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

Abstract

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.

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

Figure 1

Simplified scheme of tTG-catalyzed isopeptide formation between glutamine and lysin in a calcium-dependent manner. Glutamyl residue in one protein molecule serves as acyl donor or amine acceptor, and lysyl residue in another protein serves acyl acceptor or amine donor. With calcium, tTG catalyzes a covalent cross-linking between the proteins by forming γ-glutamyl-ε-lysine isopeptide bond. Modified from Greenberg CS et al [12].

Figure 2

Schematic representation of the structural domains of transglutaminase, amino acid residue distribution region of the catalytic core and Ca⁺⁺-binding domain. The scheme was drawn based on the data from Liu S. et al [42] with reference to [37, 38].

Figure 3

Characteristic structures of AD brain. (A) Senile plaque (arrowhead) and senile plaque with a condensed core (arrow) and (B) neurofibrillary tangles (arrows) (silver staining × 400).

Figure 4

A. Isopeptides and tau protein co-localized in neurofibrillary tangles. The section was stained with mouse monoclonal anti-isopeptide antibody manually first with HRP-DAB. Then the section was treated with DAKO double staining kit followed by CP13 antibody with AP-NACP for color-development. Brown is isopeptide and blue is tau. Arrows indicate tangle-bearing neurons stained by both anti-isopeptide and anti-tau antibodies. B. Isopeptide and Aβ double-staining show colocalization of both proteins in the plaques (arrows) and NFTs (arrow head). The intensities of isopeptide in plaques are relatively weaker that are potentially due to further protein degradation in this type of lesions during the relative lengthy morphogenesis compared to structures like NFT. Magnification: 200 ×.

Figure 5

Hypothetical mechanisms for the role of tTG in AD pathogenesis. Increased brain tTG induced by multiple factors such as trauma, inflammation and ischemic injury will cross-link protein like α-synuclein (ASN), Aβ and tau. In sporadic AD, increased Aβ due to trauma, inflammation and ischemia will further increase tTG levels. Aggregated Aβ may serve as a long-term chronic stimulant for the tTG and keep the pathogenic process going even after the initial factors no longer present. In familial AD (FAD), excessive production Aβ may be sufficient to increase tTG and initiate AD pathogenesis, with or without additional factors seen in sporadic AD. FAD: familial Alzheimer's disease; SAD: sporadic Alzheimer's disease.