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Advanced Neurology Anticoagulants as neuroprotective therapeutics

These accumulations of fibrin(ogen) frequently increase the binding affinity of Aβ for fibrinogen by a factor
co-occur with increased vascular endothelial permeability, of 50. This enhanced affinity correlates with the severity of
pericyte loss, elevated levels of activated microglia, and fibrin-Aβ clot deposition and disease progression in AD
the formation of amyloid plaques and dystrophic neurites. patients. 25,108
While fibrin(ogen) in cerebral vessels disrupts vascular The persistent formation and deposition of fibrin-Aβ
and BBB function, in parenchymal tissue, fibrin(ogen) clots, along with their associated vascular disorders, are
synergistically exacerbates neuroinflammation and Aβ further consequences of the Aβ-induced procoagulant state
pathology. 25,53,80,106,108,109,112,113 Parenchymal fibrin(ogen) has in AD. 6,25,53,61,96-98 Fibrin-Aβ deposits are typically found
been associated with glial cell activation and increased in and around the walls of cerebral vessels, contributing
expression of cytokines, chemokines, and ROS. 25,53,80,106,108,109
to the development of Aβ-CAA. 6,53,61,97 The increasing
A prospective clinical study has demonstrated that generation of fibrin-Aβ clots causes vascular lesions, such
high plasma fibrinogen levels are linked with an increased as vessel occlusion, damage to capillary pericytes and
risk of AD and vascular dementia. Mechanistically, endothelial cells, and hemorrhage. As a result, vascular
112
fibrin(ogen)’s γ-chain has been found to specifically bind and BBB dysfunction ensues. 6,25,86,96 Pathophysiologically,
to CD11b/CD18 and CD11c/CD18 receptors on microglia this leads to a decline in CBF and hypoperfusion,
and brain-infiltrating macrophages. 25,106,109 This interaction creating ischemic and hypoxic conditions. These changes
activates microglia, as observed in AD mouse models, drive neuroinflammatory and neurodegenerative seq-
initiating a signaling cascade that causes dendritic atrophy uelae. 5-9,15,16,25,27,53,96,98,108,115 In addition, this scenario
and spine loss in neurons. This microglial activation and exacerbates Aβ accumulation in the brain by stimulating
signaling cascade results in synaptic defects, disintegration parenchymal Aβ synthesis and disrupting perivascular Aβ
of neuronal networks, neuroinflammation, and cognitive clearance due to BBB damage. 25,82,115
decline. 25,106,109 Fibrin-Aβ deposits are also found in the cortical
Injection of fibrinogen in the brains of mice produced and hippocampal parenchyma, especially in regions
similar damage, which was exacerbated in the presence containing dystrophic neurites and adjacent Aβ oligomers
of Aβ. However, genetic or antibody-mediated blockage and plaques. 53,61,97,98 These deposits are associated with
25
of the fibrinogen domain responsible for binding glial neuroinflammation, synapse and neuron loss, and
receptors inhibited microglial activation in AD mouse cognitive decline. The formation of parenchymal
6
models, 25,113 reducing inflammation, neurodegeneration, fibrin-Aβ deposits is largely attributed to BBB breakdown,
and memory decline without affecting fibrinogen’s which enables thrombin and fibrinogen to infiltrate the
procoagulant properties. 25,113 brain parenchyma. 7,97
Fibrin(ogen) can also activate neutrophils, causing In summary, the accumulation of Aβ, thrombin,
excessive immune and inflammatory responses. fibrin(ogen), and fibrin-Aβ aggregates triggers inflammatory
114
Importantly, a recently discovered interaction between and damaging responses in both the vascular system and
fibrinogen and Aβ has established a causal link between brain parenchyma. This results in the activation of glial cells
the pathologies of Aβ, fibrin(ogen), and thrombin, and the release of cytokines and ROS. 27,86,92,106,107,109,113 The
contributing to the prothrombotic state in AD generation of fibrinolysis-resistant fibrin-Aβ deposits is a
(Figure 1). 6,53,96-99,108 Fibrinogen’s β-chain has a binding hallmark of AD, emerging from the pathological interactions
affinity for Aβ, leading to the formation of abnormal, between Aβ, fibrin(ogen), and thrombin (Figure 1). 15,16,25
degradation-resistant blood clots. These clots can cause Given these insights, preventing the formation of fibrin-Aβ
persistent cerebral vessel occlusion, ischemic conditions, clots has been proposed as a novel therapeutic approach
and neurovascular dysfunction. for AD. 6,116 Studies have shown that antibody or genetic
Pathogenic aggregates formed by fibrin(ogen) and suppression of the fibrinogen domain that interacts with Aβ
Aβ have been demonstrated. Both in vitro (using Aβ42) can reduce thrombotic, inflammatory, neurodegenerative,
25,96,113
and in vivo studies show that the β-chain of fibrinogen and cognitive impairment in AD mice. Similarly,
specifically interacts with the central region of Aβ, leading small molecular inhibitors, such as RU-505, which bind to
to fibrinogen oligomerization and aggregation of fibrin-Aβ Aβ and prevent fibrin-Aβ clot formation, have been shown
clots (Figure 1). 6,53,96,98,108 This interaction results in the to reduce vascular amyloid deposition, vessel infarction,
generation of abnormally tight fibrin networks, which are parenchymal microgliosis, and cognitive decline in AD
6,96,116
more resistant to plasmin-induced fibrin cleavage and clot mice.
lysis (Figure 1). 6,25,53,96,97,108 Notably, the Dutch- and Iowa- At present, therapeutic options under investigation
point mutations of Aβ, which are associated with Aβ-CAA, include antisense oligonucleotides, monoclonal antibodies,

Volume 3 Issue 4 (2024) 15 doi: 10.36922/an.3799