Post-Translational Modifications of Platelet-Derived Amyloid Precursor Protein by Coagulation Factor XIII-A*

Abstract

The physiological function of amyloid β precursor protein (APP) in platelets has remained elusive. Upon platelet activation, APP localizes to the platelet surface and is proteolytically processed by proteases to release various metabolites, including amyloid β (Aβ) and soluble APP. Synthetic Aβ is a substrate of activated coagulation factor XIII (FXIII-A*), a transglutaminase that is active both inside and on the surface of platelets. Here we tested if platelet APP and its fragments are covalently modified by FXIII-A*. Platelet-derived FXIII-A* and fibrin(ogen) bound to APP, and their bound fractions increased 7and 11-fold upon platelet activation, respectively. The processing of platelet APP was enhanced when FXIII-A* was inhibited. Soluble APPβ was covalently cross-linked by FXIII-A*. This mechanism regulating APP processing is significant, because controlling the processing of APP, such as by inhibiting specific secretases that cleave APP, is a therapeutic target for Alzheimer's disease.

Platelet-Rich Plasma in Dermatology: New Insights on the Cellular Mechanism of Skin Repair and Regeneration

“…), or can incorporate proteins from the plasma or other sources, storing all these mainly into the α-granules [86,87]. Usually, the protein content of the platelets can be modulated by protein post-translational modification and is also regulated by different rates of protein degradation (an important process for platelet function) either by the ubiquitin-proteasome system or the autophagylysosome system [88,89]. The total number of proteins within platelets is known as the platelet proteome (mainly produced in MKs and transferred to platelets), and this proteome contains approximately 4000-5000 distinct proteins [90][91][92].…”

Platelet Behavior Contributes to Neuropathologies: A Focus on Alzheimer's and Parkinson's Disease

“…208 Additionally, platelet APP binds to platelet-derived coagulation factor XIII-A and fibrinogen upon platelet activation, and platelet FXIII-A covalently crosslinks the extracellular portion of APP as well as attaches serotonin to APP, thus preventing APP processing. 209…”

“…208 Additionally, platelet APP binds to plateletderived coagulation factor XIII-A and fibrinogen upon platelet activation, and platelet FXIII-A covalently crosslinks the extracellular portion of APP as well as attaches serotonin to APP, thus preventing APP processing. 209 A relevant topic for hypercoagulation is antiplatelet drugs, which demonstrate promise in reducing AD severity. Clopidogrel, which irreversibly inhibits P2Y 12 , reduces the amount of clusterin in the circulation and prevents platelet-induced aggregation of Aβ, ultimately reducing CAA.…”