Abstract
We recently discovered a plasma proteolysis pathway, termed the FXII-FVII pathway which is composed of coagulation proteases, and found it to be mainly responsible for the clearance of Aβ42 in the plasma in mice. Aβ42 and Aβ40 are the main Aβ forms in Alzheimer’s disease (AD). In the present study, in vitro assays, wild type (WT) mice and J20 mice (a transgenic AD model) are used to assess the degradation of Aβ40 and Aβ42 by the FXII-FVII pathway and the impact of anticoagulants on such degradation. Four clinically available and mechanistically distinct anticoagulants are evaluated, including dabigatran, enoxaparin (EP), rivaroxaban and warfarin. Each anticoagulant significantly elevates plasma level of synthetic Aβ42 in WT mice, among which EP is the most effective. The differential efficacies of the anticoagulants in elevating plasma Aβ42 level match closely with their inhibitory mechanisms towards the FXII-FVII pathway. Plasma Aβ40 is also degraded by the FXII-FVII pathway and is protected by EP. Moreover, the FXII-FVII pathway is significantly activated in J20 mice, but EP inhibits the activation and significantly elevates plasma levels of both Aβ40 and Aβ42. Taken together, our results shed new light on Aβ metabolism, reveal a novel function of anticoagulants, and suggest a novel approach to potentially developing plasma Aβ as an AD biomarker.
Highlights
Amyloid beta (Aβ) is the major component of senile plaque and is widely considered a key driver of Alzheimer’s disease (AD) [1, 2]
Plasma Aβ40 is degraded by the factor XII (FXII)-factor VII (FVII) pathway and is protected by EP
All four anticoagulants evaluated strongly increase plasma level of exogenously administered Aβ42 in mice (Figure 1C), and the differential efficacies of the anticoagulants conform to their mechanisms of action against the FXII-FVII pathway (Figure 1B)
Summary
Amyloid beta (Aβ) is the major component of senile plaque and is widely considered a key driver of Alzheimer’s disease (AD) [1, 2]. Neuronal expression of mutated human APP in mice increases Aβ production, causes AD-like disease, and increases Aβ level in the blood and CSF [14, 15] Both decreased Aβ clearance and increased Aβ production in the brain have been reported in sporadic AD [16, 17]. We found that about 60% of plasma Aβ generated endogenously is degraded by the FXII-FVII pathway under normal conditions [20] These findings suggest that the FXII-FVII pathway may play an important role in Aβ clearance in AD. We compared four clinical anticoagulants, which are mechanistically distinct, for inhibition of degradation of plasma Aβ42 in mice, examined the impact of the FXII-FVII pathway and an anticoagulant on plasma Aβ40, and investigated the status of the FXIIFVII pathway in a transgenic mouse model of AD and the effect of an anticoagulant on plasma Aβ level in these mice. The study was intended to gain better understanding about plasma Aβ degradation by the FXII-FVII pathway and the impact of anticoagulants on plasma Aβ levels
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