Potential Breakthrough in Alzheimer’s Treatment Through Heparan Sulfate Modification

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Alzheimer’s disease research

Neurodegenerative diseases occur when nerve cells in the brain and peripheral nervous system lose function and eventually die. They include Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS — also known as motor neuron disease), among others.

In the United States, an estimated 6.9 million people aged 65 and over are living with Alzheimer’s disease, and around a million have Parkinson’s. ALS is less common; the CDC estimates that around 31,000 people in the U.S. have the condition.

Current treatments can alleviate symptoms and some slow the progression of the diseases, but no cures are yet available. New monoclonal antibody treatments for Alzheimer’s have shown some potential for modifying the course of the disease, but many experts are concerned about side effects.

The researchers, who have a patent related to this work, found that reducing the function of heparan-sulfate-modified proteoglycans (HSPGs) helped reverse cell damage from neurodegenerative diseases.

Their study is published iniScience. HSPGs, which are found on the surface of cells and in the extracellular matrix, regulate cell repair and enhance cell growth-signaling systems. The heparan sulfate (sugar) chains attach to proteins so they can influence processes including cell growth, interaction between the cell and its environment, and autophagy — a process that clears out protein aggregates (a feature of Alzheimer’s disease) and damaged parts of cells.

Studies have noted heparan sulfate abnormalities in Alzheimer’s disease, but their specific role in the development of the disorder has not yet been uncovered.

By carrying out analyses on human cell lines and mouse brain cells that express aspects of Alzheimer’s, researchers in this study first showed that HSPGs regulate cell processes that are affected in several neurodegenerative diseases.

They then reduced the function of the HSPGs in these cells and found that two changes that happen early in the course of neurodegenerative diseases were reversed. The function of the mitochondria — which provide energy for the cell — was improved, and that lipid (fat) buildup in the cells was reduced.

To verify their findings, the researchers used an animal model of Alzheimer’s. They used fruit flies that had been modified to have deficits in presenilin protein, which mimics the effect of a mutation in the presenilin gene, PSEN1, the most common cause of familial (early-onset) Alzheimer’s.

Selleck explained that a rare genetic change in another protein, APOE, can delay the effect of the PSEN1 mutation, sometimes for decades. He suggested that targeting these two substances and the enzymes that make heparan sulfate could help prevent neurodegeneration in people.

In the fruit flies, the researchers reduced the functioning of HSPGs, which suppressed the death of nerve cells and corrected other cell defects.

They suggest that disrupting the structure of heparan sulfate modifications blocks or reverses early cellular problems in these models of Alzheimer’s.

There is a critical need to focus on cellular changes that occur at the earliest times in disease progression and develop treatments that block or reverse them.

Courtney Kloske, Ph.D., Alzheimer’s Association director of scientific engagement, welcomed the findings but emphasized that further research was needed.While animal models of the disease are somewhat similar to how Alzheimer’s progresses in humans, they do not replicate the disease in humans exactly.

Models are important in helping us understand the basic biology of the disease, but we need human studies in representative populations for ideas to be fully validated. Therefore, more research is needed to understand the possible role of heparan sulfate-modified proteins in Alzheimer’s as studied in this manuscript.

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