Age-dependent changes in TDP-43 levels in a mouse model of Alzheimer disease are linked to Aβ oligomers accumulation

Antonella Caccamo,Andrea Magrí,Salvatore Oddo

doi:10.1186/1750-1326-5-51

Abstract

BackgroundTransactive response DNA-binding protein 43 (TDP-43) is the pathological protein found in frontotemporal lobar degeneration with ubiquitin positive inclusions and in amyotrophic lateral sclerosis. In diseased tissue, TDP-43 translocates from its physiological nuclear location into the cytoplasm, where it accumulates. Additionally, C-terminal fragments of TDP-43 accumulate in affected brain regions and are sufficient to cause TDP-43 mislocalization and cytoplasmic accumulation in vitro. TDP-43 also accumulates in 30% of Alzheimer disease (AD) cases, a finding that has been highly reproducible. The role of TDP-43 in AD and its relation with Aβ and tau pathology, the two neuropathological hallmarks of AD, remains to be elucidated.ResultsHere we show that levels of TDP-43 and its ~35 kDa C-terminal fragment are significantly increased in the 3×Tg-AD mice, an animal model of AD that develops an age-dependent cognitive decline linked to the accumulation of Aβ and tau. We also report that the levels of TDP-43 and its C-terminal fragment correlate with the levels of soluble Aβ oligomers, which play a key role in AD pathogenesis. Notably, genetically reducing Aβ42 production restores the levels of TDP-43 and its ~35 kDa C-terminal fragment to control levels.ConclusionsThese data suggest a possible relation between Aβ oligomers and TDP-43.

Highlights

Transactive response DNA-binding protein 43 (TDP-43) is the pathological protein found in frontotemporal lobar degeneration with ubiquitin positive inclusions and in amyotrophic lateral sclerosis
We address the relation between amyloid-b peptide (Ab), tau and TDP-43 in the 3×Tg-Alzheimer disease (AD) mice, an animal model of AD that develops Ab and tau pathology, with a temporal- and regional-specific profile that closely mimics their development in the human AD brain [38]
We found that in the brains of 2month-old mice, the steady-state levels of TDP-43 and the ~35 kDa C-terminal fragment, which can be detected by overexposing the blots, were similar between 3×Tg-AD and age- and gender-matched non transgenic (NonTg) mice (Figure 1AB)

Summary

Introduction

Transactive response DNA-binding protein 43 (TDP-43) is the pathological protein found in frontotemporal lobar degeneration with ubiquitin positive inclusions and in amyotrophic lateral sclerosis. TDP-43 translocates from its physiological nuclear location into the cytoplasm, where it accumulates. TDP-43 accumulates in 30% of Alzheimer disease (AD) cases, a finding that has been highly reproducible. Alzheimer disease (AD) is the most common cause of dementia among the elderly [1]. Two hallmark neuropathological lesions of AD include the aberrant accumulation of the amyloid-b peptide (Ab) and neurofibrillary tangles (NFTs) [5]. The strongest evidence for this position is derived from molecular genetic studies of the three genes (amyloid precursor protein, presenilin 1, and presenilin 2) that underlie familial AD cases, as they all modulate some aspect of Ab metabolism, increasing the propensity of Ab to aggregate [13,14,15,16]. In the past few years, in vitro and in vivo studies have shown soluble Ab oligomers to be the major neurotoxic species for neurons [19]

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