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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 A?42, 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.

SUBMITTER: Tremblay C

PROVIDER: S-EPMC3197017 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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

Tremblay Cyntia C St-Amour Isabelle I Schneider Julie J Bennett David A DA Calon Frédéric F

Journal of neuropathology and experimental neurology 20110901 9

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 im ...[more]

PMID: 21865887

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Project description:Importance:Transactive response DNA-binding protein 43 (TDP-43) is associated with Alzheimer disease (AD), progressive hippocampal atrophy, and cognitive decline. The apolipoprotein E (APOE) ?4 allele is strongly associated with ?-amyloid (A?) aggregation and risk of AD, but its association with TDP-43 is unknown. Objective:To determine whether the APOE ?4 allele is a risk factor for TDP-43. Design, Setting, Participants:This cross-sectional, genetic-histologic study analyzed APOE genotype, TDP-43 status (positive vs negative), A? status (positive vs negative), and tau neurofibrillary tangle stage (B0, Braak stage 0; B1, Braak stages I-II; B2, Braak stages III-IV; B3, Braak stage???V). We fit structural equation models to map the association between APOE and TDP-43, A?, and tau, accounting for age and hippocampal sclerosis. We identified 751 participants with an AD pathological spectrum diagnosis and completed A?, tau, and TDP-43 data who were enrolled in the Mayo Clinic Alzheimer Disease Research Center, Mayo Clinic Alzheimer Disease Patient Registry, or the population based Mayo Clinic Study of Aging and died between May 12, 1999, and December 31, 2015. However, 13 were excluded from the analyses because of missing APOE data, leaving a total of 738 participants. Main Outcomes and Measures:Transactive response DNA-binding protein 43 was the main outcome of interest. We hypothesized that the APOE ?4 allele would be significantly directly and indirectly associated with TDP-43. Results:The 751 study participants were older (median age [interquartile range], 87 years [51-105 years]), 395 (54%) were women, and 324 (44%) were APOE ?4 carriers. The patients died between May 12, 1999, and December 31, 2015. Accounting for age, A?, and tau, APOE ?4 had a direct association with TDP-43 (estimate [SE], 0.31 (0.11); P?=?.01). The association was present among individuals with an intermediate to high likelihood of having AD (neurofibrillary tangle stage B2/B3; n?=?604 [81.8%]; estimate [SE], 0.51 [0.11]; P?<?.001), with a similar trend for those with a low likelihood of having AD (B1; n?=?134 [18.2%]; estimate [SE], 0.54 [0.32]; P?=?.10). We also found an indirect association of APOE ?4 with TDP-43 via A? and tau (estimate [SE], 0.34 [0.06]; P?<?.001), which was similar in magnitude to the direct association and an indirect association of APOE ?4 with hippocampal sclerosis via TDP-43 (estimate [SE], 0.65 [0.26]; P?=?.01). Conclusions and Relevance:The study's findings, which mapped a system of risk factors and outcomes, showed that the APOE ?4 allele appears to be a risk factor for TDP-43 independently of A? in patients with AD.

Dataset Information

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

Publications

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

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