Novel Protein Target for Alzheimer’s Therapy Is Studied

Heparan-sulfate-modified proteins, or proteoglycans (HSPGs), may be a useful early-stage target for novel treatments for Alzheimer’s disease, according to research led by Pennsylvania State University.

Up to seven million Americans suffer with Alzheimer’s disease, a neurological condition that is steadily on the rise. The majority of these patients are over 65.

While many late-stage trials have failed in the challenging task of developing medicines for this complex ailment, there have been some triumphs in the last few years. For instance, the monoclonal antibody lecanemab, created by Biogen and Eisai, was approved in the summer of 2023 to treat early-stage, symptomatic disease. This was the first major therapeutic approval in a long time, and it supports the “amyloid hypothesis” of the disease.

Comparably, the FDA has only this week approved donanemab, another antibody therapy, to treat early-stage, symptomatic Alzheimer’s disease. Eli Lilly created this medication.

According to Scott Selleck, a professor in Penn State University’s department of biochemistry and molecular biology, and colleagues, “despite these successes, there is good reason to identify cellular and molecular pathologies that occur early in the Alzheimer’s disease process” in the journal iScience.

“Further investment in broad, mechanistic approaches to Alzheimer’s disease development is required to effectively prevent and treat this disease at a level that significantly alters the disease trajectory.”

Using Drosophila as a model to examine the effects of HSPG alterations on the drosophila version of the presenilin gene and mice to examine the effects of these proteins on APOE variants, Selleck and colleagues examined the role of HSPGs in Alzheimer’s disease in this study.

Alzheimer’s disease may result from mutations in the presenilin gene in humans. Normally, beta and gamma secretase enzymes break down amyloid precursor protein to create amyloid beta protein. As a component of gamma secretase, presenilin can cleave the precursor protein in a way that increases the formation of amyloid plaques when it carries mutations. In a similar vein, individuals with specific APOE protein variants, like APOE4, have a markedly elevated risk of Alzheimer’s disease.

HSPGs are present between and on the surface of cells. By binding to other proteins, they create signaling pathways that control how cells interact with their surroundings and control autophagy, a process that aids in cell repair by removing broken or malfunctioning cell components.

According to a news release from Selleck, “autophagy is compromised in the early stages of several neurodegenerative diseases, which means cells have a reduced repair capacity.” This may facilitate the unchecked accumulation of conditions like amyloid plaques.

The researchers discovered that altering the HSPGs’ activity to make them less active can aid in the restoration of autophagy as well as enhance other physiological aspects, such as reducing lipid accumulation and enhancing mitochondrial function, that may be involved in the very early stages of neurodegenerative illness.

“In this study, we determined that heparan sulfate-modified proteins suppress autophagy-dependent cell repair. What’s more, we show that by compromising the structure and function of the sugar modifications of these proteins, the levels of autophagy increase so cells can take care of damage,” said Selleck.

Researchers verified connections between HSPGs and disease progression in genetically engineered animals and flies. The human cell line was mutated to prevent it from producing heparin sulphate, and this alteration affected the expression levels of more than 50% of the genes that have been connected to Alzheimer’s disease.

“There is a critical need to focus on cellular changes that occur at the earliest times in disease progression and [to] develop treatments that block or reverse them,” stated Selleck. “We demonstrate that reduced autophagy, mitochondrial defects and lipid build-up—all common changes in neurodegenerative disease—can be blocked by altering one class of proteins, those with heparan sulfate modifications. We think these molecules are promising targets for drug development.”

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