Three Alzheimer's genetic risk factors linked to immune cell dysfunction

[GenePoole0304]

People with a variant copy of the TREM2 gene have an increased risk of developing Alzheimer's disease, but researchers are only beginning to understand why.

A Genentech study has uncovered details of how a type of immune cell helps the brain get rid of the tiny amyloid-beta aggregates that can clump together to form the plaques characteristic of Alzheimer's. The researchers, reporting July 20 in Neuron, found that TREM2 mutations can derail the immune cell's plaque-clearing activity, as can two other genes already known to increase a person's risk for Alzheimer's: APOE and APOJ (known as clusterin).

"I think we're only scratching the surface of what TREM2 does," said Morgan Sheng, a senior author of the paper and Vice-President of Neuroscience at Genentech.

In healthy people, immune cells called microglia patrol the brain, surrounding and engulfing potential threats. Research published in May found that mice with a mutation in the TREM2 gene have microglia that can't efficiently surround amyloid deposits (DOI: 10.1016/j.neuron.2016.05.003). Scientists know that the TREM2 gene codes for a receptor protein located on the surface of microglia and when certain molecules bind to TREM2, it can stimulate microglia activity.

In their study, Sheng and colleagues ran an unbiased protein microarray screen of 1,559 extracellular proteins to see which ones might bind and interact with TREM2. A select group of lipoproteins were found to bind to TREM2, including LDL (low density lipoprotein) and the apolipoproteins APOE and APOJ (both risk factors in Alzheimer's disease).

"Lipoproteins float around in the blood, and their purpose is to carry cholesterol or lipids from one cell to another--as we all know, too much LDL is associated with high cholesterol and increased risk of cardiovascular disease," says Sheng. "Lipoproteins also exist in the brain, but less is understood about their role there."

Using cells purified from mice, the researchers explored how microglia reacted to amyloid-beta aggregates in different conditions. The team found that microglia could engulf amyloid-beta aggregates much more efficiently in the presence of LDL and APOJ, because the lipoproteins formed complexes with the amyloid-beta aggregates. The uptake of the lipoprotein-amyloid beta complexes by microglia depended on TREM2.

"It was a surprise that amyloid-beta was much more efficiently engulfed when bound in a lipoprotein complex, rather than when amyloid-beta aggregates were free and naked," says Sheng.

In another experiment, researchers tested blood samples of volunteers to see how variants of the TREM2 gene could change the way that human cells handled lipoproteins and amyloid-beta. While they couldn't get microglia from volunteers, they could test TREM2 found on the surface of macrophages, which are immune cells similar to microglia but can be obtained from blood.

They found that macrophages from people carrying a TREM2 variant associated with Alzheimer's disease had a diminished ability to engulf lipoprotein-amyloid beta complexes. And the researchers found that it only takes one variant copy of the TREM2 gene--not two--to impair this ability.

"Overall, these studies further point towards microglia as playing an important role in the pathogenesis of Alzheimer's disease," says Sheng.

Sheng hopes future studies will extend beyond the culture dish to confirm the activity of TREM2 on lipoproteins and amyloid-beta clearance in the brain.

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Neuron, Sheng et al.:"TREM2 binds to apolipoproteins including APOE and APOJ and thereby facilitates uptake of amyloid-beta by microglia" http://www.cell.com/neuron/fulltext/S08 ... 16)30292-6

Neuron (@NeuroCellPress), published by Cell Press, is a bimonthly journal that has established itself as one of the most influential and relied upon journals in the field of neuroscience and one of the premier intellectual forums of the neuroscience community. It publishes interdisciplinary articles that integrate biophysical, cellular, developmental, and molecular approaches with a systems approach to sensory, motor, and higher-order cognitive functions. Visit http://www.cell.com/neuron. To receive Cell Press media alerts, contact press@cell.com.

http://www.eurekalert.org/pub_releases/ ... 071316.php

[Tiramisu1984]

I read this too. How does one find out if they have the TREM2 gene?

[circular]

Promethease reports on two TREM2 SNPs, but I don't know if they're the ones referenced by the article. There are probably other SNPs on TREM2. I ran 23andM3 version 4 chip results through Promethease. Version 3 chip may have different TREM2 results.

It drives me nuts when papers and articles are all about a gene mutation and they don't say specifically what it is.

Promethease for me gives:

rs7748513(A;A) (93% frequency so must be normal but there's not really anything on it but an odd notation for C-Reactive Protein)

rs28939079(A;A) (This one is noted 'good' by Promethease but only one reference supports it. This SNP seems linked somehow to this mouthful of marbles: 'Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy')

Methinks these aren't the TREM2 SNPs the article reports on.

[BerniF]

In this paper http://www.sciencedirect.com/science/ar ... 8016001834 the risk SNP mentioned on TREM2 is rs75932628, SNPedia has this

rs75932628(T), a SNP in the TREM2 gene on chromosome 6 resulting in an R47H substitution, was found to confer a significantly higher risk of late-onset Alzheimer's disease based on two articles published together in the New Engl. J. of Med.
In one study, the odds ratio for rs75932628(T) was 2.9 (CI: 2.09 to 4.09, P=3.42×10−10). The mutation had a frequency of 0.46% in controls 85 years of age or older. The authors also observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10−12 in combined discovery and replication samples), and found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P=0.003).[PMID 23150908OA-icon.png]

In the other study, analysis of the rs75932628(T) in a series that included 1887 patients with Alzheimer's disease showed a strong, highly significant association (odds ratio, 5.05, CI: 2.77 to 9.16; P=9.0×10−9). Four other TREM2 gene variants (D87N, T66M, Y38C, and Q33X) were also associated with higher risk for a frontotemporal dementia–like syndrome when homozygous

Obviously don't know for sure if the more recent study has found other SNPs but this one is worth a look at.

[Tiramisu1984]

Thanks for the info!