Novel approach reveals crucial role of brain gene activity in Alzheimer's disease

Recent innovative research has shed light on the connection between brain gene activity and the accumulation of tau protein, a crucial factor in Alzheimer's disease, reports ScienceDaily. The University of Exeter Medical School conducted this groundbreaking study using state-of-the-art "long-read" sequencing technology. The findings not only enhance our understanding of gene expression in the brain but also identify potential targets for future drug development aimed at treating dementia.

Unlike the standard perception of genes, where we have about 20,000 encoded in our DNA sequence, each gene can actually be expressed in multiple versions called isoforms. These isoforms are generated through a process known as "alternative splicing," which combines different sections of the coding sequence in various combinations.

Published in Nature Communications and funded by Alzheimer's Research UK, the Medical Research Council, and the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre, the study conducted by the Exeter team employed long-read genetic sequencing and novel data analysis tools. This advanced technology allowed the researchers to analyze intricate and more extensive genetic material sequences in a single instance, achieving unprecedentedly detailed mapping of isoform diversity in mice brains engineered to carry a human variant of the tau protein.

In addition to discovering numerous new isoforms associated with genes already known to contribute to Alzheimer's disease, the team also identified specific isoforms linked to tau protein accumulation. Furthermore, they demonstrated that many of these isoforms, found in mice brains, showcased differential expression patterns in brain tissues taken from deceased human donors diagnosed with Alzheimer's disease. This indicates the relevance and potential translatability of these findings to human brains. Alzheimer's Research UK supported this work through a research grant.

This research builds upon previous studies by the team which unraveled thousands of new brain isoforms associated with various diseases.

Professor Jonathan Mill from the University of Exeter Medical School, senior author of the paper, expressed great enthusiasm for this promising research. He emphasized that it offers superior insights into gene expression patterns related to dementia, thereby identifying potential drug targets that could disrupt the accumulation of tau protein. As more is learned about the nuanced expression of Alzheimer's disease genes in the brain, the significance of further exploration in this field becomes evident. Professor Mill considers this study as a significant milestone in that direction.

Dr. Szi Kay Leung, lead author at the University of Exeter Medical School, emphasized that technological advancements enable the team to examine molecular changes in the brain at an unprecedented level of precision. Such meticulous investigation of the complex pathways of gene expression in Alzheimer's disease holds immense potential for understanding the disease's development and identifying promising therapeutic avenues. Additionally, the analysis pipeline developed by the researchers is made accessible to the scientific community as a resource, aiming to stimulate additional research in this crucial domain.

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