Newly discovered gene variants link innate immunity and Alzheimer's disease

July 17, 2017, Perelman School of Medicine at the University of Pennsylvania
Beta-amyloid plaques from an AD mouse model. Pink represents beta-amyloid deposits (plaques), brown represents microglia cells and blue/purple is nuclei of neurons and glial cells. Credit: Stefan Prokop, MD, Perelman School of Medicine, University of Pennsylvania

Three new gene variants, found in a genome wide association study of Alzheimer's disease (AD), point to the brain's immune cells in the onset of the disorder. These genes encode three proteins that are found in microglia, cells that are part of the brain's injury response system. The study is an international collaboration of four AD research consortia that analyzed DNA from 85,000 subjects. The results are reported online this week in Nature Genetics.

Studies of this type focus on identifying new therapeutic targets for treatment or prevention of AD, a goal of researchers world-wide. Genetic variation of the type described in this paper are "experiments of nature," of a sort, that reveal when a specific gene is altered, disease risk can be affected.

"This is direct evidence that if drugs can be designed to target these proteins, we have a chance to alter disease risk in people," said senior author Gerard Schellenberg, PhD, a professor of Pathology and Laboratory Medicine, and director of the Alzheimer Disease Genetics Consortium (ADGC) at the Perelman School of Medicine at the University of Pennsylvania. "It's been known for decades that microglia—a first-line-of-defense cell we are born with—surround amyloid plaque deposits associated with Alzheimer's. These multiple gene 'hits' all originating from microglia are the clearest demonstration that these cells are part of Alzheimer's pathology and, more importantly, provide clear protein targets where we can start to intervene with drugs."

The ADGC, supported by the National Institute on Aging (NIA) at the National Institutes of Health, is one of the four consortia of the International Genomics of Alzheimer's Project on this study. The others are Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE), European Alzheimer's Disease Initiative (EADI), and Genetic and Environmental Risk in Alzheimer's Disease (GERAD).

The variants the team found—PLCG2, ABI3, and TREM2—are all protein-coding mutations in genes that are highly expressed in microglia and are part of an immune cell protein network where multiple components contribute to AD risk. One of the genes, PLCG2, is an enzyme that is a potential drug target.

Key questions remain in how microglia should be targeted and whether the injury response should be inhibited or activated and at what stage of disease. "Since prevention is a key goal of therapy, influencing microglial cells before onset of cognitive changes needs to be explored," Schellenberg said.

The three variants they identified are fairly rare and he accounts for their success in finding them to their three-stage study. In the first stage, the entire protein coding regions of 34,290 samples were sequenced. In the second and third stages, the team further refined the sequences of variants and verified the significant hits against untested samples from AD patients.

"Our findings show that microglia and the innate immune system—via microglia—directly contribute to susceptibility of late-onset Alzheimer's disease, and are not just a down-stream 'after-the-fact' consequence of damage to the brain," Schellenberg said.

Explore further: 'Pac-Man' gene implicated in Alzheimer's disease

More information: Rebecca Sims et al, Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease, Nature Genetics (2017). DOI: 10.1038/ng.3916

Related Stories

'Pac-Man' gene implicated in Alzheimer's disease

July 26, 2016
A gene that protects the brain from the harmful build-up of amyloid-beta, one of the causative proteins implicated in Alzheimer's disease, has been identified as a new target for therapy by NeuRA researchers.

Skin stem cells used to generate new brain cells

April 25, 2017
Using human skin cells, University of California, Irvine neurobiologists and their colleagues have created a method to generate one of the principle cell types of the brain called microglia, which play a key role in preserving ...

Abnormal brain protein may contribute to Alzheimer's disease development

September 30, 2016
A recently-recognized pathologic protein in the brain may play a larger role in the development of clinical Alzheimer's disease dementia than previously recognized, according to a study by researchers at Rush University Medical ...

Early signs of Alzheimer's disease identified

December 6, 2016
Researchers from the University of Aberdeen have detected key changes in the brains of people with Alzheimer's disease.

Hayling Island scientist sheds light on factors driving Alzheimer's

January 23, 2017
Cassidy Fiford, a native of Hayling Island and a PhD student at University College London, has celebrated after making a discovery showing that damage to blood vessels in the brain can drive shrinking of the hippocampus, ...

New approaches to understanding Alzheimer's and Parkinson's disease

July 26, 2016
In a study presented today at the Alzheimer's Association International Conference 2016, researchers at the Douglas Mental Health University Institute have explored how some people may develop the hallmarks of Alzheimer's ...

Recommended for you

Scientists cut main heart disease risk locus out of DNA by genome editing

December 6, 2018
Over the past decade we've learned that billions of people carry a mysterious specter in their DNA that strongly increases their risk for life threatening cardiovascular diseases, such as heart attacks, aneurysms or strokes, ...

What can a snowflake teach us about how cancer spreads in the body?

December 6, 2018
What can seashells, lightning and the coastline of Britain teach us about new drugs for cancer?

New genetic insight could help treat rare debilitating heart and lung condition

December 6, 2018
The largest study of genetic variation in patients with pulmonary arterial hypertension has associated two important genes with the disease.

Are scientists studying the wrong kind of mice?

December 5, 2018
Mice represent well over half of the non-human subjects of biomedical research, and the vast majority of those mice are inbred. Formed by generation after generation of mating between brothers and sisters, inbred mice are ...

Researchers find evidence of prenatal environment tuning genomic imprinting

December 5, 2018
A team of researchers from the U.S., Australia and Denmark has found evidence of the prenatal environment tuning genomic imprinting. In their paper published in Proceedings of the National Academy of Sciences, the group describes ...

Gene that lets you eat as much as you want holds promise against obesity

December 4, 2018
It sounds too good to be true, but a novel approach that might allow you to eat as much food as you want without gaining weight could be a reality in the near future.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.