By Rikke Skovgaard Lindhard with assistance of Alena Salasova 

Most people have known a relative or a neighbor who developed difficulties remembering events and close friends, who stopped recognizing their own home or written language. As described already in 1906 by German psychiatrist Alois Alzheimer, Alzheimer’s disease (AD) is a devastating type of dementia, which affects around 55 million people worldwide, with the number constantly increasing. The disease is characterized by the progressive death of brain cells called neurons leading to memory loss, disorientation, speech problems, and other cognitive and behavioral issues, which ultimately cause the patient’s death. Disturbingly, there is still no efficient treatment available to help these patients since we do not really understand why and how the disease develops and progresses in the first place.

Have any new avenues surfaced in recent years for researchers to explore?

Even though there have been several breakthroughs and technological advances in the field, all clinical trials have been unsuccessful so far. To tackle this problem, researchers from DANDRITE and PROMEMO center of excellence at Aarhus University compiled evidence from 371 research articles to capture, explain, and demonstrate new principles behind brain degeneration.

The five members of the VPS10p-D receptor family
The review article highlights the involvement of a specific protein family called “VPS10p-domain receptors” in AD. This family consists of five members; SorLA, Sortilin, and Sorcs1-3, which are almost exclusively present in neuronal tissue. They are critical for multiple biological processes such as neuronal survival, cell death, glucose and lipid metabolism, and brain connectivity. Their specific roles differ; however, they are mostly responsible for cell-to-cell communication, and for the correct transportation of AD-related proteins within a neuron. If something goes wrong in these processes, the cell will struggle to compensate, and over time it can lose the connection to the other neurons, and thus it might eventually die.

Up until now, the research has mostly recognized one of the members, SorLA, as the major risk factor for Alzheimer’s disease development. However, for the first time, this review sheds new light on the entire family as having a fundamental role in a healthy brain, and that a genetic mutation or dysfunction of any of its members might contribute to diseases like Alzheimer’s.  

“Patients with Alzheimer’s disease do not have just a single mutation in a single gene, there are so many factors involved such as patient’s diet, stress, or physical exercise. Sadly, regardless of the tremendous research efforts in the past decades, we still cannot resolve the disease complexity”, explains Dr. Alena Salasova, Assistant Professor and corresponding author of the article. She continues:

“Since we must consider new possibilities, we decided to bring attention to this receptor family that was previously not well known in the field. We described the extent of how various dysregulation of the receptors contribute differently to AD prognosis and associated deficits, and that it might be essential to fully understand these mechanisms for future therapeutic purposes.”

Detailed models of the family represent a roadmap
Besides covering the extensive research, what makes this review article unique is the integration of detailed, high-quality models and tables that visualize how each individual protein works in the healthy brain, where exactly it is localized, and how its dysfunction generates pathological features observed in AD patients and related disorders.  

“Presenting so many detailed models in one paper is rare, considering that some have never been illustrated before. Our visualization will make it easier for other researchers in the field – but also for young researchers starting in the field – to get an overview, understand the current observations, and put them in perspective. So, it’s kind of like handing colleagues a whole new roadmap based on past and present discoveries”, Alena states.

Two of the co-authors, Professor Anders Nykjær and Associate Professor Olav Andersen are considered pioneers within the field because of their many years of research focused on this receptor family and its relation to AD. Dr. Giulia Monti, who originally initiated this project, has recently joined Harvard Medical School where she will continue her work on protein metabolism and degenerative diseases.

The four authors hope that their publication will help to boost and inspire not only research in Alzheimer’s disease and its related comorbidities but also other specializations, for instance in the field of psychiatric disorders, where this family also seems to play an important role.

“Our models explain that if you disable, for instance, the specific receptor’s sorting event, it might induce AD pathology, while if you disable the specific receptor’s signaling instead, it might help to prevent neurons from dying. We still do not fully understand how these proteins function, and that’s why it is important to study them in detail and to further explore their features experimentally,” Alena explains.

Finding memo(ry)
The article is published in the peer-reviewed journal Molecular Neurodegeneration, which has been ranked by Journal Citation Reports (JCR) as the number one open-access neuroscience journal for the past 9 years, and as the number seven of all 274 neuroscience journals, with an impact factor of 18,8.

Since her doctoral studies at Karolinska Institute, where Alena Salasova first came across one of the receptors SorCS2, the VPS10p-D family “has become her life”. The pun in the title “Finding memo” was her idea, and besides having a playful movie side to it, it also describes the higher purpose of the article: 

“It highlights what we ultimately want to achieve in the AD research. First, we need to understand why the patients are losing memory, and then we need to figure out how to stop it and how to restore it. That presupposes we know what is going on with the cells before they die.”


 Further information:

Ph.D. Alena Salasova
PROMEMO Center of Excellence, Department of Biomedicine, Aarhus University
Mobile phone: +45 27 51 33 58
Mail: alena.salasova@biomed.au.dk

• Systematic review article = comprehensive and extensive research overview that systematically gathers all scientific evidence on the selected topic. This study collected and described 371 research articles published in the past 30 years and put them in perspective for future advances in Alzheimer’s disease research and development strategies.
• Co-authors: Ph.D. Giulia Monti, Associated Professor Olav Andersen, Professor Anders Nykjær, Department of Biomedicine, Aarhus University
• Funding: PROMEMO and Danish National Research Foundation
• The article is published in the peer-reviewed open-access journal Molecular Neurodegeneration: https://rdcu.be/c30Cv