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Advanced Neurology Anticoagulants as neuroprotective therapeutics

4. Amyloid β-induced cerebral a significant vasculopathy in AD. Among the several
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vasculopathies and neuronal sequelae in types of SVD, CAA and non-amyloid SVD are the most
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AD common. CAA is a cerebrovascular disorder frequently
observed in the elderly and is categorized according to the
In AD, Aβ deposits are found not only in the type of amyloid protein involved. 7,9,10,15,35,65 In AD, vascular
brain parenchyma but also in cerebral blood deposits of misfolded Aβ lead to Aβ-CAA, 9,10,15,35,65 in which
vessels. 2-10,15,16,35,49,64,85,86 These deposits trigger both Aβ oligomers and filaments accumulate within the walls
neurodegenerative and vasculopathic changes, which of cerebral blood vessels. 6,7,9,10,35 While parenchymal Aβ
collectively participate in cognitive decline. Recent studies deposits in AD are primarily composed of the longer Aβ42
in AD mouse models have shown that microvascular subtype, Aβ40 is the predominant form found in vessel
damage in cortical and hippocampal brain areas occurs walls in Aβ-CAA. The occurrence of Aβ-CAA is closely
before the formation of parenchymal Aβ plaques and related to age and an increased risk of dementia with rapid
deposition of NFTs. 75,87 Similarly, in AD patients, age- cognitive decline. 6,7,9,35,49,65 Aβ-CAA is especially prevalent
related vasculopathic changes in the brain are aggravated, in the vascular systems of the neocortical and hippocampal
including increased vessel resistance, thickening of vessel brain regions, which are also primary sites of parenchymal
walls, and reduced wall elasticity. 6,49,88 In fact, vascular Aβ deposition in AD. In Aβ-CAA, congophilic material
abnormalities in the AD brain, such as Aβ-CAA, have long composed of Aβ is deposited in the walls of small- to
been recognized as early and typical manifestations of the medium-sized leptomeningeal and cortical brain
disease. 1,6-10,35,49,65,88 Aβ-CAA is a vasculopathy associated vessels. 6,7,9,35,49,91 These vascular lesions are associated
with occlusive, cellular, and hemorrhagic lesions, leading with an increased risk of brain hemorrhage (e.g., primary
to vascular and BBB dysfunction. 6-10,35,49,64,65,88 Aβ-induced lobar hemorrhage, cortical microhemorrhage, and
damage primarily affects the inner endothelial cell layer cortical superficial siderosis) and ischemic damage
of the vessel walls and the surrounding structures of (e.g., cortical microinfarcts and ischemic changes in the
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the BBB, which form the critical interface between the white matter). As a result, vascular and BBB function
blood and brain tissue. 6,7,35,49,64,86 In addition to damaging are impaired, leading to decreased cerebral perfusion.
vessel walls, Aβ induces capillary constriction, 64,89 further This cascade of events contributes to inflammatory and
impairing CBF, brain perfusion, and neuronal and neurodegenerative changes in the brain, which eventually
cognitive functions. 6,35,49,88 In particular, ischemic and culminate in cognitive impairment in AD. 6,7,9,10,15,49,85,91
hypoxic conditions in the brain cause a marked reduction Studies in AD mouse models suggest that Aβ is the key
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in cerebral metabolism, which is associated with a self- trigger for Aβ-CAA and its associated sequelae. For
reinforcing cycle of increased Aβ generation. 6,7,35,49,64,86 instance, peripherally applied Aβ-containing inoculates
This vasculopathic aspect of Aβ pathology has only have been shown to induce Aβ-CAA in cortical and
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gained significant attention in AD research over the hippocampal blood vessels. Moreover, individuals who
past 15 years. 6,7,15,35,49,64,86 More recently, the procoagulant received cadaver-derived pituitary growth hormone
activity of Aβ has been found as a key factor in triggering contaminated with Aβ in childhood developed Aβ-CAA,
vasculopathic, inflammatory, and neurodegenerative parenchymal Aβ pathology, and AD-like dementia. 92,93 On
changes in AD. 6,16,25,51-53 Aβ promotes a procoagulant the other hand, tau deposits observed around Aβ-loaded
state in the blood, leading to increased production of cerebral vessels are considered to play a minor role in the
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proinflammatory thrombin and fibrin(ogen). This process development of Aβ-CAA. Collectively, Aβ-CAA and
results in the formation of Aβ-containing fibrin clots, other Aβ-induced vascular abnormalities are increasingly
which are resistant to degradation and are involved in the recognized not merely as symptoms of AD but as integral
development of vasculopathies, such as Aβ-CAA. 6,16,25,27,53 components of Aβ pathology in the disease. 6-10,15,49
Consequently, the involvement of Aβ-induced In fact, Aβ-CAA is a common phenomenon in AD.
vasculopathies in cognitive decline presents novel Clinical studies have found that 82 – 98% of AD patients
therapeutic strategies for AD. Particularly, anticoagulants suffer from Aβ-CAA. 35,65,91 In both sporadic and familial
could be suitable agents for normalizing the Aβ-induced forms of Aβ-CAA, elevated prion-like infectivity and
procoagulant state in AD and counteracting the associated spreading of Aβ have been detected in postmortem brain
neurovascular and cognitive dysfunction. 15,16,19,22-24,26,49,64,90 tissue. Familial Aβ-CAA often manifests more severely
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and at an earlier age than sporadic Aβ-CAA. In familial
4.1. Aβ-CAA
cases, mutations in the APP gene, duplications of APP,
Cerebral SVD is a major contributor to cognitive or mutations in PSEN1 and PSEN2 – genes involved in
impairment in vascular dementia and also represents the γ-secretase complex – are frequently observed. 6,7,9,35,49

Volume 3 Issue 4 (2024) 10 doi: 10.36922/an.3799