A protective factor against Alzheimer's disease?

August 29, 2019

Science Daily/DZNE - German Center for Neurodegenerative Diseases

Researchers at the German Center for Neurodegenerative Diseases (DZNE) and the Institute for Stroke and Dementia Research (ISD) at the University Hospital of the Ludwig-Maximilians-Universität (LMU) in Munich have found that a protein called TREM2 could positively influence the course of Alzheimer's disease. When TREM2 is present in the cerebrospinal fluid at higher concentrations, patients at any stage of the disease have a better prognosis. This observation provides a starting point for the development of new therapeutic strategies. The study was led by Prof. Christian Haass (DZNE) and Prof. Michael Ewers (ISD, LMU) and is published in the journal Science Translational Medicine.

In the brain, TREM2 is exclusively produced by microglia, the immune cells of the brain. These cells patrol the brain and clear it from cellular waste products and debris to keep it healthy. In previous studies on mice, Haass and his colleagues demonstrated that TREM2 activates microglia to enclose and selectively destroy toxic protein aggregates typical for Alzheimer's disease. "These observations indicate that TREM2 can protect the brain from the degenerative effects of the disease -- at least in animal models," said Haass.

But what about patients with Alzheimer's disease? Does TREM2 protect the human brain as well? To answer these questions, Haass, Ewers, and their colleagues correlated the concentration of TREM2 in the cerebrospinal fluid of Alzheimer patients with their respective disease progression over several years. To this end, they used data of 385 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a large clinical dataset containing records and samples from patients and healthy seniors taken at regular checkups over many years. The study thus allows to establish associations between certain biochemical changes and disease progression.

Indeed, Haass and Ewers found that high levels of TREM2 improved the prognosis of subjects at all stages of the disease. Their memory remained more stable and the degradation of the hippocampus, a brain region responsible for learning and recollection, was less pronounced. "Our findings are clinically relevant because we found that higher levels of TREM2 were associated also with a reduced rate of the development of full blown dementia over a time period up to 11 years," explained Ewers. "Microglia activation is a double-edged sword, entailing both protective effects and neurotoxic inflammation. TREM2 signaling may play a key role in the regulation of the brain's protective immune response."

The concentration of TREM2 in the cerebrospinal fluid usually increases at early stages of the disease, when the first symptoms appear. "TREM2 production is a response to brain damage that has already occurred," said Haass. "It stimulates the microglia to protect the brain. However, this protection does not seem to be sufficient in patients with Alzheimer's disease." This is where Haass and his colleagues see an option for new therapeutic strategies. "We are currently developing a therapeutic antibody that stimulates the TREM2 function and thus improves its protective function," said Haass.

https://www.sciencedaily.com/releases/2019/08/190829150718.htm

Genes linked to Alzheimer's risk, resilience ID'd

Genes in the brain's immune cells may point to strategy to protect against the disease

August 14, 2019

Science Daily/Washington University School of Medicine

An international team of researchers led by scientists at Washington University School of Medicine in St. Louis has identified a pair of genes that influence risk for both late-onset and early-onset Alzheimer's disease.

Most genes implicated thus far in Alzheimer's affect neurons that transmit messages, allowing different regions of the brain to communicate with one another. But the newly identified genes affect an entirely different population of cells: the brain's immune cells. The findings, published online Aug. 14 in the journal Science Translational Medicine, could provide scientists with new targets and a strategy for delaying the onset of Alzheimer's symptoms.

The genes -- known as MS4A4A and TREM2 -- operate in the microglia, the brain's immune cells. They influence Alzheimer's risk by altering levels of TREM2, a protein that is believed to help microglia cells clear excessive amounts of the Alzheimer's proteins amyloid and tau from the brain.

"The findings point to a new therapeutic strategy," said co-senior investigator Carlos Cruchaga, PhD, a professor of psychiatry and director of the NeuroGenomics and Informatics Group. "If we can do something to raise levels of the TREM2 protein in the cerebrospinal fluid, we may be able to protect against Alzheimer's disease or slow its development."

In this study, the researchers measured soluble TREM2 levels in the cerebrospinal fluid of 813 older adults, most of whom were ages 55 to 90. Of those subjects, 172 had Alzheimer's disease, 169 were cognitively normal, and another 183 had early mild cognitive impairment. They also analyzed the participants' DNA, conducting genomewide association studies to look for regions of the genome that may influence TREM2 levels in the cerebrospinal fluid.

Although variants in TREM2 are found in a very small percentage of patients with Alzheimer's disease, the gene previously had been linked to the disorder. People who carried those previously identified risk mutations were excluded from the study. Common variants in the MS4A4A gene also had been associated with risk for Alzheimer's, but this study connects those genes.

"We observed TREM2 risk variants more often in people who had Alzheimer's or were mildly cognitively impaired, compared with those who were cognitively normal," said co-senior investigator Celeste Karch, PhD, an assistant professor in the Department of Psychiatry. "It turns out that about 30 percent of the population in the study had variations in the MS4A4A gene that appear to affect their risk for developing Alzheimer's disease. Some variants protected people from Alzheimer's or made them more resilient while others increased their risk."

When the researchers dug further, they noted that variants in the MS4A4A gene cluster linked to an increase in risk for developing Alzheimer's disease are associated with lower levels of soluble TREM2 protein. The other variant, associated with higher levels of TREM2 in the cerebrospinal fluid, seemed to protect against Alzheimer's.

The research team validated its results in DNA from another 580 older adults. Once again, they found that higher soluble TREM2 levels in the cerebrospinal fluid seemed protective, while lower levels increased risk. And those protein levels -- whether high or low -- were linked to variants in the MS4A4A gene.

"For the past several years, we've been looking at TREM2 and increasing our focus on the involvement of the brain's immune cells in Alzheimer's disease" said another co-senior author, Bruno A. Benitez, MD, an assistant professor of psychiatry. "These findings give us a new therapeutic strategy to pursue, one focusing not only on neurons but on how the microglia may be involved in helping to clear damaging proteins, such as beta amyloid and tau, that are linked to Alzheimer's disease."

Those gene variants also may play a role in other diseases of the central nervous system, according to Laura Piccio, MD, PhD, an associate professor of neurology and another co-senior author.

"By combining large genetic and spinal fluid analyses with laboratory work, we have provided strong evidence of a biological link between TREM2 and proteins in the MS4A gene cluster, both of which previously had been associated with Alzheimer's disease," Piccio said. "We are beginning to elucidate a molecular pathway in microglia that could be critical not only in Alzheimer's disease but also in other neurodegenerative and inflammatory diseases in the central nervous system."

https://www.sciencedaily.com/releases/2019/08/190814140501.htm