Heparan Sulfate Proteoglycans Influence Alzheimer’s Cell Pathology

A group of American researchers used mouse astrocytes and human cells to investigate the effects of heparan sulfate proteoglycans (HSPGs) on pathways linked to Alzheimer’s disease in mitochondrial activity, autophagy, and liposomes. Their work was just published in IScience.

Additionally, they looked at whether altered signaling mediated by HSPGs mitigated the impact of impaired presenilin function in Drosophila.

Context

Three primary histological characteristics of Alzheimer’s disease are adipose saccules, or intracellular lipid buildup in the glia, neurofibrillary tangles, and amyloid plaques.

These histopathological abnormalities, particularly amyloid plaques, have been the focus of most pharmaceutical initiatives for creating treatments for Alzheimer’s disease, and some of these strategies have been helpful in delaying the loss of cognitive function.

On the other hand, risk-associated variations found through genome-wide association studies are shared by the late-onset and early-onset familial forms of Alzheimer’s disease, along with additional cellular abnormalities.

Research has linked Alzheimer’s disease to changes in genes related to innate immunity, lipid metabolism, and membrane trafficking.

Concerning the study

In the current work, the impact of HSPGs on autophagy, mitochondrial activity, and lipid synthesis was investigated using mouse astrocytes and human cell cultures.

Additionally, they looked into how these processes were affected in fruit flies or Drosophila by modifying HSPG-mediated signaling, which compensated for the deficiencies caused by a mutant PSEN1 gene.

Early-onset or familial Alzheimer’s disease is linked to mutations in the PSEN1 gene, which codes for the presenilin protein, which is involved in the processing of the amyloid precursor protein.

ApoE3 Christchurch, one of the apolipoprotein E gene variations, has been discovered to guard against cognitive decline in cases of early-onset Alzheimer’s disease with a PSEN1 mutation.

The heparan-sulfate binding domain of this variant protein contains a changed lysine residue, which may indicate that heparan-sulfate is engaged in apolipoprotein E functions that mitigate the effects of impaired presenilin protein in Alzheimer’s disease.

HSPGs bind to a variety of growth factors, proteins, and growth factor receptors. They are widely distributed in the extracellular matrix and on the surface of cells. They play a crucial role in the building of signaling complexes, the regulation of fibroblast growth factor, and the actions of other proteins related to endocytosis and exocytosis.

Additionally, HSPGs alter a number of signaling cascades related to membrane trafficking and mitochondrial activity.

Lowering the activity levels of HSPGs has been found in earlier studies to improve autophagy flux in Drosophila and to reduce cell death and mitochondrial dysmorphology in models of Parkinson’s disease.

The researchers used 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, which codes for N-deacetylase N-sulfotransferase, involved in heparan-sulfate elongation, to investigate whether heparan-sulfate synthesis is involved in the molecular and cellular events linked to Alzheimer’s disease.

Additionally, they looked at the genes linked to the main processes that Alzheimer’s disease affects, including autophagy, lipid metabolism, and mitochondrial function.

One of the main membrane trafficking mechanisms, autophagy aids in the lipophagy-mediated lipid catabolism by eliminating damaged organelles and protein aggregates. It’s also one of the cellular functions most hampered by Alzheimer’s.

Because it provides the catabolic machinery for lipid metabolism and energy for the cell energetics of autophagy, mitochondrial function is critical for membrane trafficking and lipid metabolism.

Outcomes

The study discovered that human cell lines, mouse astrocytes, and Drosophila all shared the same function of HSPGs in controlling autophagy, mitochondrial activity, and lipid metabolism.

Furthermore, autophagy and mitochondrial activity were enhanced and the creation of intracellular lipid droplets was inhibited by the loss-of-function mutations that reduced heparan-sulfate function. These findings demonstrated that the mechanisms linked to Alzheimer’s disease were relieved by reducing HSPG function.

Furthermore, autophagy flux increased in Drosophila when any gene encoding for changed core proteins in heparan-sulfate or for enzymes involved in heparan-sulfate production was compromised.

Conversely, autophagy flux was decreased by mutations in the Drosophila Psn gene, which codes for the Drosophila presenilin protein.

Reduced expression of the enzymes involved in heparan-sulfate production also prevented the phenotypes of cell loss and apoptosis in the brain that resulted from loss of function of the Psn gene in Drosophila.

Similar outcomes were seen for Psn knockdown-induced defects in liposome formation, autophagosome-derived structures, and mitochondrial function, all of which were restored by reducing heparan-sulfate activity.

In conclusion

The investigators carried out knockdown experiments on Drosophila, mouse astrocytes, and human cell lines. They discovered that some important processes hampered in early-onset Alzheimer’s disease are improved by reducing the activity of HSPGs.

The knockout of the genes encoding the enzymes involved in the manufacture of heparan-sulfate reversed the decrease in autophagy and mitochondrial activity as well as the rise in intracellular lipid droplets.

These findings support the idea that HSPGs play a part in the etiology of Alzheimer’s disease in families.

For more information: Altering heparan sulfate suppresses cell abnormalities and neuron loss in Drosophila presenilin model of Alzheimer Disease, IScience, DOI:https://doi.org/10.1016/j.isci.2024.110256