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Advanced Neurology Anticoagulants as neuroprotective therapeutics

3.2. Tau pathology to toxic levels and is involved in triggering tau

Intraneural accumulation of misfolded tau proteins in pathology. 2,14,57,73 Oligomeric Aβ has been shown to promote
the brain is a pathological hallmark of AD and is strongly tau hyperphosphorylation by activating tau kinases and
In addition, variants
inactivating tau phosphatases.
2,14,57,73
correlated with the severity of neurodegeneration and of the APOE gene, which are associated with late-onset AD,
cognitive impairment. 5,15,58,71 Tau pathology, also referred have been linked to impaired tau uptake by neurons, as well
to as tau proteinopathy or tauopathy, occurs not only as intensified tau hyperphosphorylation and aggregation.
57
in AD but also in a variety of dementias and movement Vascular dysfunction, such as the disruption of smooth
disorders. 5,15,58,71 As a result, the search for anti-tau muscle cells and declines in CBF and brain perfusion, also
drugs, either as standalone treatments or in combination appears to be involved in tau hyperphosphorylation. 6,64,71,74
with anti-Aβ therapies, is a major focus of intensive Conversely, tau-related pathological alterations contribute
pharmaceutical and clinical research. 14,71
to cerebrovascular dysfunction. 75
Tau is a small protein that usually attaches to
microtubules and is primarily found in the microtubule- 3.3. Inflammation and glial reactions
rich axons of the nervous system. In a healthy brain, In addition to Aβ- and tau-related therapeutic approaches,
5,71
tau stabilizes and bundles microtubules, which is vital the current drug research in AD also focuses on
to fundamental functions, such as axonal transport, cell addressing inflammatory and degenerative changes that
signaling, and neuron structural maintenance. 4,5,71 In contribute to synapse and neuron loss, ultimately leading
contrast, in the AD brain, six tau isoforms are present, to cognitive decline. 2-5,15,16,27,38,76,77 While inflammation
which form oligomers and progressively aggregate into typically serves as a protective tissue response in the
abnormal assemblies of tau filaments. 4,5,71 Key triggers for early stages of AD, as the disease progresses, systemic
tau aggregation include tau cleavage, disrupted cellular inflammation, chronic inflammation, and oxidative stress
transport, and, in particular, aberrant tau phosphorylation reactions occur in the brain parenchyma, exacerbating
by kinases, which begins in the entorhinal cortex and both Aβ and tau pathologies. 3,57,76-79 Inflammatory
spreads to the hippocampus. Hyperphosphorylated reactions in AD are primarily driven by activated glial
5,71
tau proteins adopt conformations that induce misfolding cells (e.g., microglia, astrocytes, and oligodendrocytes)
in naïve tau through a prion-like mechanism, enabling as well as the release of proinflammatory proteins (e.g.,
the spread of tau aggregates within neurons and between cytokines and chemokines), complement proteins
4,37
neurons through neuronal synapses. In neurons, involved in immune defense, and reactive oxygen species
hyperphosphorylated tau dissociates from axonal (ROS) and nitric oxide (NO) species. 3,27,57,76-79 Beyond
microtubules, modifying their structure, and relocates the brain parenchyma, progressive inflammation in AD
from the axon to the somatodendritic compartment. also affects the cerebrovascular system and its function,
5,71
Here, hyperphosphorylated tau assembles into two types which has been largely overlooked in therapeutic rese-
of unbranched filaments – straight filaments and paired arch. 6-10,13,15,16,20,27,35,38,76,77 In the microvasculature of the
helical filaments – which cluster in parallel to form AD brain, elevated levels of inflammatory inducers –
NFTs. 4,5,43,71 Both types of tau filaments comprise two including cytokines, interleukins (ILs), chemokines, tumor
protofilaments sharing a specific conformation known as necrosis factor-alpha, transforming growth factor-beta,
the “Alzheimer tau fold,” a structural feature also observed Aβ, thrombin, and fibrin(ogen) – are found. 6,7,9,13,15,16,27,77
in inherited forms of AD caused by APP mutations. NFTs Collectively, these factors create an inflammatory and
4
are usually observed in the most advanced stages of AD, procoagulant environment in the cerebrovascular
where they are closely associated with neuronal cell death system, which further accelerates neurodegeneration in
5,71
and brain atrophy. Pathologically, the accumulation of AD. 6,7,9,13,15,16,27,77
misfolded tau in the brain disrupts synaptic and neuronal In the central nervous system (CNS), astrocytes (the
function, contributes to neuroinflammation, and interferes most abundant cell type and a key component of the
with neuron-glial interactions. Tau, along with Aβ, also tripartite synapse) and microglia (resident phagocytosing
5,71
causes axonal myelin sheath loss and cellular deficits, cells) form the first line of defense in the immune
such as neurotransmitter shortages and the activation system. 38,57,76,78,79 This “firewall” is indispensable for the
of apoptotic processes, which contribute to synapse and proper functioning of neurons and synapses, neural
neuron death. Furthermore, immune responses through connectivity, and maintaining extracellular homeostasis
5,71
activated microglia and T cells appear to be involved in the in the brain. 38,57,76,78,79 Myelinating oligodendrocytes are
72
neurodegeneration associated with tau pathology. Studies another type of glial cells 38,76 that produce the insulating
have shown that Aβ pathology precedes tau accumulation sheath around axons, which facilitate neuronal transmission

Volume 3 Issue 4 (2024) 8 doi: 10.36922/an.3799