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Heparan-sulfate proteoglycans found to influence Alzheimer’s cell pathology

Heparan-sulfate proteoglycans found to influence Alzheimer’s cell pathology


In a recent study published in IScience, a team of researchers from the United States examined the impact of heparan-sulfate-modified proteoglycans (HSPGs) on Alzheimer’s disease-associated pathways in mitochondrial function, autophagy, and liposomes using mouse astrocytes and human cells.

They also examined whether HSPG-mediated signaling modulations countered the effect of compromised presenilin function in Drosophila.

Study: Altering heparan sulfate suppresses cell abnormalities and neuron loss in Drosophila presenilin model of Alzheimer Disease. Image Credit: PopTika/Shutterstock.com

Background

Alzheimer’s disease is characterized by three major histopathological features — amyloid plaques, neurofibrillary tangles, and adipose saccules or intracellular lipid accumulation in the glia.

Most of the pharmaceutical strategies for developing Alzheimer’s disease treatments have focused on these histopathological abnormalities, especially amyloid plaques, and some have been successful in slowing cognitive loss.

However, other cellular deficits are common to the early-onset, familial form of Alzheimer’s disease and the late-onset form of the disease, with risk-associated variants identified through genome-wide association studies.

Studies have identified modifications in genes involved in membrane trafficking, innate immunity, and cholesterol metabolism associated with Alzheimer’s disease.

About the study

In the present study, the researchers used mouse astrocytes and human cell cultures to examine the influence of HSPGs on autophagy, mitochondrial function, and lipid synthesis.

They also investigated whether modulating HSPG-mediated signalling impacted these processes in fruit flies or Drosophila, which countered the deficits of a mutated PSEN1 gene.

Mutations in the PSEN1 gene, which codes for the protein presenilin that is involved in the processing of the amyloid precursor protein, are implicated in the development of familial or early-onset Alzheimer’s disease.

One of the variants of the apolipoprotein E genes, known as ApoE3 Christchurch was found to protect against cognitive decline in early-onset Alzheimer’s disease involving PSEN1 mutation.

This variant protein has a modified lysine residue in the heparan-sulfate binding domain, suggesting that heparan-sulfate is involved in apolipoprotein E functions that counter the impact of compromised presenilin protein in Alzheimer’s disease.

HSPGs are found abundantly in the extracellular matrix and the cell surface and are binding sites to various growth factors, proteins, and growth factor receptors. They are also vital in signaling complex assembly and regulating fibroblast growth factor and other proteins involved in exocytosis and endocytosis.

HSPGs also modulate various signaling pathways involved in mitochondrial function and membrane trafficking.

Previous studies have shown that lowering the activity levels of HSPGs has improved autophagy flux in Drosophila, and suppressed mitochondrial dysmorphology and cell death in Parkinson’s disease models.

To examine whether heparan-sulfate synthesis plays a role in the molecular and cellular events associated with Alzheimer’s disease, the researchers performed ribonucleic acid (RNA) sequence profiling of human cell lines and mouse astrocytes with loss-of-function mutations in the EXT1 gene which is involved in heparan-sulfate polymerization and the NDST1 gene that codes for N-deacetylase N-sulfotransferase involved in heparan-sulfate elongation.

They also investigated the genes associated with the major processes, such as lipid metabolism, autophagy, and mitochondrial function, affected by Alzheimer’s disease.

Autophagy is one of the major membrane trafficking processes that removes damaged organelles and protein aggregates and helps in lipid catabolism through lipophagy. It is also one of the most compromised cellular processes in Alzheimer’s disease.

Mitochondrial function is essential for membrane trafficking and lipid metabolism because it delivers energy for the cell energetics of autophagy and provides the catabolic machinery for lipid metabolism.

Results

The study found that the role of HSPGs in modulating autophagy, mitochondrial function, and lipid metabolism was conserved across Drosophila, human cell lines, and mouse astrocytes.

Furthermore, the loss-of-function mutations that lowered heparan-sulfate function increased autophagy and mitochondrial function and decreased the formation of intracellular lipid droplets. These results showed that lowering HSPG function alleviated the processes implicated in Alzheimer’s disease.

Additionally, compromising the function of any of the genes coding for enzymes involved in heparan-sulfate biosynthesis or for the modified core proteins in heparan-sulfate resulted in an increase in autophagy flux in Drosophila.

On the other hand, mutations in the Psn gene in Drosophila, which codes for the Drosophila presenilin protein, lowered autophagy flux.

Loss-of-function of the Psn gene in Drosophila also caused cell loss and apoptosis in the brain, and these phenotypes were also countered by lowering the expression of heparan-sulfate biosynthesis enzymes.

Similar results were observed for abnormalities induced by Psn knockdown in mitochondrial function, autophagosome-derived structures, and liposome formation, which were rescued by lowering heparan-sulfate activity.

Conclusions

The researchers conducted knockout studies in human cell lines, mouse astrocytes, and Drosophila. They found that lowering the activity of HSPGs improves some key processes compromised in early-onset Alzheimer’s disease.

The lower levels of autophagy and mitochondrial activity, as well as the increase in intracellular lipid droplets, were countered when the genes coding for enzymes involved in the biosynthesis of heparan-sulfate were knocked out.

These results provide evidence for the role of HSPGs in the pathogenesis of familial Alzheimer’s disease.

Journal reference:

  • Schultheis, N., Connell, A., Kapral, A., Becker, R. J., Mueller, R., Shah, S., O’Donnell, M., Roseman, M., Swanson, L., De-Guara, S., Wang, W., Yin, F., Saini, T., Weiss, R. J., & Selleck, S. B. (2024) Altering heparan sulfate suppresses cell abnormalities and neuron loss in Drosophila presenilin model of Alzheimer Disease. IScience. doi:10.1016/j.isci.2024.110256. https://www.cell.com/iscience/fulltext/S2589-0042(24)01481-0



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