Researchers study immune basis of Alzheimer's

Genetic research has shed light on the role played by the immune system in the development of Alzheimer's.

Scientists at the Massachusetts Institute of Technology used a mouse model of the condition to analyse changes that occur in genes and in regions that regulate genes as Alzheimer's disease progresses.

The mice were engineered so that the gene for a protein called p25 can be overstimulated in the brain, prompting them to develop symptoms very similar to Alzheimer’s disease in humans.

Multiple chemical modifications known as epigenetic marks in the hippocampus of mice with overexpressed p25 were profiled and compared with control mice.

These marks reveal the activity of diverse genomic regions - in particular, the regulatory control regions that control the expression of nearby genes. 

"Neuronal plasticity processes that are involved in learning and memory were dampened, and immune and inflammatory pathways were activated," explained Elizabeta Gjoneska, joint first author of the paper and a postdoc at the Picower Institute.

The active regions specifically matched regions active in a type of immune cells known as microglia, which clear away infected or damaged cells and secrete chemicals that produce inflammation. 

Comparing the results of their experiment with their knowledge of Alzheimer's in humans revealed differences in gene levels in the Alzheimer's-like mouse brain matched differences previously seen in the brains of Alzheimer's patients.

They found epigenetic signatures were also conserved, with the same regulatory regions that were active or repressed in mice showed the same patterns in humans.

It was also found that regions with increased activity in the mouse model of Alzheimer’s disease had immune functions in humans, and the regions that showed decreased activity had neural functions in humans.

Genetic variants associated with Alzheimer's were only associated with immune processes and not neural processes, suggesting the condition primarily affects the circuitry of the former.

"Our results suggest that repression of neural pathways does not represent genetic predisposition, even though it is a hallmark of Alzheimer's," said professor Li-Huei Tsai, who co-led the study.

"Instead, it may occur as a consequence of environmental factors and aging, and result from interactions with the altered immune pathways."

Identifying the role of immune function in the pathogenesis of the condition could lead to new therapies, the researchers said.

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