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Advanced Neurology HS-proteoglycans and brain function

A C

B D

Figure 3. Structural organization of proteins involved in neurofibrillary tangles and extraneural plaque formations in Alzheimer’s disease (AD) and
Parkinson’s disease (PD). (A) Enzymatic generation of amyloid βpeptide by β- and γsecretases and the subsequent extraneural oligomerization, fibril
formation, and βamyloid plaque formation in AD. (B) Prion protein and its modular organization, identifying its functional regions and release from
the cell surface, and the generation of prion N1- and C1-terminal peptides by ADAM10. (C) αsynuclein, depicting its functional domains that convey
neurotoxicity and protein aggregate formation in PD. (D) Tau protein and its central tubulin-interactive modules that contribute to cytoskeletal stabilization
and cell shape through the stabilization of microtubules.

therapeutics. Current research is increasingly focused on 7.2. Neurexins and neurodegeneration
the role of highly sulfated HS, which promotes protein Neurexins, which are HSPGs, stabilize synapses through
aggregate formation in amyloidosis. Interestingly, p53, a interactions with cell adhesion synaptic glycoproteins,
phosphoprotein tumor suppressor, also induces amyloid- playing a critical role in neuronal function and signal
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like fibrils and aggregates in a prion-like manner. transduction. There is a clear link between neurexins
Enzymatic remodeling of HS S-domains by sulfate-2 and neuropsychiatric disorders, including autism,
has been shown to downregulate the cellular uptake of schizophrenia, and neurodegenerative diseases. Changes
p53 aggregates, offering a potential therapeutic avenue in neurexin expression are observed in AD and PD. 69
(Figure 3D).
7.3. Syndecans and AD
7. Roles for specific HS proteoglycans in
normal and neurodegenerative disease Elevated expression of SDCs in AD is associated with
processes the aggregation and modulation of cellular uptake of Aβ.
APOE isoforms exert effects on AD development. Neuronal
7.1. CD47 and betaglycan HS/chondroitin sulfate SDC3 increases the cellular uptake of APOEs; APOE2
hybrid co-receptors enhances the internalization of Aβ, while APOE4 increases
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CD47 is ubiquitously expressed in the CNS and regulates the extraneural buildup of Aβ plaques. Intraneuronal
cell adhesion, proliferation, apoptosis, migration, tissue accumulation of Aβ1 – 42 is an early feature of AD, with
homeostasis, and the immune system. It functions as a cell surface HSPGs promoting cellular uptake of Aβ1 –
temporally dually-modified HS/CS thrombospondin-1 42. SDC3 and SDC4 colocalize with amyloid plaques in
co-receptor, modulating glioma cell invasion and AD, and the neuron-specific SDC3 isoform enhances the
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angiogenesis. Examination of synapse components in the cellular uptake of Aβ1 – 42.
normal and AD brain demonstrates elevated hippocampal 7.4. Glypicans and AD
pathologic tau and CD47 expression. Betaglycan (TGFBR3),
another co-receptor, has a widespread distribution and is Tau protein aggregates are a major driver of
an important TGFβ receptor in the regulation of normal neurodegeneration and behavioral impairment. APOE4,
brain development. the highest genetic risk factor for late-onset AD,

Volume 3 Issue 3 (2024) 9 doi: 10.36922/an.3812