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Int J Clin Exp Pathol. 2008 Jan 1;1(1):5-18.

Tissue transglutaminase, protein cross-linking and Alzheimer's disease: review and views.

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  • 1Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.


Extensive protein cross-linking and aggregation are some of the most common molecular events in the pathogenesis of Alzheimer's disease (AD). Both beta-amyloid (Abeta) plaques and neurofibrillary tangles, which are extracellular and intracellular proteinaceous aggregates, respectively, contribute to neuronal death and progressive cognitive decline. Although protein cross-linking has been recognized and extensively studied for many years, the underlying mechanisms are largely unknown. Recent data indicates that tissue transglutaminase (tTG), which catalyzes the cross-linking of a wide spectrum of proteins including Abeta, tau, alpha-synuclein and neurofilament proteins, may be involved in protein aggregation in AD. Many AD risk factors, such as trauma, inflammation, ischemia and stress, up-regulate tTG protein and activity levels. In this review, we summarize the evidence that tTG plays a role in AD, especially in cross-linking of Abeta, tau, alpha-synuclein and neurofilament proteins. An experimentally testable hypothesis is that tTG may play a central role in AD pathogenesis and that it provides a conceptual link between sporadic and familial AD through a shared pathogenic pathway.


Alzheimer's disease; Tissue transglutaminase (tTG, TG2); neurofilament proteins; protein cross-linking; tau; α-synuclein; β-amyloid (Aβ)

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