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Protein Linked to Alzheimer’s May Shape Neuron Growth

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A new study has described how a protein that helps to shape the growth of neurons – contactin-4 – also interacts with a protein involved in neurodevelopmental diseases and Alzheimer’s.

The study, which sheds light on the interplay between proteins and their effect on neurons in disease, is published in Open Biology.

Identifying novel protein functions in the cortex

The mechanisms driving neurodevelopmental and neurodegenerative disorders are complex, and often not fully understood. Identifying these processes could help us understand the development of these disorders and potentially lead to future therapies.

In the new study, researchers began studying a neuronal cell adhesion molecule called contactin-4 (CNTN4) due to its strong links to autism spectrum disorder (ASD), as the exact mechanisms behind this association were unclear.

This led the researchers to characterize how CNTN4 functions within the brain and investigate how it interacts with proteins involved in neurodegenerative diseases such as Alzheimer’s.

A previous study using chick embryos found that CNTN4 interacts with amyloid precursor protein (APP), which plays a central role in Alzheimer’s disease. In the new study, the researchers demonstrated interactions between CNTN4 and APP for the first time.

Utilizing gene knockout models

The researchers began their investigation in animal models, using mouse models engineered not to express CNTN4. They found abnormalities in the brain’s cortex – the area responsible for memory, thinking and reasoning – as neurons developed in a different way than normal.

Using human cells, they found that CNTN4 interacted with APP and had a co-dependent relationship that is essential for healthy neuron growth.

CNTN4 contributes to neural elongation in the frontal cortex region of the brain, and its expression is regulated via APP. Knocking out CNTN4 expression decreased APP levels, but did not reduce it to zero. The researchers believe that APP may compensate for low CNTN4 levels and vice versa.

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“It was quite remarkable to discover that CNTN4, a gene linked to developmental processes, also plays a role in modulating factors involved in Alzheimer’s disease,” said the study’s lead author Dr. Rosemary Bamford, a postdoctoral research fellow at the University of Exeter. “This intersection of developmental and neurodegenerative pathways offers exciting new insights into the broader implications of these proteins.”

Uncovering how interactions may impact neural activity

“Looking ahead, my group is keen to further dissect the molecular mechanisms underpinning the interaction between CNTN4 and APP and explore their wider implications for disorders like Alzheimer’s and autism spectrum disorder,” explained the study’s senior author Dr. Asami Oguro-Ando, a lecturer at the University of Exeter Medical School.

“Our next steps involve clarifying how the CNTN4–APP interaction impacts neural activity,” she added. “Understanding this interaction is crucial as it represents a fundamental step towards a comprehensive grasp of neurodevelopmental and neurodegenerative disorders.”

Reference: Bamford RA, Zuko A, Eve M, et al. CNTN4 modulates neural elongation through interplay with APP. Open Biology. 2024;14(5):240018. doi: 10.1098/rsob.240018

This article is a rework of a press release issued by the University of Exeter. Material has been edited for length and content.