Accumulation of transactive response DNA binding protein 43 in mild cognitive impairment and Alzheimer disease.

Publication Type:

Journal Article

Authors:

Tremblay, Cyntia; Isabelle St-Amour; Schneider, Julie; Bennett, David A; Calon, Frédéric

Source:

J Neuropathol Exp Neurol, Volume 70, Issue 9, p.788-98 (2011)

Keywords:

Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Analysis of Variance, Brain, Cognition Disorders, DNA-Binding Proteins, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Mental Status Schedule, Peptide Fragments, Postmortem Changes

Abstract:

<p>Transactive response DNA binding protein 43 (TDP-43) plays a central role in the neuropathology of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, but the relationship between TDP-43 abnormalities and Alzheimer disease (AD) remains unclear. To determine whether TDP-43 can serve as a neuropathologic marker of AD, we performed biochemical characterization and quantification of TDP-43 in homogenates from parietal neocortex of subjects with aclinical diagnosis of no cognitive impairment (NCI, n = 12), mild cognitive impairment (MCI, n = 12), or AD (n = 12). Immunoblots revealed increased detergent-insoluble TDP-43 in the cortex of 0, 3, and 6 of the 12 individuals with NCI, MCI, or AD, respectively. Detergent-insoluble TDP-43 was positively correlated with the accumulation of soluble Aβ42, amyloid plaques, and paired helical filamenttau. In contrast, phospho-TDP-43 was decreased in the cytosolic fraction and detergent-soluble membrane/nuclear fraction from AD patients and correlated with antemortem cognitive function.Immunofluorescence analysis confirmed that the frequencies of individuals with TDP-43 or phospho-TDP-43 cytoplasmic inclusions were higher in AD than in NCI, with MCI at an intermediate level. These data indicate that abnormalities of TDP-43 occur in an important subset of MCI and AD patients and that they correlate with the clinical and neuropathologic features of AD.</p>