New hope for Alzheimer’s disease: Exploring the VCAM1–ApoE pathway and advanced protein interaction tools


Alzheimer’s disease poses a serious challenge affecting the lives of many. However, recent research is paving the way for new treatments. In this article, we provide a comprehensive explanation of the latest research on the VCAM1–ApoE pathway published in the journal Nature Aging, and tools for analyzing protein interactions.

What is Alzheimer’s Disease:

Basic Overview of Alzheimer’s Disease:
Alzheimer’s disease is a progressive disorder of the central nervous system and is the most common cause of cognitive decline. This disease manifests as the nerve cells in the brain gradually die. Early symptoms of Alzheimer’s include the loss of short-term memory, but as the disease progresses, there’s a decline in language skills, judgment, long-term memory, and the ability to perform daily activities.

Characteristics changes in the brains of those with Alzheimer’s include clumps of a protein called amyloid-beta and abnormal tangles of tau protein within nerve cells. These changes lead to the decline and death of nerve cells, resulting in cognitive impairment.

Current Treatments and Their Limitations:
The treatment for Alzheimer’s aims to slow down the progression of symptoms, but as of now, there is no cure for the disease. The most commonly used drugs include acetylcholinesterase inhibitors and NMDA receptor antagonists. These drugs adjust the balance of neurotransmitters in the brain, temporarily slowing cognitive decline.

However, these drugs only alleviate symptoms and do not treat the root cause of the disease. There are also concerns about their long-term effects and side effects. Recent research has focused on new treatments that prevent the accumulation of amyloid-beta and drugs with neuroprotective effects, but clinically established treatments are still few and far between.

Discovery of the VCAM1–ApoE Pathway:

Overview of the Research in Nature Aging:
The research published in Nature Aging revealed a new pathway, the VCAM1–ApoE pathway, that is involved in the progression of Alzheimer’s disease (AD). This study indicates that microglia (immune cells in the brain) regulate the removal of neurotoxic danger-associated molecular patterns (DAMPs). The mechanism of DAMP removal by microglia is controlled by a step-wise process where the microglia move towards the DAMPs and subsequently phagocytize them.

Impact of the VCAM1–ApoE Pathway on Alzheimer’s Disease:
The induction of VCAM1 has been shown to enhance microglial chemotaxis towards Aβ (amyloid-beta) and subsequent Aβ removal. Specifically, after stimulation with a substance called IL-33, microglia acquire a chemotactic state moving towards Aβ, and then transition into a phagocytic state. In this process, VCAM1 detects ApoE within the Aβ plaque and regulates microglial chemotaxis towards the Aβ plaque.

Potential New Treatments This Pathway Offers:
The discovery of the VCAM1–ApoE pathway offers a new approach to Alzheimer’s treatment. Activating this pathway may enhance the microglial response to Aβ, potentially reducing its accumulation. This could potentially slow or even reverse the progression of Alzheimer’s. Furthermore, understanding the detailed mechanism of this pathway might also lead to the identification of new therapeutic targets.

Tools for Analyzing Protein Interactions:

In the aforementioned paper, STRINGdb was used to investigate the relevance of protein functions. I took a moment to see how it differs from the commonly used IPA.

Overview of Ingenuity Pathway Analysis (IPA) and STRINGdb

  • Ingenuity Pathway Analysis (IPA):
    IPA is a tool provided by QIAGEN for analyzing and interpreting ‘omics data. It’s based on a manually curated extensive knowledge base and supports analysis of various data types such as RNA-seq, proteomics, and metabolomics.
  • STRINGdb:
    STRINGdb is a database focused on protein-protein interactions, offering comprehensive interaction information across numerous species. It also provides scores indicating the reliability of interactions, enabling users to easily identify high-confidence interactions.

How these tools benefit research:

  • IPA:
    IPA is capable of performing a comprehensive analysis of ‘omics data. It has features for predicting upstream regulators and downstream effects, aiding in understanding the causes and results of specific biological changes. Additionally, it is used to determine how gene or protein variations relate to specific diseases or biological functions.
  • STRINGdb:
    STRINGdb is immensely helpful in constructing protein interaction networks. These networks are employed to understand biological processes and signaling pathways. It also incorporates a function to integrate public datasets, allowing users to conduct interaction analysis using these datasets.

Key distinctions and characteristics of each:

  • IPA:
    • Features: Comprehensive ‘omics data analysis, causality prediction, analysis of relationships with diseases or biological functions.
    • When to use: Suitable for comprehensive analysis and interpretation of ‘omics data or when investigating the relationship with diseases or biological functions.
  • STRINGdb:
    • Features: Focused on protein-protein interactions, provision of reliability scores, integration of public datasets.
    • When to use: Suitable when information focusing on protein interactions is needed or when the goal is to construct or evaluate interaction networks.


Significance and future prospects of the VCAM1–ApoE pathway:

Alzheimer’s disease is the leading cause of dementia, which is on the rise worldwide. Among them, the discovery of the VCAM1–ApoE pathway indicates a new direction in understanding the pathogenesis and development of treatments for Alzheimer’s disease.

The VCAM1–ApoE pathway is involved in the mechanism by which microglia recognize the accumulation of amyloid beta (Aβ) and effectively remove it. Activation of this pathway suggests that Aβ accumulation may decrease and the progression of Alzheimer’s disease may be delayed.

Future prospects:
Elucidating the detailed mechanism of the VCAM1–ApoE pathway may lead to the identification of new therapeutic targets. Furthermore, with the development of drugs or treatments that activate this pathway, new options for Alzheimer’s disease treatment may emerge.

Evolution of protein interaction analysis tools and their significance:

In recent years, life science research has rapidly progressed, with protein interaction analysis playing a central role. This progression is largely attributed to the evolution of analysis tools.

Early protein interaction analysis tools primarily aimed to provide simple interaction information. However, modern tools, such as Ingenuity Pathway Analysis (IPA) and STRINGdb, combine extensive databases and advanced algorithms to enable more sophisticated analyses.

Thanks to the evolution of protein interaction analysis tools, researchers can now gain a deeper understanding of biological processes and disease mechanisms. This has accelerated the identification of new therapeutic targets, early diagnosis of diseases, and development of treatments. Moreover, these tools enable the capture of complex life phenomena from a systems biology perspective, paving new frontiers in life sciences.