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Advanced Neurology Anticoagulants as neuroprotective therapeutics

In addition to Aβ pathogenesis in the brain parenchyma, individuals, more than 85% developed AD symptoms
Aβ is also implicated in cerebrovascular dysfunction in within the subsequent 10 years. In the few people
54
AD. 6,7,10,15,16,25,35,49 Aβ is transported from the parenchymal with amyloid plaques who remained asymptomatic,
tissue through interstitial fluid (ISF) along blood vessel walls lower total levels of Aβ, as well as Aβ filaments with
to the meningeal cerebrospinal fluid (CSF) and lymphatic different structural and biochemical properties,
vessels. This pathway is particularly important for the were detected on average compared to those who
50
elimination of parenchymal Aβ, which moves from the ISF developed AD. 55
across the vascular BBB into the bloodstream –a process (ii) The most critical gene variants associated with a
50
known as perivascular Aβ clearance. As Aβ accumulates high risk of AD are implicated in the generation,
in the blood, oligomers and amyloid filaments, primarily aggregation, and clearance of Aβ, as well as in the
composed of Aβ40, begin to accumulate around and within innate immune system, including glial function.
2,12
the walls of leptomeningeal and cortical blood vessels. Each patient with inherited AD shows excessive Aβ
7,10
Aβ40, being shorter and more soluble compared to Aβ42, accumulation in the brain. In particular, genotypes
4
is believed to diffuse more easily along the perivascular associated with mutations in the APPgene are causally
drainage route into the bloodstream. On the other hand, linked to dominant inherited forms of AD. These
10
the lower solubility of Aβ42 tends to keep this subtype mutations affect the cleavage of APP, the production
within the parenchymal tissue, promoting the formation of Aβ, and the structure and binding properties of
of insoluble plaques. In addition, blood platelets are an Aβ. Likewise, mutations in the PSEN1 and PSEN2
12
10
important source of Aβ synthesis. Studies have shown genes, which encode the presenilin component of
44
that activated platelets from AD patients produce more γ-secretase, and SORL1, which encodes an endosomal
Aβ than those from healthy individuals, contributing to an recycling receptor for cell-surface proteins like APP,
elevated procoagulant state. 16,44 Aβ itself can activate the are recognized as AD risk factors. 2,12,56 In addition,
coagulation cascade, triggering a prothrombotic state in the multiplications of the APP gene, such as those seen
blood. 6,16,25,51-53 This activation of the coagulation cascade in individuals with Down syndrome, trigger amyloid
boosts thrombin and fibrin production, resulting in the and NFT deposition in the brain, 2,12,37 often leading
formation of fibrin clots, especially Aβ-containing fibrin to dementia by age 40 – similar to early-onset AD.
clots, that are resistant to fibrinolysis. 6,15,16,25,44,51-53 These Mutations that increase the Aβ42/Aβ40 ratio or
clots, along with oligomeric Aβ deposits, accumulate in promote Aβ42 accumulation and assembly into
cerebral blood vessels, contributing to vasculopathies such filaments are also associated with a heightened risk
as Aβ-CAA. These conditions are associated with vascular of AD. Moreover, mutations in genes involved in
43
dysfunction, inflammation, and neurodegenerative the innate immune system, especially those affecting
sequelae. 6,7,10,15,16,35,49,50 Aβ-induced vasculopathies also glial cells, can increase Aβ deposition and contribute
impair BBB function, including perivascular clearance to AD risk. One of the strongest and most widespread
of Aβ. This clearance process is further hampered by the genetic risk factors is the E4 allele of the lipid carrier
reduction in the size of meningeal lymphatics, which limits protein APOE4 gene, which influences Aβ deposition
Aβ outflow. As a result, Aβ increasingly accumulates in the and impairs its clearance from the brain. 2,48,57-61
parenchymal tissue. 6,7,10,15,35,49,50 Despite the significant role Other potential risk factors include gene variants
of vascular Aβ pathology in AD, this aspect of the disease encoding microtubule-associated protein tau, which
has long been underappreciated in AD research. Notably, is highly expressed in neurons, and variants in the
vascular amyloid extracted from the brains of AD and gene encoding triggering receptor expressed on
Down syndrome patients served as the starting material for myeloid cells (TREM2), which functions in microglial
the first structural analysis of Aβ nearly 40 years ago. 6-10,20,49 activation. 62,63
(iii) Recent studies have suggested a prion-like mechanism
3.1.1. Evidence for a causative role of Aβ driving Aβ pathology in AD. 2-4,37,42,48 Misfolded Aβ
Recent research has revealed that misfolded Aβ plays a adopts a self-replicating, oligomeric structure that
key role in neuronal and vascular dysfunction in AD, can induce misfolding in native proteins. These
ultimately leading to cognitive decline. 2-11,14-16,25,35,36,38,43,49 misfolded Aβ seeds can then spread throughout
Several lines of evidence support this conclusion: the brain, aggregating into filaments that form Aβ
(i) Data from a cohort study of cognitively normal plaques. 2-4,37,42,48
participants showed that approximately one-third (iv) Mechanistically, misfolded Aβ disrupts neural
of individuals over the age of 65 have parenchymal transmission and brain connectivity by interfering
amyloid deposits in the brain. 11,54 Among these with neurotransmitter receptors, synaptic sodium-

Volume 3 Issue 4 (2024) 6 doi: 10.36922/an.3799