Bleeding is increased in amyloid precursor protein knockout mouse

Abstract

Background Amyloid precursor protein (APP) is highly expressed in platelets. APP is the precursor to amyloid beta (Aβ) peptides that accumulate in cerebral amyloid angiopathy and plaques in Alzheimer disease. APP and its metabolites interact with many components of the coagulation system, and have both anticoagulant and procoagulant properties, but it is unclear if APP contributes to hemostasis in vivo. Objectives To determine whether APP contributes to hemostasis in mice, including when inhibitors of coagulation are administered. Methods Blood loss in APP knockout (KO) mice was measured in liver laceration and tail transection models of hemorrhage. Blood loss was also measured following tail transection in mice given an inhibitor of coagulation factor Xa (apixaban), platelet inhibitors (aspirin + clopidogrel), tissue‐type plasminogen activator (t‐PA), or the antifibrinolytic tranexamic acid (TXA). Results and Discussion Blood loss from liver lacerations was similar between APP KO mice and wild‐type (WT) mice, but APP KO mice bled more from tail transections. When mice were challenged with aspirin + clopidogrel, the difference in bleeding between APP KO and WT mice was abrogated. In contrast, a difference in bleeding between the strains persisted when mice were treated with apixaban, t‐PA, or TXA. Blood collected from APP KO mice and analyzed with thromboelastography had longer clotting times, and the clots were less stiff and more susceptible to fibrinolysis compared to blood from WT mice. Conclusions The absence of APP measurably increases bleeding in mice, which is consistent with a role for platelet‐derived APP and Aβ peptides in hemostasis.

Nanofiber Peptides for Bacterial Trapping: A Novel Approach to Antibiotic Alternatives in Wound Infections

“…It has been recurrently documented that native AMPs or AMP‐laden gels possess procoagulant attributes. [ 33,34 ] Additionally, several studies have elucidated that in Alzheimer's disease, amyloid precursor protein (APP), the antecedent to amyloid beta (Aβ) peptides, is intricately associated with the genesis of cerebral blood clots, [ 35 ] and that the formation of platelet‐reactive protein amyloid structures induces a procoagulant effect. [ 36 ] By testing the platelet activation marker CD62p, [ 36 ] we also demonstrated that all the newly designed peptides have the function of activating platelets (Figure S23, Supporting Information).…”

Clinical considerations in early-onset cerebral amyloid angiopathy

“…Finally, it is important to consider the potential impact of these mutations on other non-vascular functions of a given protein. As an example, amyloid-β might have a physiological role in clotting 311 ; it is produced by platelets and can induce their aggregation, 87 and further influences clotting via its interactions with fibrinogen. 312 There is evidence that the Dutch and Iowa APP mutations result in altered amyloid-β interactions with fibrinogen and subsequent alterations in clot structure.…”

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

“…The most prominent binding partners of platelet APP following platelet activation were fibrin­(ogen), FXIII-A, and PF4, which are key proteins in hemostasis. Because APPKO mice do not appear to have a severe bleeding phenotype, APP may contribute to the nonhemostatic processes to which fibrinogen and FXIII-A also contribute, including those in inflammation and wound healing . Intracellular FXIII-A modulates the cytoskeletal proteins of platelets, such as vinculin and actin, to modulate the platelet morphology .…”