Heparan Sulfate Proteoglycans in Alzheimer's Disease Pathology

Heparan sulfate proteoglycans (HSPGs) are ubiquitous components of the cell surface and extracellular matrix in the central nervous system. Comprising a core protein with covalently attached heparan sulfate (HS) glycosaminoglycan chains, they participate in a wide array of physiological processes, from synaptic plasticity to growth factor signalling. In Alzheimer’s disease (AD), HSPGs are intimately involved in hallmark pathologies. They co-deposit with extracellular amyloid-β (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau, where sulphated HS chains promote peptide aggregation and protect fibrils from proteolytic clearance. Genetic variation in HS biosynthetic enzymes alters sulphation patterns and influences disease risk by modulating Aβ and tau interactions. Vascular HSPGs contribute to cerebral amyloid angiopathy, exacerbating blood–brain barrier dysfunction and neuroinflammation. Conversely, enzymatic degradation of HS chains can enhance microglial recruitment, augment Aβ clearance and attenuate inflammatory responses. Emerging evidence also positions HSPGs as regulators of neural stem cell differentiation and as mediators of prion-like spreading of pathological proteins. Collectively, these insights highlight HSPGs as central modulators of AD pathogenesis and as potential targets for therapeutic intervention aimed at altering HS-protein interactions or modifying HS chain structure to restore proteostasis and vascular integrity.

Research from Nature Portfolio

A landmark genome-wide meta-analysis across multiple European cohorts identified novel Alzheimer’s risk loci that converge on HS biosynthesis. One key locus encodes a 3-O-sulphotransferase enzyme highly expressed in the cerebellar cortex, implicating specific 3-O-sulphation motifs in neuronal HS chains as modulators of Aβ aggregation and tau phosphorylation. This genetic evidence establishes a direct link between HSPG sulphation patterning and AD susceptibility, reinforcing the concept that fine-tuning HS chain modification is crucial to disease onset and progression. By illuminating a heritable contribution of HS-modifying enzymes, this work provides a foundation for precision-medicine approaches targeting HS biosynthesis pathways in at-risk individuals.

Heparan Sulfate Proteoglycans in Alzheimer's Disease Pathology publication trend

The graph below shows the total number of articles in heparan sulfate proteoglycans in alzheimer's disease pathology across all publications each year (not limited to Nature Index journals).

Technical terms

Heparan sulfate proteoglycan (HSPG): A macromolecule consisting of a core protein and one or more covalently attached heparan sulfate chains, involved in cell signalling and molecular assembly.

Heparan sulfate (HS): A linear sulphated glycosaminoglycan that binds a variety of proteins, including growth factors, chemokines and amyloidogenic peptides.

Amyloid-β (Aβ): Peptide fragments derived from amyloid precursor protein that aggregate extracellularly to form plaques in Alzheimer’s disease.

Tau protein: A microtubule-associated protein that, when hyperphosphorylated, forms intracellular neurofibrillary tangles characteristic of Alzheimer’s disease.

Cerebral amyloid angiopathy (CAA): Deposition of amyloid-β within the walls of cerebral blood vessels, contributing to vascular dysfunction and microhaemorrhages.

Glycosaminoglycan (GAG): A long, unbranched polysaccharide chain composed of repeating disaccharide units that are variably sulphated, influencing protein interactions and extracellular matrix properties.

References

1. Vascular Heparan Sulfate and Amyloid-β in Alzheimer’s Disease Patients. International Journal of Molecular Sciences (2024).
2. Exploring Heparan Sulfate Proteoglycans as Mediators of Human Mesenchymal Stem Cell Neurogenesis. Cellular and Molecular Neurobiology (2024).
3. Towards Understanding the Roles of Heparan Sulfate Proteoglycans in Alzheimer’s Disease. BioMed Research International (2014).
4. The Unifying Hypothesis of Alzheimer’s Disease: Heparan Sulfate Proteoglycans/Glycosaminoglycans Are Key as First Hypothesized Over 30 Years Ago. Frontiers in Aging Neuroscience (2021).
5. Overexpression of Heparanase Lowers the Amyloid Burden in Amyloid-β Precursor Protein Transgenic Mice*. Journal of Biological Chemistry (2014).
6. Proteoglycan-mediated Inhibition of Aβ Proteolysis A POTENTIAL CAUSE OF SENILE PLAQUE ACCUMULATION *. Journal of Biological Chemistry (1995).