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Advanced Neurology HS-proteoglycans and brain function

disrupt neuronal electrophysiological properties due to pharmacology and molecular docking studies demonstrate
impairment in the Ca binding properties of the α-syn that EA, UM5, and UM6 play roles in the activation of
2+
N-terminal. Proper Ca mobilization through depolarized the PI3K-Akt cell signaling pathway and the inhibition
2+
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neuronal membranes is fundamental to neuron activation of mitogen-activated protein kinase. Specific targeting of
and neurotransduction, which regulates the transport of Fyn kinase has been proposed as a therapeutic strategy
synaptic vesicles containing neurotransmitters. Phenolic for AD. AZD0530 (Saracatinib), a dual inhibitor of the
compounds have been shown to inhibit the aggregation tyrosine kinases c-Src (proto-oncogene tyrosine-protein
of αsyn and reduce cellular and synaptic toxicities. kinase) and Abl (Abelson murine leukemia viral oncogene
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Flavonoids, known for their anti-inflammatory and homolog 1), potently inhibits Fyn kinase (non-receptor
antioxidant properties, are efficacious in the treatment of cytoplasmic proto-oncogene tyrosine-protein kinase),
neurodegenerative processes and can penetrate the BBB. preventing APOE-induced Fyn signaling and downstream
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Analog flavonoid derivatives with improved efficacy target phosphorylation of the AD risk gene products proline-rich
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multiple neurodegenerative signaling pathways, including tyrosine kinase 2 (PYK2) and tau. PYK2 is a non-receptor
those involving nitric oxide synthase, cyclooxygenase-2, tyrosine kinase highly enriched in forebrain neurons and is
monoamine oxidase, and peroxide-induced neuronal closely related to focal adhesion kinase, playing important
death. roles in sensing cell-ECM contacts and in ECM signaling
that controls cellular adhesion and cell survival. Targeting
8.4. Amyloid Fyn kinase has been shown to reverse memory deficits
The APP is a highly expressed neuronal single-pass in AD mouse models and to rescue the reduced synaptic
transmembrane proteoglycan that is processed by density that occurs in AD. 86
several proteases to release the Aβ peptide (consisting Atomic force microscopy and fluorescent imaging
of amino acids 36 – 43), which forms Aβ plaques. show that 6Ophosphorylated HS/heparin oligosaccharides
Hyperphosphorylated forms of microtubule-associated inhibit amyloid fibril formation in vitro and hold
tau protein are also prominent in these plaque formations. promising in vivo applications. The pathogenesis of
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Misfolded Aβ can act as a template, promoting the AD in humans is associated with impaired clearance of
misfolding of other β peptides, thereby seeding the extracellular amyloid deposits and the accumulation of
production of Aβ protein aggregates and inducing similar insoluble plaque formations. Removal of neuronal HS by
changes in tau protein associated with aggregate Aβ1 – 40 conditional deletion of EXT1 in postnatal neurons leads
and Aβ1 – 42 peptides. Soluble Aβ oligomers exhibit both to a reduction in Aβ oligomerization and deposition
extracellular and intracellular neurotoxic effects through of amyloid plaques in APP/S1 mice. An elevation in the
interactions with membrane receptors and the formation HSPG content in AD brains highlights their roles in the
of ion-permeable pores in membranes. The accumulation pathogenesis of AD and identifies them as potential
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of Aβ peptides results in synaptic dysfunction and therapeutic targets. While HSPGs are known to promote
disturbances in intracellular Ca homeostasis. Ca is a key plaque formation in AD, HS analogs have been shown to
2+
2+
messenger in neuron activation and electrophysiological inhibit βsecretase, a transmembrane neuronal aspartic acid
2+
signaling. Disturbance of astrocyte Ca signaling by protease involved in myelination. The use of enoxaparin
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Aβ can disrupt gliotransmitter release processes vital to (Lovenox) and dalteparin (Fragmin) in a mouse AD model
astrocyte-neuron communication and homeostasis. 83 reduced amyloid deposition by re-solubilizing plaques
and promoting fibril disassembly. Studies on modified
Flavonoids significantly improve cognitive functions
and inhibit or delay Aβ aggregation and neurofibrillary heparins have examined the effects of GAG size and
sulfation on interactions with tau, αsyn, and Aβ in terms
tangle formation in AD. Diets rich in flavonoids are of cellular uptake and protein aggregation. Tau aggregates
associated with increased intellectual abilities and may have specific requirements for GAG length and sulfation
postpone or hinder the senescence cycle and related positions, whereas α-syn and Aβ aggregates have less
neurodegenerative issues, including cognitive decline stringent binding requirements. 20
and psychological impairment in AD. The mode of action
of flavonoids stems from their anti-inflammatory and 8.5. Application of HS glycomics in diseases of
antioxidative neuroprotective properties. 26,84 cognitive decline
Ellagic acid (EA), a dietary flavonoid, is converted HS-like pseudo-hexasaccharides have been prepared by
in vivo to urolithin metabolites. EA and its urolithin linking HS disaccharides in a “head-to-tail” manner.
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metabolites, UM5 and UM6, exert neuroprotective This new class of compounds binds FGF-2 in a similar
effects, improving Aβ 25–35 -induced cell damage. Network manner to native HS oligosaccharides, and they may serve

Volume 3 Issue 3 (2024) 11 doi: 10.36922/an.3812