Amyloid peptides and the vascular system : the link between cerebrovascular angiopathy and Alzheimer's disease

  • Aisha Alsheikh Abubaker

Student thesis: Doctoral ThesisPhD

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that results in progressive impairment of brain cognitive functions and memory. Amyloid beta (Aβ) peptides are protein fragments present as insoluble and misfolded polymeric depositions in the brain parenchyma and cerebral blood vessel walls of AD patients. Pathological accumulation of Aβ peptides within the cerebrovasculature, especially cerebral cortex and leptomeninges vessels, is referred to as cerebral amyloid angiopathy (CAA) and it can compromise the blood brain barrier (BBB) integrity. In addition, capillary dysfunction, such as pericyte degradation and pericapillary fibrosis, is also observed in AD. These
conditions affect blood rheology and hemodynamics leading to impaired cerebral blood flow to tissues. Circulating blood platelets are responsible for haemostasis and thrombosis, and have also been shown to mediate immunity, tissue repair, and inflammation. Several studies have revealed that platelets in AD patients exhibited abnormalities, including an aberrant preactivation state. When combined together with compromised blood vessels integrity, a
highly pro-thrombotic environment within the cerebrovascular system is established, which leaves AD patients extremely vulnerable to the formation of microthromboses and thromboembolic events. This further exacerbates brain tissue degeneration. The exact intracellular mechanisms underlying platelet activation triggered by Aβ peptides are not well established. Emerging evidence suggests a strong correlation between Aβ peptide effects on platelets and reactive oxygen species (ROS) generation, but a complete picture
of the link between Aβ peptides and platelet redox homeostasis is still missing. Therefore, the present PhD project aimed to investigate the mechanisms underlying Aβ peptidedependent activation of platelets and the potential role of ROS in this pathophysiological event. In phase I, the effects of Aβ peptides on platelet functional responses were explored, such as adhesion, aggregation, and thrombus formation under static and physiological flow conditions. Phase II, explores different methodologies to assess oxidative changes in platelets upon treatment with Aβ peptides. Finally in Phase III, the redox- and NADPH oxidase-dependence of platelet functional alterations induced by Aβ peptides was
investigated. Taken together, this work suggests that Aβ1-42 binds to platelets through collagen receptor GPVI, which induces intracellular redox stress and potentiates platelet activation. Aβ1-42 most likely also binds to scavenger receptor CD36 (GPIV). Aβ1-42 induced significant platelet adhesion and thrombus formation in whole blood under venous flow condition, while other Aβ peptides did not. This suggests a role for this peptide in the cerebrovascular abnormalities associated with AD. Finally, we highlighted the importance
of NOXs in the activation of platelets in response to Aβ1-42 peptides and have shown that both NOX1 and NOX2 are important for the induction of superoxide anion formation in platelets activated by Aβ1-42. This work sheds new light on the pro-thrombotic activity of amyloid peptides and provides new insights into the molecular mechanisms underlying cerebral microthrombosis and impaired blood flow in the cerebrovasculature associated
with AD progression.
Date of AwardDec 2019
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorIan Eggleston (Supervisor), Amanda Mackenzie (Supervisor) & Giordano Pula (Supervisor)

Cite this

Amyloid peptides and the vascular system : the link between cerebrovascular angiopathy and Alzheimer's disease
Alsheikh Abubaker, A. (Author). Dec 2019

Student thesis: Doctoral ThesisPhD