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Advanced Neurology HS-proteoglycans and brain function

stability. The accumulation of Aβ generated from APP proteases in intracellular granules in an inactive form.
through an amyloidogenic pathway involving consecutive SRGN colocalizes with plasminogen activator in secretory
cleavages by β-secretase and Q-secretase is causally linked vesicles, regulating plasminogen activator secretion and
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to the pathogenesis of AD. The co-deposition of HS with MMP activation. Microglial SRGN is upregulated in the
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Aβ in plaques in the AD brain accelerates pathological ischemic brain. SRGN’s interactions with properdin
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neurodegenerative changes in brain tissues. promote the production of proinflammatory mediators,
thereby activating the complement system and innate
5.5. Testicans regulating matrix metalloproteinases immune response. Properdin, secreted by neutrophils,
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Testican-1, -2, and -3, also known as SPOCK (secreted monocytes, and T-cell thymocytes, accumulates in
protein acidic and rich in cysteine [SPARC]/osteonectin the ischemic brain and acts as a damage-associated
and kazal-like domain proteoglycan), are members of a molecular pattern that exacerbates neuroinflammation in
widely distributed modular five-domain proteoglycan the injured brain. T-cell infiltration through the blood–
family that contains two C-terminal HS chains, extensively brain barrier (BBB) promotes AD and cognitive decline.
expressed in brain tissues (Figure 2B). Domain I of The innate immune response thus contributes to CNS
testicans is a unique N-terminal domain, while domain II neurodegeneration. In AD, the BBB may be impaired,
is a cysteine-rich module homologous to follistatin/kazal- leading to elevated T-cell and mast-cell infiltration. 45
type protease inhibitors. Testican-1 and -2 are expressed by 5.8. Agrin
multiple neuronal cell types in the olfactory bulb, cerebral
cortex, thalamus, hippocampus, cerebellum, and medulla. Agrin contains nine follistatin KPI domains, which may
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Testican-1 modulates matrix metalloproteinase (MMP) confer resistance to the proteolytic clearance of protein
activation by inhibiting membrane-type MMPs and aggregates in AD, thereby prolonging the duration of
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cathepsin L. In contrast, testican-2 abrogates the inhibition neurotoxic effects. Agrin also has a laminin-binding
of membrane type 1-MMP- or membrane type 3-MMP- domain that is structurally related to tissue inhibitor
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mediated pro-MMP-2 activation by testican-1. Testican-3, of MMP-1, and it features multiple epidermal growth
an HSPG exclusive to brain tissues, suppresses membrane factors (EGF)-like and laminin G modules, a central
type 1-MMP-mediated activation of MMP-2. Increased sperm-enterokinase-agrin (SEA) domain, and a Ser/
levels of testican-1 have been observed in AD brain tissues, Thr-rich module that contains the HS substitution sites
where it accumulates in co-aggregates with Aβ plaques (Figure 2D). Agrin interacts with laminin, neural cell
in the frontal, temporal, and entorhinal cortices of AD adhesion molecule (NCAM, CD56), α-dystroglycan, low-
patients. This accumulation impedes the clearance of Aβ density lipoprotein receptor-related protein (LRP) 4, and
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from AD brains, thereby impacting normal brain function. integrins. α-neurotrypsin cleaves agrin at two cleavage
sites in the agrin core protein: PIER↓ASCY (a-cleavage
5.6. Bikunin site) and LVEK↓SVGD (b-cleavage site).
Bikunin contains two KPI domains that may inhibit the
clearance of Aβ deposits. These KPI domains inhibit a 6. Propagation of pathological brain
range of serine proteases, including trypsin, chymotrypsin, protein aggregates by HS proteoglycans
leukocyte elastase, cathepsin G, kallikrein, and plasmin. HS proteoglycans play essential roles in neurodegeneration
The inhibition of these serine proteases prevents the associated with neuritic plaques and cerebrovascular
activation of MMPs. 41 blood vessels in AD. SDCs, a type of HSPG, promote the
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cellular uptake and fibrillation of αsyn, tau protein, and Aβ
5.7. Serglycin
1 – 42, which contribute to the formation of senile plaques
Serglycin (SRGN) is widely distributed in brain tissues, in AD. HSPGs act as mediators between monomeric tau
as shown in the Human Protein Atlas (http://www. and the activation of the ERK1/2 cell signaling pathway,
proteinatlas.org/ENSG00000122862-SRGN/brain). facilitating tau internalization. The aggregation of tau
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SRGN is an intracellular secretory granule proteoglycan fragments and the formation of filaments is influenced by
found in neurons, endothelial cells, endocrine cells, and the sulfation code of HS in HSPGs, particularly regulated
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hematopoietic cells. It carries 7 – 15 GAG chains, each by the 6O-sulfate content and promoted by 3O-sulfation.
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over 100 disaccharides in length, attached to a central core In AD, HSPGs promote amyloid pathology by promoting
protein region composed of 9 – 24 Ser-Gly repeats, giving the formation of amyloid aggregates and filaments,
the protein its name (Figure 2C). These Ser-Gly repeats similar to their roles in the assembly of prion aggregates
are exceptionally resistant to proteolytic degradation, and in Creutzfeldt-Jakob disease and scrapie. Amyloid fibrils,
along with their attached GAG chains, they package active which are formed by several normally soluble proteins,

Volume 3 Issue 3 (2024) 7 doi: 10.36922/an.3812