Cognitive Performance Correlates with Cortical Isopeptide Immunoreactivity as Well as Alzheimer Type Pathology

Article type: Research Article

Authors: Wang, Deng-Shun^{a; 1} | Uchikado, Hirotake^a | Bennett, David A.^{b; d} | Schneider, Julie A.^{b; c; d} | Mufson, Elliott J.^b | Wu, Joanne^b | Dickson, Dennis W.^{a; *}

Affiliations: [a] Departments of Neuroscience and Pathology, Mayo Clinic College of Medicine, Jacksonville, FL, USA | [b] Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA | [c] Department of Pathology, Rush University Medical Center, Chicago, IL, USA | [d] Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA

Correspondence: [*] Address for correspondence: Dennis W. Dickson, M.D., Neuropathology Laboratory, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Tel.: +1 904 953 7137; Fax: +1 904 953 7117; E-mail: [email protected].

Note: [1] Current address: University of Wisconsin School of Medicine, Madison, WI, USA.

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.

Keywords: Amyloid, isopeptide, mental status, neuropsychology, tau, transglutaminase, ubiquitin

DOI: 10.3233/JAD-2008-13106

Journal: Journal of Alzheimer's Disease, vol. 13, no. 1, pp. 53-66, 2008