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Advanced Neurology Anticoagulants as neuroprotective therapeutics

of electrical signals and support axoglial metabolism while effects. 38,76,80 This is particularly evident when Aβ plaques
detoxifying oxidative radicals. In AD, Aβ plaque formation, form, and microglia surround the plaques and NFT-
neuroinflammation, and oxidative stress are accompanied containing neurons, attempting to remove them but
by decreased myelin production due to oligodendrocyte ultimately lacking the sufficient phagocytic capacity
dysfunction, 38,57,76 resulting in myelin defects and impaired to do so. 5,38,76 Oligomeric Aβ has been proven to be a
neuronal signaling, both of which contribute to cognitive potent activator of microglia. 2,5,38,76 Likewise, Aβ plaques
decline. Astrocytes also play a crucial role in supporting can directly stimulate glial cells to release a variety of
the vascular and nervous systems. 38,76 They are an integral toxic agents into the brain parenchyma, including ROS,
part of the BBB, contributing to its function and ensuring NO, proinflammatory cytokines, chemokines, and
proper blood flow within the vasculature. 38,76 Astrocytes complex protein mediators. 38,76,79,81 These toxic products
further participate in mediating the transport of recruit more microglia and astrocytes to the sites of Aβ
metabolites and neurotransmitters between the CNS and deposition, generating an environment of inflammation,
the periphery, including the elimination of waste products oxidative stress, and neuronal cell death. 76,78,79,81 This
such as toxic Aβ from the CNS through the glymphatic inflammatory condition reduces the brain’s capacity
and blood systems. 38,76 Microglia, on the other hand, are to eliminate Aβ, promoting further accumulation
engulfing and degrading cerebral debris and foreign and, ultimately, accelerating AD progression. 76,78,79,81 In
substances through phagocytosis, and they also promote addition, cytokines, such as ILs, are able to promote Aβ
the repair of damaged tissues. 38,76,79,80 In addition, a network synthesis and spreading in the brain. Certain cytokines
of microglial cell-surface receptors and intracellular can induce the expression of inflammasome multiprotein
signaling pathways regulates the production and secretion complexes, such as interferon-induced transmembrane
of both pro-inflammatory and anti-inflammatory proteins, protein 3 (IFITM3), in neurons and astrocytes. 81,82 IFITM3
as well as the oxidative stress reactions through the release enhances Aβ production by modulating γ-secretase. On
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of ROS and NO. 38,76,79,80 the other hand, certain cytokines like IL-3, secreted by
The response of glial cells changes when brain tissue astrocytes, can activate microglial cells to cluster around
is injured, diseased, or during advancing age. 38,76,78 In Aβ and tau aggregates and eliminate them through
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these cases, the gradual loss of physiological function phagocytosis. In contrast, IL-17 has been implicated
and chronic hyperactivation in the brain leads to in Aβ-induced neuroinflammation, cognitive decline,
excessive activation of astrocytes and microglia, shifting systemic inflammation, peripheral vascular dysfunction,
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them into reactive and neurotoxic phenotypes. 38,57,76,78 and a prothrombotic state. Microglial cells detect Aβ
Activation of glial cells has been observed in the brains through a range of cell surface receptors and respond
of AD patients, closely linked to increased inflammation through multiple signaling cascades. 5,38,76 These receptors
and disease progression. Astrocytes can undergo gliosis, include triggering TREM2 and pattern recognition
adopting different reactive states characterized by distinct receptors, such as formyl peptide receptors. 5,38,76 Antibodies
morphology, gene expression, and function. 38,76 In these that bind to and modify microglia-activating receptors
reactive states, astrocytes can compensate for microglial are currently promising candidates for the treatment of
dysfunction, taking on key roles such as interacting with neuroinflammation in AD, potentially in combination
and phagocytosing Aβ. 38,76 In addition, reactive astrocytes with anti-Aβ therapies. 5,38,76 Among these receptors,
respond to proinflammatory proteins, such as cytokines, TREM2 is considered a key receptor on the surface of
and promote inflammatory and neurodegenerative microglia. 62,63,76 TREM2 promotes the phagocytic activity
processes. 38,76 In the known as microgliosis, activated of microglia and regulates their signaling response to
microglia become highly mobile, secrete proinflammatory inflammation, Aβ, and tau in AD. 62,63,76 Loss of TREM2
proteins, and migrate to the affected brain tissue. 38,79,80 function has been found to increase amyloid pathology
They phagocytose various components, such as misfolded and the risk of AD, particularly by impairing Aβ clearance
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proteins (e.g., Aß and tau), debris from damaged cells, through phagocytosis. On the other hand, excessive
defective neurons and synapses, and pathogens, such phagocytic activity can cause the loss of healthy neurons
as bacteria and viruses. 38,79,80 In the early phases of AD, and synapses, contributing to neurodegeneration.
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as Aβ accumulates, microglia are initially activated to Collectively, the microglial response to Aβ and associated
the M2 phenotype, which enhances both the expression disease progression appear to be context-dependent.
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of proinflammatory proteins and the phagocytosis of Microglia can switch from a protective role, characterized
Aβ. 5,38,76,79,80 However, as the disease progresses, chronic by Aβ phagocytosis, to a disease-promoting role, marked
activation shifts microglia to the M1 phenotype, by proinflammatory protein expression and associated
which promotes Aβ pathology and induces neurotoxic neurotoxic effects.

Volume 3 Issue 4 (2024) 9 doi: 10.36922/an.3799