Amyloid, Tau Buildup in AD Spur Gene Expression that Causes Brain Inflammation

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investigators discover a rare genetic variant shown to protect people who carry known genetic risk factors for Alzheimer's disease

New research from the UK has revealed that the build-up of proteins in neuronal cells—the hallmark of Alzheimer’s disease—might be affecting the activity of genes implicated in the disease. This novel discovery may help shed more light on how and why these proteins build up, and how they lead to neuronal death and destruction.

“Currently, no treatments are available that can change the course of Alzheimer’s disease. [This new information can be used to help scientists in their] understanding the interaction between genes and progression of the disease,”  said Prof. Jonathan Mill, of the University of Exeter Medical School, who led the project. “[It] will help us identify new targets for treatment, which we hope will one day lead to drugs that can effectively treat this terrible disease.”

Alzheimer’s disease is a disease of the elderly, commonly associated with loss of memory as it progressives, and eventual loss of all cognitive function. How it develops is not a well understood process, but it is suspected that genetics play a role. The tale-tell histological confirmation of Alzheimer’s disease is the presence of amyloid plaques and neurofibrillary tangles (made up of the protein tau)—each the product of normal proteins which become over-expressed in diseased neuronal brain tissue to the point the neurons are poisoned and die. These proteins are found in lower amounts in normal brains, and the number of plaques and tangles found in patients tends to correspond to the severity of the disease phenotype.

Researchers at the University of Exeter, working in collaboration with Eli Lilly, and funded by Alzheimer’s Research UK and Alzheimer’s Society, have examined the brains of mice with mutations in the genes that code for amyloid and tau proteins, hoping to build an animal model to understand the disease better. The build-up of both proteins in specific regions of the brain is known to play a role in Alzheimer’s disease, so by recreating the genetic conditions, they hope to be able to determine what else must occur for disease development.

The results of this study were published in Cell Reports, and the researchers found evidence that the levels of gene activity changed dramatically as tau and amyloid accumulated in the brain. The team also observed significant changes in the levels of gene expression involved with regulating inflammation through the immune system, which became more active as tau levels increased. The research also found new pathways potentially involved in the progression of Alzheimer’s disease, which adds weight to theories of brain inflammation being a key component in the build-up of tau.

First author Dr. Isabel Castanho, of the University of Exeter, said: “Our results suggest that the genes which are disrupted through the build-up of tau and amyloid in the entorhinal cortex region of the brain influence the function of the immune response in the brain, which is known to be a key component of Alzheimer’s disease.”

The team monitored the build-up of both proteins in the brain and the expression levels of their corresponding genes as the mutant mice aged, so they could track the same corresponding time associated in humans with disease worsening.  The sequence of events is believed to be similar in the model organism.

Castanho and her team observed the expected build-up of both tau and amyloid, and noted that these changes corresponded to widespread changes in gene expression – particularly in the case of tau.

This new information suggests that the accumulation of tau might have a more dramatic effect on gene regulation in the brain than amyloid. Furthermore, several genes observed to be upregulated in this experiment are also known risk factors for Alzheimer’s disease, and the overall changes observed in the mutant mice mirrored those seen in human Alzheimer’s disease brains, suggesting this is a sound model.

Dr. Sara Imarisio, head of Research at Alzheimer’s Research UK, added: “Genetics plays an important role in the development diseases like Alzheimer’s and teasing apart the processes contributing to disease is crucial in the hunt for new breakthroughs, which will change lives. Future research capitalizing on genetic findings like this is a top priority for dementia researchers around the world. It’s only thanks to the generosity of our supporters that Alzheimer’s Research UK is able to fund vital dementia research like this.”

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