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

Deng Shun Wang, Hirotake Uchikado, David A. Bennett, Julie A. Schneider, Elliott J. Mufson, Joanne Wuu, Dennis W. Dickson

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)53-66
Number of pages14
JournalJournal of Alzheimer's Disease
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

Fingerprint

formic acid
Pathology
Alzheimer Disease
Proteins
transglutaminase 2
Brain
Enzymes
Ubiquitin
Cognition
Linear Models
Fluorescence
Regression Analysis
Cognitive Dysfunction

Keywords

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

ASJC Scopus subject areas

  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

Cognitive performance correlates with cortical isopeptide immunoreactivity as well as Alzheimer type pathology. / Wang, Deng Shun; Uchikado, Hirotake; Bennett, David A.; Schneider, Julie A.; Mufson, Elliott J.; Wuu, Joanne; Dickson, Dennis W.

In: Journal of Alzheimer's Disease, Vol. 13, No. 1, 01.01.2008, p. 53-66.

Research output: Contribution to journalArticle

Wang, Deng Shun ; Uchikado, Hirotake ; Bennett, David A. ; Schneider, Julie A. ; Mufson, Elliott J. ; Wuu, Joanne ; Dickson, Dennis W. / Cognitive performance correlates with cortical isopeptide immunoreactivity as well as Alzheimer type pathology. In: Journal of Alzheimer's Disease. 2008 ; Vol. 13, No. 1. pp. 53-66.
@article{70d2af5a574e4ae9b133ff696cbcb4b0,
title = "Cognitive performance correlates with cortical isopeptide immunoreactivity as well as Alzheimer type pathology",
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",
author = "Wang, {Deng Shun} and Hirotake Uchikado and Bennett, {David A.} and Schneider, {Julie A.} and Mufson, {Elliott J.} and Joanne Wuu and Dickson, {Dennis W.}",
year = "2008",
month = "1",
day = "1",
doi = "10.3233/JAD-2008-13106",
language = "English (US)",
volume = "13",
pages = "53--66",
journal = "Journal of Alzheimer's Disease",
issn = "1387-2877",
publisher = "IOS Press",
number = "1",

}

TY - JOUR

T1 - Cognitive performance correlates with cortical isopeptide immunoreactivity as well as Alzheimer type pathology

AU - Wang, Deng Shun

AU - Uchikado, Hirotake

AU - Bennett, David A.

AU - Schneider, Julie A.

AU - Mufson, Elliott J.

AU - Wuu, Joanne

AU - Dickson, Dennis W.

PY - 2008/1/1

Y1 - 2008/1/1

N2 - 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.

AB - 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.

KW - Amyloid

KW - Isopeptide

KW - Mental status

KW - Neuropsychology

KW - Tau

KW - Transglutaminase

KW - Ubiquitin

UR - http://www.scopus.com/inward/record.url?scp=40549119152&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=40549119152&partnerID=8YFLogxK

U2 - 10.3233/JAD-2008-13106

DO - 10.3233/JAD-2008-13106

M3 - Article

VL - 13

SP - 53

EP - 66

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 1

ER -