Vascular Dysfunction in Alzheimer's Disease: Alterations in the Plasma Contact and Fibrinolytic Systems

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting millions of people worldwide. The classical hallmarks of AD include extracellular beta-amyloid (Aβ) plaques and neurofibrillary tau tangles, although they are often accompanied by various vascular defects. These changes include damage to the vasculature, a decrease in cerebral blood flow, and accumulation of Aβ along vessels, among others. Vascular dysfunction begins early in disease pathogenesis and may contribute to disease progression and cognitive dysfunction. In addition, patients with AD exhibit alterations in the plasma contact system and the fibrinolytic system, two pathways in the blood that regulate clotting and inflammation. Here, we explain the clinical manifestations of vascular deficits in AD. Further, we describe how changes in plasma contact activation and the fibrinolytic system may contribute to vascular dysfunction, inflammation, coagulation, and cognitive impairment in AD. Given this evidence, we propose novel therapies that may, alone or in combination, ameliorate AD progression in patients.

Keywords: Alzheimer’s disease; beta-amyloid; contact system; fibrinogen; vasculature.

Figure 1

Vascular dysfunction in Alzheimer’s disease (AD) patient brains and blood vessels. (1) Healthy individuals have an intact blood-brain barrier. Endothelial cells are connected by tight junctions and lined by pericytes (not shown) and astrocytes. (2) This intact blood-brain barrier prevents the extravasation of blood proteins into the brain parenchyma, thereby helping to limit neuroinflammation and protect neurons from damage. (3) The blood-brain barrier in AD patients is damaged as tight junctions are lost and endothelial cells and pericytes (not depicted) degenerate. Cerebral blood flow is decreased due in part to an increase in beta-amyloid (Aβ) along blood vessel walls (cerebral amyloid angiopathy). (4) This vascular damage allows for the extravasation of blood proteins, like fibrinogen (Fbg), into the brain parenchyma. Fibrinogen may promote neuronal degeneration and induce an immune response in the brain, both through its interaction with Aβ and its binding to and activation of the CD11b/Mac-1 receptor on microglia. tPA and plasmin activities are decreased while PAI-1 levels are increased, limiting the removal of Aβ plaques from the brain parenchyma. (5) There is increased plasma contact system activation in AD patient blood due to enhanced interaction of plasma Aβ with factor XII (FXII). Bradykinin (BK) levels are increased, promoting neuroinflammation and further vascular damage. (PK, plasma kallikrein; FXI, factor XI; HK, high molecular weight kininogen).