Accumulation of Transactive Response DNA Binding Protein 43 in Mild Cognitive Impairment and Alzheimer Disease

• Published in: Journal of neuropathology and experimental neurology Vol. 70; no. 9; pp. 788 - 798
• Main Authors: Tremblay, Cyntia, St-Amour, Isabelle, Schneider, Julie, Bennett, David A., Calon, Frédéric
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01.09.2011; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Analysis of Variance; Biological and medical sciences; Brain - metabolism; Brain - pathology; Cognition Disorders - metabolism; Cognition Disorders - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA-Binding Proteins - metabolism; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Medical sciences; Mental Status Schedule; Neurology; Peptide Fragments - metabolism; Postmortem Changes; Human; Nervous system diseases; Cognitive disorder; Alzheimer disease; Tau; Cerebral disorder; Binding protein; Immunoblot; Tau protein; DNA; TDP-43; Central nervous system disease; Immunoblotting assay; Degenerative disease; Amyloid; mild cognitive impairment
• ISSN: 0022-3069; 1554-6578; 1554-6578
• DOI: 10.1097/NEN.0b013e31822c62cf

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.