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Advanced Neurology Anticoagulants as neuroprotective therapeutics

this exchange, perivascular clearance of neurotoxic 5. Potential therapeutics with vascular
compounds and proteins, such as Aβ, occurs as they are targeting in AD: Thrombin-inhibiting
transferred from the brain parenchyma into the blood. anticoagulants
A healthy BBB ensures a favorable environment for
brain metabolism, neuronal function, and protection. In AD, the interplay between a prothrombotic,
7,86
In contrast, BBB breakdown is an early hallmark in AD, proinflammatory blood milieu, and cerebrovascular
playing an important role in the initiation and progression damage forms a critical pathogenic unit. 6-10,15,16,25,27,76,105,111
of the disease. This disruption is driven by Aβ, thrombin, This pathological condition is largely driven by Aβ-triggered
and fibrin(ogen) pathologies, which collectively contribute thrombin formation through the coagulation cascade.
to the deterioration of BBB integrity. 6,7,86 Thrombin-mediated inflammation and the formation
of degradation-resistant fibrin-Aβ clots contribute
Studies in AD patients with the APOE4 genotype have to vasculopathies, such as Aβ-CAA, within the brain
shown that Aβ-CAA is a major cause of BBB breakdown. 7,121 (Figure 2). Similarly, elevated thrombin levels are believed
BBB breakdown in capillaries is associated with damage to be implicated in the pathogenesis of conditions such as
to the endothelial cell layer and pericytes, disruption atherosclerosis, diabetes, and traumatic brain injury, all
of transporter systems, and increased endothelial bulk known risk factors for AD. At the cellular level, excessive
27
transcytosis. As a result, BBB dysfunction permits an thrombin particularly damages vascular endothelial
7,86
uncontrolled influx of substances from the blood into cells and disrupts BBB function. Once thrombin and
swollen perivascular areas of the brain parenchyma. 7,80,86 fibrin(ogen) infiltrate the brain parenchyma, they also
These substances include proinflammatory proteins affect glial cells and neurons. 15,27 Therefore, inhibiting
(e.g., prothrombin, thrombin, and fibrinogen), neurotoxic thrombin could represent a plausible idea to normalize
protein aggregates (e.g., Aβ and tau), autoantibodies, ions, the procoagulant and proinflammatory states in AD and
water, cells, and pathogens. 7,80,86 prevent thrombin-mediated vasculopathies and neuronal
The consequences for the brain include edema; damage (Figure 2). 15,16,22-24,26,27,76,105,111
disrupted ion homeostasis; and harmful immune, Thrombin-inhibiting anticoagulants, especially
inflammatory, and neuronal responses. This scenario small-molecule DOACs, have been proposed as
7,86
is further exacerbated by impaired local ISF formation suitable therapeutics for AD (Figure 2). 15,16,22-24,26,27 By
and flow, as well as disruption of normal cargo transport blocking excessive thrombin and its downstream effects,
from the blood into the brain parenchyma. In addition, including inflammation, fibrin-Aβ clot formation, and
7,86
BBB dysfunction hampers the transport of parenchymal vasculopathy development, these anticoagulants could
Aβ into the blood, thereby impairing the perivascular help preserve vascular integrity and BBB function
clearance of toxic Aβ through its dilution and degradation (Figure 2). Consequently, CBF, brain tissue perfusion,
in the bloodstream. 7,86 and the associated nutrient supply and metabolism could
Key cellular transport mechanisms affected by this be maintained (Figure 2), potentially preventing chronic
dysfunction include transcytosis pathway involving brain hypoperfusion, hypoxia, metabolic collapse, and the
endothelial phosphatidylinositol-binding clathrin exacerbation of Aβ and tau pathology.
assembly protein and low-density lipoprotein receptor- Furthermore, intact BBB, CBF, and brain perfusion
related protein 1, which are located in the membranes of promote perivascular clearance of Aβ and limit the
endothelial cells, pericytes, and perivascular astrocytes. accumulation of thrombin, fibrin(ogen), and fibrin-Aβ
7,86
Reduced CBF has also been found to decrease the activity deposits within the brain parenchyma (Figure 2).
of these transporter systems and reduce the removal of Aβ This counteracts vascular-driven neuroinflammatory
by glial cells. A further mechanism of Aβ degradation (e.g., through glial and oxidative responses) and
64
is mediated by neuronal enzymes, such as neprilysin neurodegenerative changes (e.g., synapse and neuron
and insulin-degrading enzymes, both of which have loss) (Figure 2). Collectively, inhibition of excessive
altered production in AD patients. Collectively, BBB pathological thrombin by DOACs could mitigate vascular-
5
dysfunction causes increased Aß accumulation in the triggered neuropathogenesis and associated cognitive
brain parenchyma, primarily by impairing perivascular decline (Figure 2). Ultimately, this treatment could modify
Aß clearance, but also by facilitating the re-entry of the progression of AD, potentially slowing cognitive
Aß from the blood. In parallel, blood-borne proteins, and physical deterioration (Figure 2). 15,16,22-24,26,27,76,96,105,111
7
such as thrombin and fibrinogen, can infiltrate the However, early intervention with anticoagulant is of
brain parenchyma, where they accumulate and trigger primary importance to effectively address Aβ-induced
neuroinflammatory responses. 7,86 procoagulant and proinflammatory states and prevent

Volume 3 Issue 4 (2024) 17 doi: 10.36922/an.3799