CERAD, Braak and Regan score, the scores of individuals with MCI-p and MCI-n were intermediate level between AD and NCI. In the neuropathological score of hippocampal atrophy, the severity of the individuals with MCI-p was similar to AD compared to NCI and MCI-n (not significant). The accumulation of TDP-43 and p65, and the presence of phosphorylated p65 in TBS-soluble fraction were superior in MCI-p compared to NCI, MCI-n and AD.

Bottom Line: 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.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Research Centre of Institut universitaire en santé mentale de Québec, Québec, QC, Canada. jean-pierre.julien@fmed.ulaval.ca.

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.

Show MeSH
Related in: MedlinePlus