title: Accumulation of transactive response DNA binding protein 43 in mild cognitive impairment and Alzheimer disease.
abstract: 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.
authors.affiliation: Faculté de pharmacie, Université Laval and Centre Hospitalier de l'Université Laval Research Center, Quebec, Canada.
authors.forename: Cyntia
authors.initials: C
authors.lastname: Tremblay
authors.forename: Isabelle
authors.initials: I
authors.lastname: St-Amour
authors.forename: Julie
authors.initials: J
authors.lastname: Schneider
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Frédéric
authors.initials: F
authors.lastname: Calon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003072:Cognition Disorders / Q000378:metabolism* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008609:Mental Status Schedule; D010446:Peptide Fragments / Q000378:metabolism; D011180:Postmortem Changes
chemical_list: D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)