Interconnected neurons with glowing TrkB receptors and APP proteins

Unlocking Alzheimer's: How TrkB Isoforms Could Hold the Key to Prevention

Soraya Malik in Health & Wellness June 2025 • 5 min read.

"New research highlights the diverse roles of TrkB isoforms in APP metabolism, offering potential new targets for Alzheimer's prevention and treatment."

Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting millions worldwide. As the population ages, the number of individuals impacted by AD continues to rise, making the search for effective prevention and treatment strategies increasingly urgent. At the heart of AD pathology lies the accumulation of amyloid-beta (Aβ) plaques, which disrupt neuronal function and ultimately lead to cognitive decline. Therefore, understanding the mechanisms that regulate Aβ production and clearance is crucial in the fight against this disease.

A key player in neuronal health and synaptic function is TrkB, a tyrosine kinase receptor activated by brain-derived neurotrophic factor (BDNF). TrkB is involved in neuronal development, survival, and plasticity. Intriguingly, studies have shown that TrkB levels are often reduced in AD brains, suggesting a potential link between TrkB signaling and AD pathogenesis. The NTRK2 gene, which encodes the TrkB receptor, is located on a chromosomal region genetically linked to AD, further strengthening this connection.

The NTRK2 gene produces several different versions of the TrkB receptor, known as isoforms, through a process called alternative splicing. These isoforms, including TrkB full-length (FL), TrkB SHC, and TrkB T, possess distinct intracellular domains that dictate their specific functions. While TrkB FL promotes neuronal survival and synaptic plasticity, the roles of the truncated isoforms, TrkB SHC and TrkB T, are less clear. Recent research has begun to explore how these different TrkB isoforms might differentially influence APP metabolism and, consequently, AD development.

How Do Different TrkB Isoforms Influence APP Metabolism?

Interconnected neurons with glowing TrkB receptors and APP proteins

A recent study investigated the distinct effects of TrkB isoforms on APP metabolism, focusing on the production of amyloid precursor protein intracellular domain (AICD), a fragment generated during APP processing. The researchers hypothesized that these different TrkB isoforms differentially affect APP metabolism and could play a role in the pathogenesis of AD.

To test this hypothesis, the researchers used a human neuroblastoma cell line (SH-SY5Y) and manipulated the levels of different TrkB isoforms through knockdown (reducing expression) and overexpression (increasing expression). They then assessed the impact of these manipulations on APP metabolism, specifically measuring AICD levels, APP full-length levels, and the levels of APP proteolytic products.

TrkB FL: Increased AICD-mediated transcription and APP levels, while decreasing sAPP levels. These effects were primarily mediated by the receptor's tyrosine kinase activity and partially by the PLC-γ- and SHC-binding sites.
TrkB T: Did not have significant effects on APP metabolism when transfected alone. However, it abolished the effects of TrkB FL on APP metabolism when co-transfected.
TrkB SHC: Decreased AICD-mediated transcription. When co-transfected with TrkB FL, it still showed increased APP levels.

The researchers found that TrkB FL increases AICD-mediated transcription and APP levels while decreasing sAPP levels. These effects were mainly mediated by the tyrosine kinase activity of the receptor and partially by the PLC-γ- and SHC-binding sites. The TrkB T truncated isoform did not have significant effects on APP metabolism when transfected by itself, while the TrkB SHC decreased AICD-mediated transcription. The TrkB T abolished TrkB FL effects on APP metabolism when cotransfected with it while TrkB SHC cotransfected with TrkB FL still showed increased APP levels.

A New Path for AD?

This research provides crucial insights into the complex roles of TrkB isoforms in APP metabolism. By demonstrating that different isoforms have opposing effects on AICD production and APP processing, the study highlights the potential for targeted therapies that modulate TrkB signaling to prevent or treat Alzheimer's disease. Further research is needed to fully elucidate the mechanisms underlying these isoform-specific effects and to explore the therapeutic potential of selectively targeting TrkB isoforms in AD.

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This article is based on research published under:

DOI-LINK: 10.4061/2011/729382, Alternate LINK

Title: Trkb Isoforms Differentially Affect Aicd Production Through Their Intracellular Functional Domains

Subject: Behavioral Neuroscience

Journal: International Journal of Alzheimer's Disease

Publisher: Hindawi Limited

Authors: Sara Ansaloni, Brian P. Leung, Neeraj P. Sebastian, Rohini Samudralwar, Mariana Gadaleta, Aleister J. Saunders

Published: 2011-01-01

Everything You Need To Know

What is the role of TrkB in Alzheimer's disease?

TrkB, a tyrosine kinase receptor activated by BDNF (brain-derived neurotrophic factor), plays a crucial role in neuronal health and synaptic function. Studies show that TrkB levels are often reduced in Alzheimer's disease (AD) brains, suggesting a link between TrkB signaling and AD pathogenesis. The NTRK2 gene, which encodes the TrkB receptor, is located on a chromosomal region genetically linked to AD, further strengthening this connection. The different isoforms of TrkB play distinct roles in APP metabolism. TrkB full-length (FL) promotes neuronal survival and synaptic plasticity and the truncated isoforms (TrkB SHC and TrkB T) roles are less clear.

How do TrkB isoforms influence APP metabolism differently?

The different TrkB isoforms have distinct effects on APP metabolism. TrkB FL increases AICD-mediated transcription and APP levels while decreasing sAPP levels. TrkB T, when transfected alone, did not have significant effects on APP metabolism. However, it abolished the effects of TrkB FL on APP metabolism when co-transfected. TrkB SHC decreased AICD-mediated transcription. When co-transfected with TrkB FL, it still showed increased APP levels. These differences highlight the potential for targeted therapies that modulate TrkB signaling to prevent or treat Alzheimer's disease.

What are the key findings regarding TrkB FL's impact on APP metabolism?

TrkB FL increases AICD-mediated transcription and APP levels, while decreasing sAPP levels. These effects are primarily mediated by the receptor's tyrosine kinase activity and partially by the PLC-γ- and SHC-binding sites. These findings suggest that activating TrkB FL could potentially increase the production of AICD, which might have implications for AD development. The precise effects of these changes need further investigation, but they offer a valuable starting point for developing treatments.

What are the implications of the truncated TrkB isoforms, TrkB T and TrkB SHC, in relation to APP metabolism?

TrkB T, when transfected alone, did not have significant effects on APP metabolism, but it abolished the effects of TrkB FL on APP metabolism when co-transfected. This indicates that TrkB T may act as a regulator of TrkB FL's function, potentially by competing for binding sites or interfering with downstream signaling pathways. TrkB SHC decreased AICD-mediated transcription. When co-transfected with TrkB FL, it still showed increased APP levels. This shows that TrkB SHC may have a different signaling cascade and have an impact on the production of APP proteolytic products.

How could targeting TrkB isoforms lead to new Alzheimer's disease treatments?

The research demonstrates that different TrkB isoforms have opposing effects on AICD production and APP processing, which opens the door for new therapeutic strategies. The possibility of selectively targeting TrkB isoforms to modulate APP metabolism could lead to the development of treatments that either reduce the production of amyloid-beta (Aβ) plaques or enhance their clearance. For example, activating TrkB SHC or inhibiting TrkB FL might be potential approaches. Further research is needed to fully understand the mechanisms underlying these isoform-specific effects and to explore the therapeutic potential of selectively targeting TrkB isoforms in AD, but it represents a promising new direction in the fight against this devastating disease.