Cognitive performance correlates with cortical isopeptide immunoreactivity as well as Alzheimer type pathology

Document Type

Article

Abstract

Background: Protein cross-linking and aggregation are important molecular processes in Alzheimer's disease (AD), and tissue transglutaminase (tTG) catalyzes protein cross-linking. Objectives: To measure tTG, tTG enzyme activity and isopeptide, which is the product of tTG, in brain and to relate them to cognitive scores. Methods: tTG and isopeptide levels were measured in frontal gray matter of 10 normal (NCI), 10 mild cognitive impairment (MCI) and 9 AD brains from the Religious Orders Study. tTG enzymatic activity was measured with a fluorescence assay. Results: tTG protein and enzyme activity were highest in AD, but not significantly greater than MCI or NCI. In contrast, isopeptide immunoreactivity in formic acid extracts was significantly greater in AD than NCI and MCI. The level of insoluble formic acid extractable isopeptide correlated with several measures of cognitive function, including word generation and perceptual speed. Multiple linear regression analyses indicated that insoluble isopeptide immunoreactivity could be accounted for by a combination of factors in the formic acid extract, including Aβ, ubiquitin and tau. Conclusions: Accumulation of insoluble proteins with isopeptide bonds correlates with cognitive impairment. The relationship of isopeptide to other proteins that are also enriched in formic acid extracts suggests that several substrates of tTG may play a role in the pathogenesis of AD. © 2008 - IOS Press and the authors. All rights reserved.

Keywords

Amyloid, Isopeptide, Mental status, Neuropsychology, Tau, Transglutaminase, Ubiquitin

Publication Date

1-1-2008

Publication Title

Journal of Alzheimer's Disease

ISSN

13872877

Volume

13

Issue

1

First Page

53

Last Page

66

PubMed ID

18334757

Digital Object Identifier (DOI)

10.3233/JAD-2008-13106

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