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Advanced Neurology HS-proteoglycans and brain function

become resistant to enzymatic degradation when they shortened HS chains contain a rare 3Osulfate motif, which
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interact with HS, resulting in the assembly of macro- binds tau. Misfolding of cellular prion protein, PrP , into
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aggregates that persist in brain tissues. To date, more than its amyloidogenic isoform, PrP , leads to the formation of
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36 plasma proteins have been identified that can form infectious protein aggregates in prion diseases. Influenza
amyloid deposits. Despite the absence of a common amino A virus has been shown to cause the conversion of PrP
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acid sequence among these proteins, they all share the into misfolded PrP infectious prion particles in mouse
ability to self-assemble into stable, stacked βpleated sheet neuroblastoma cells. Furthermore, the SARS-CoV-2
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fibrillar structures. The HSPG binding site in amyloid is spike protein contains prion-like peptide sequences that
a 13- to 16-amino-acid segment containing the His-His- are capable of propagating insoluble protein aggregates. 52
Gln-Lys sequence. Low-molecular-weight heparins have
been shown to reverse this binding step, thereby inhibiting 6.2. Tau
fibril formation, and have been suggested as potential Hyperphosphorylated tau protein, a microtubule-
therapeutic agents for treating amyloid plaque formation associated protein, is a major component of the insoluble
in AD. helical and straight filaments found in AD and other
neurodegenerative disorders. The hyperphosphorylation
6.1. Prion disease of tau is essential for filament formation and is a defining
Transmissible spongiform encephalopathies, or prion feature of AD. Highly sulfated GAGs present in nerve cells
diseases, are a group of devastating neurological disorders promote interactions with tau, leading to the formation
characterized by neuronal loss, mental deterioration, and of neurofibrillary tangles—interactions that are central to
spongiform degeneration. Although rare in humans, prion neuronal pathology in AD (Figure 3B).
diseases have a high prevalence in deer and elk and also
occur in sheep and goats, where the condition is known 6.3. Synuclein
as scrapie. Human prion diseases include Kuru, as well Lewy bodies, which contain GAGs and αsyn protein
as sporadic, iatrogenic, and familial forms of Creutzfeldt- aggregates, are key features of PD. HS is critical for the
Jakob disease, Gerstmann-Sträussler-Scheinker disease, aggregation and cellular uptake of αsyn. Studies using
and fatal familial insomnia. Kuru is a form of prion high-speed atomic force microscopy, dynamic light
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disease restricted to Papua New Guinea, spread by scattering, and nuclear magnetic resonance have shown
ritualistic familial cannibalism. The causative agent of that the interaction between human prion protein and
prion disease is a misfolded form of prion protein, PrP αsyn results in the formation of a disordered complex
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(Figure 3A). The normal prion glycoprotein, PrP , is a that suppresses further aggregation, thereby inhibiting
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glycosylphosphatidylinositol (GPI)-anchored cell surface amyloidogenesis. HSPG interactions with tau facilitate
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protein widely expressed in the immune and nervous the prion-like propagation of tau aggregates in AD, leading
systems, and it serves as a key neuronal receptor for Aβ to insoluble neurofibrillary tangles and senile plaque
oligomers, mediating neurotoxicity, neurodegeneration, formation in dementia, which are detrimental to normal
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and the pathogenesis of AD. Misfolding of PrP is also neural function and disrupt brain cognitive processes.
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associated with transmissible spongiform encephalopathies. The transcellular spreading of tau in AD is mediated by its
A disintegrin and metalloproteinase (ADAM10) binding to neuronal cell surface HS, which contains a rare
proteolytically releases PrP from the cell surface as a 3Osulfate motif. The addition of 3Osulfate HS 12mers to
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soluble form devoid of its GPI anchor, which is a potential cell cultures significantly reduces the cell surface binding
biomarker of neurodegeneration and a modulator of prion and internalization of tau (Figure 3C).
disease. The shedding of PrP from human neurons by
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ADAM10 prevents the binding and cytotoxicity of Aβ 6.4. Amyloid
oligomers. Confocal immunofluorescence microscopy has It has been more than 30 years since the hypothesis was
shown that normal PrP and gylpican (GPC)1 colocalized proposed that neurodegeneration in AD is caused by
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inside an immortalized neuronal cell line (GT11). This the deposition of Aβ in plaques within brain tissue. The
colocalization does not occur in scrapie-infected GT11 cells accumulation of Aβ in the brain has long been considered
(ScGT11), where GPC-1 remains at the cell surface, the primary driver of AD pathogenesis. The formation of
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separate from PrP . Scrapie infection stimulated GPC-1 neurofibrillary tangles containing tau protein is thought to
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autoprocessing, and silencing of GPC1 elevates levels result from an imbalance between Aβ production and Aβ
of intracellular PrP aggregates in infected cells. GPC1 clearance. However, the repeated failure of clinical trials
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autoprocessing clears PrP from infected cells, promoting aimed at improving Aβ clearance from pathological tissues
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the deposition of prions in brain tissues. Ext1 mice with has resulted in a shift in focus for neurodegenerative
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Volume 3 Issue 3 (2024) 8 doi: 10.36922/an.3812