Page 29 - AN-3-4

Advanced Neurology Anticoagulants as neuroprotective therapeutics

Death in these patients usually occurs around the age of 50, Aβ-CAA can also provoke vessel inflammation, which is
often without significant tau accumulations. The APOE4 subtyped into inflammatory angiitis or Aβ-related angiitis. 9
48
genotype, which is associated with a higher risk of late-onset Ultimately, Aβ-CAA and its associated disorders
AD, is linked to both Aβ and tau pathologies, 57,59 as well manifest in severe cerebral vascular pathology, leading
as conditions such as type 2 diabetes, atherosclerosis, and to vascular and BBB dysfunction and a series of
sporadic Aβ-CAA. 9,57,59 Sporadic Aβ-CAA is subdivided pathophysiological sequelae. 7,35,64,66,88 These include
into two types: type 1 is more frequently associated with reduced CBF, brain hypoperfusion, and a resulting
APOE4 and is characterized by Aβ deposition in and nutrient deficiency in cerebral tissue. Vascular defects
around the walls of cortical capillary, larger vessels, and also impair the perivascular clearance of Aβ, further
leptomeningeal vessels and type 2, less strongly associated increasing parenchymal Aβ load. 6,7,10,35,50,94 In addition, the
with APOE4, exhibits Aβ deposition in arteries, arterioles, pathophysiological effects of Aβ-CAA are exacerbated by
veins, and venules, but not in capillaries. 7,9,35,49,91 In the CNS, a reduction in capillary diameter, caused by Aβ-induced
the carrier protein APOE is secreted primarily by glial vessel constriction. 64
cells, especially astrocytes. 57,60 APOE transfers cholesterol
and phospholipids in the form of APOE-containing, high- 4.2. Aβ-induced capillary constriction
density lipoprotein-like particles to neurons, supporting Vascular resistance in the brain is particularly influenced
neuronal plasticity, synaptogenesis, and synapse growth. 57,60 by capillaries rather than arterioles and venules.
64
However, in individuals carrying the APOE4 allele, APOE4 Consequently, the regulation of CBF through changes
activity is associated with increased Aβ deposition, in vascular diameter is mainly controlled by pericytes
impaired Aβ clearance, increased BBB permeability, and on the outer wall of capillaries, with less involvement
abnormal cholesterol accumulation in oligodendrocytes, from VSMCs around arterial vessels. Oligomeric Aβ
10
which disrupts myelin synthesis. 2,48,57-61 An insulating deposits in the capillary walls have been found to decrease
myelin sheath around axons is necessary for the efficient capillary diameter and, as a consequence, reduce CBF by
axonal transmission of electrical impulses. Therefore, triggering localized vessel constrictions through pericyte
58
reduced axon myelination slows neuronal transmission contraction. 64,89 Capillary constrictions develop early in
of electrical signals, impairing cognitive function. In AD, even before significant pericyte loss due to Aβ-CAA,
58
addition, the accumulation of cholesterol can increase and are closely correlated with the extent of Aβ deposition
the interaction of APP with β- and γ-secretases, thereby in capillary walls. 64,89 Studies in both AD mouse models
enhancing Aβ production in neurons. 60 and human brain biopsies have demonstrated that
Arteriolar Aβ-CAA is first diagnosed in the peripheral capillary vasoconstriction is caused by the contraction of
extracellular matrix of the tunica media, extending to the contractile pericytes on the vessel wall. Mechanistically,
89
adventitia, which includes the Aβ seeding sites at the outer pericyte contraction is initiated by Aβ-triggered ROS
regions of the vessels. 7,9,50,92 Depending on the severity, Aβ signaling, which promotes the release of endothelin-1
deposition can progress through all layers of the arterioles (ET) release. ET then activates contractile pericyte ET
and small arteries, gradually replacing all vascular smooth receptors, leading to vasoconstriction. This process may
89
muscle cells (VSMCs) and other tissue elements within the also affect cerebral arterioles and the middle cerebral
vessel wall, except for the endothelial cells. 7,9,35,50,91,92 This artery. Additional pathological processes impairing CBF
64
process progressively debilitates the vessel wall and disrupts include the formation of fibrin and Aβ-containing fibrin
both vascular and BBB function. Consequently, Aβ-CAA is clots that are resistant to degradation as well as aggregates
associated with vascular disorders such as fibrinoid necrosis, of platelets and neutrophil extracellular traps within blood
microaneurysms, concentric splitting or hyaline thickening vessels. 15,16,64,95 Collectively, these factors contribute to
of the vessel wall, and arteriolar degeneration. 7,9,35,50,91,92 In thrombotic vessel occlusions in AD.
capillary Aβ-CAA, Aβ deposition occurs in the basement
membrane, which is a component of the BBB formed by 4.3. Aβ-induced procoagulant and proinflammatory
endothelial cells, pericytes, and astrocytic endfeet. 9,10,35,91,92 states
This process leads to degeneration of the endothelial A notable pathological feature of Aβ is its procoagulant
cells, loss of tight junctions, and a decline in pericytes, activity, which leads to the upregulation of the protease
eventually culminating in BBB breakdown, a condition cascade in the plasma contact system and coagulation
often observed in severe AD. Moreover, vascular deposits of pathways. 6,16,25,51,52,96 Recently, this function of Aβ, which
Aβ tend to infiltrate the adjacent brain parenchyma, which induces a procoagulant state with increased thrombin
has been associated with neuritic Aβ plaque formation, production, has been demonstrated in AD mouse models,
hyperphosphorylated tau, and neuroinflammation. 9,35,91 individuals with mild cognitive impairment at high risk

Volume 3 Issue 4 (2024) 11 doi: 10.36922/an.3799