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

作者：Tremblay Cyntia; St Amour Isabelle; Schneider Julie; Bennett David A; Calon Frederic^*

来源：Journal of Neuropathology and Experimental Neurology, 2011, 70(9): 788-798.

DOI：10.1097/NEN.0b013e31822c62cf

• Alzheimer disease
• Amyloid
• Human
• Immunoblot
• Mild cognitive impairment
• Tau
• TDP-43

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 a clinical 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 beta(42), amyloid plaques, and paired helical filament tau. 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.

• 出版日期2011-9