New potential drug target for Alzheimer’s disease identified

Studying protein-sugar interaction proved to be a sweet success for researchers.

Recent research has shed light on the interactions between Apolipoprotein E (ApoE) and heparan sulfate (HS), uncovering potential therapeutic targets to slow the progression of the debilitating neurodegenerative disease Alzheimer’s. A new study published in Angewandte Chemie, Chunyu Wang, PhD, professor of biological sciences at Rensselaer Polytechnic Institute, and his team have made significant strides in understanding the mechanisms underlying Alzheimer’s disease [1].

ApoE, a protein responsible for cholesterol transport in the body, plays a crucial role in Alzheimer’s disease – specifically, a variant known as ApoE4 has been identified as the most significant genetic risk factor for late-onset Alzheimer’s disease. Heparan sulfate, a sugar molecule present on cell surfaces, is involved in cellular communication. Wang’s team set out to explore the interactions between ApoE and heparan sulfate.

“It’s tremendously interesting to explore why ApoE4 can increase Alzheimer’s risk,” said Wang [2].

Longevity.Technology: Alzheimer’s disease exacts a heavy toll on individuals, families and societies worldwide. According to the World Health Organization (WHO), approximately 55 million people globally are currently living with dementia, the majority of whom have Alzheimer’s disease – and this number is growing, with 10 million new cases every year [3]. It’s a significant challenge to healthcare systems, but the development of effective treatments for Alzheimer’s disease has been elusive, and the available options are limited. Recent drug approvals have offered some hope, but they often come with a hefty price tag. For example, the approval of aducanumab, a monoclonal antibody targeting amyloid-beta plaques, has generated significant attention. However, the high cost of this therapy raises concerns about accessibility and affordability for patients and healthcare systems.

Moreover, approved treatments for Alzheimer’s disease primarily focus on managing symptoms and providing temporary relief rather than addressing the underlying causes. This underscores the urgent need for innovative and targeted therapeutic strategies. Wang et al‘s research on the interactions between Apolipoprotein E and heparan sulfate offers a promising avenue for advancing our understanding of Alzheimer’s and potentially identifying novel drug targets.

In their investigation, Wang and his team examined various isoforms of ApoE, including ApoE3 (the most common), ApoE4 (the risk variant), and the protective isoforms ApoE2 and ApoE Christchurch. The researchers discovered that a specific modification of heparan sulfate, known as 3-O-sulfo (3-O-S), played a critical role in the interactions between ApoE and heparan sulfate. Interestingly, all isoforms of ApoE recognized the 3-O-S modification, but the strength of their interactions correlated with the risk of Alzheimer’s disease.

“In the initial glycan array experiment, which is basically a chip with a collection of different heparan sulfate oligosaccharide on it, we flowed ApoE over it,” said doctoral student Dylan Mah. “We were quite surprised to see that it had a binding pattern that looked very similar to Tau protein. It binds very well to the 3-O sulfated structures [2].”

Tau protein is implicated in many neurogenerative diseases, including Alzheimer’s.

The team’s findings pave the way for identifying new drug targets to slow the progression of Alzheimer’s disease. One potential target lies in the enzymes responsible for sulfation, known as heparan sulfate 3-O transferases.

Wang and his team plan to delve deeper into the ApoE and heparan sulfate interaction by developing a three-dimensional structural model. This model will provide further insights into the molecular mechanisms underlying the disease. Additionally, the team intends to investigate this interaction in cell cultures and animal models to validate their findings and explore potential therapeutic interventions.

“Ultimately, we want to prevent or mitigate enough of the symptoms of Alzheimer’s disease so people can continue to live independently,” said Mah. “Understanding how the disease works on a molecular basis is really critical to finding new treatments [2].”

“As our population ages, Dr. Wang’s research on Alzheimer’s disease is increasingly significant,” said Deepak Vashishth, director of Rensselaer’s Shirley Ann Jackson, PhD Center for Biotechnology and Interdisciplinary Studies, of which Wang is a member. “The identification of a new potential drug target to fight this progressive disease is enormously exciting for not only the six million patients in the United States, but for their families and caregivers [2].”