Transglutaminase Induces Protofibril-like Amyloid β-Protein Assemblies That Are Protease-resistant and Inhibit Long-term Potentiation

• Published in: The Journal of biological chemistry Vol. 283; no. 24; pp. 16790 - 16800
• Main Authors: Hartley, Dean M., Zhao, Chaohui, Speier, Austin C., Woodard, Gavitt A., Li, Shaomin, Li, Zongli, Walz, Thomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.06.2008; American Society for Biochemistry and Molecular Biology
• Subjects: Alzheimer Disease - metabolism; Amyloid beta-Peptides - metabolism; Animals; Cross-Linking Reagents - chemistry; Cross-Linking Reagents - pharmacology; Disease Progression; GTP-Binding Proteins - metabolism; Guinea Pigs; Hippocampus - metabolism; Humans; Insulysin - chemistry; Long-Term Potentiation; Mice; Neprilysin - chemistry; Peptide Hydrolases - metabolism; Peptides - chemistry; Transglutaminases - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M802215200

An increasing body of evidence suggests that soluble assemblies of amyloid β-protein (Aβ) play an important role in the initiation of Alzheimer disease (AD). In vitro studies have found that synthetic Aβ can form soluble aggregates through self-assembly, but this process requires Aβ concentrations 100- to 1000-fold greater than physiological levels. Tissue transglutaminase (TGase) has been implicated in neurodegeneration and can cross-link Aβ. Here we show that TGase induces rapid aggregation of Aβ within 0.5-30 min, which was not observed with chemical cross-linkers. Both Aβ40 and Aβ42 are good substrates for TGase but show different aggregation patterns. Guinea pig and human TGase induced similar Aβ aggregation patterns, and oligomerization was observed with Aβ40 concentrations as low as 50 nm. The formed Aβ40 species range from 5 to 6 nm spheres to curvilinear structures of the same width, but up to 100 nm in length, that resemble the previously described self-assembled Aβ protofibrils. TGase-induced Aβ40 assemblies are resistant to a 1-h incubation with either neprilysin or insulin degrading enzyme, whereas the monomer is rapidly degraded by both proteases. In support of these species being pathological, TGase-induced Aβ40 assemblies (100 nm) inhibited long term potentiation recorded in the CA1 region of mouse hippocampus slices. Our data suggest that TGase can contribute to AD by initiating Aβ oligomerization and aggregation at physiological levels, by reducing the clearance of Aβ due to the generation of protease-resistant Aβ species, and by forming Aβ assemblies that inhibit processes involved in memory and learning. Our data suggest that TGase might constitute a specific therapeutic target for slowing or blocking the progression of AD.