Cognitive performance correlates with cortical isopeptide immunoreactivity as well as Alzheimer type pathology.
BACKGROUND
Protein cross-linking and aggregation are important molecular processes in Alzheimer's disease (AD), and tissue transglutaminase (tTG) catalyzes protein cross-linking.


OBJECTIVE
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 Abeta, 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.
Wang
Deng-Shun
DS
Departments of Neuroscience and Pathology, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Uchikado
Hirotake
H
Bennett
David A
DA
Schneider
Julie A
JA
Mufson
Elliott J
EJ
Wu
Joanne
J
Dickson
Dennis W
DW
D000544:Alzheimer Disease / Q000201:enzymology* / Q000453:epidemiology* / Q000473:pathology; D000682:Amyloid / Q000378:metabolism; D000911:Antibodies, Monoclonal; D019759:Carbon-Nitrogen Lyases / Q000378:metabolism*; D002540:Cerebral Cortex / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D003072:Cognition Disorders / Q000175:diagnosis / Q000453:epidemiology*; D005625:Frontal Lobe / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019204:GTP-Binding Proteins; D006801:Humans; D009483:Neuropsychological Tests; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012720:Severity of Illness Index; D011503:Transglutaminases / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D000682:Amyloid; D000911:Antibodies, Monoclonal; D025801:Ubiquitin; D016875:tau Proteins; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D019759:Carbon-Nitrogen Lyases; C034300:isopeptidase