New drug targets for Alzheimer's disease identified in cerebrospinal fluid

For the first time, researchers at Washington University School of Medicine in St. Louis use cerebrospinal fluid (CSF) from living patients to link disease-related proteins and genes and identify specific cellular pathways involved in the onset and progression of Alzheimer's disease. did. Because these proteins were collected from the CSF, they are a good proxy for activity in the brain, and some of them could be potential targets for therapy.

The survey results are available at: natural genetics.

Using patient CSF is a step forward for such research and may be the best way to obtain relevant samples to help map out the array of protein activity known as the proteome, Carlos Curuchaga, Ph.D., Barbara Barton said Dr. Reuben Morris. III Professor of Psychiatry and Director of the Center for Neurogenomics and Informatics at WashU Medicine.

“Our goal is to identify risk-related and protective genes, and also the causal role they play,” Kuruchaga said. “To do this, we need to study human-derived data. Therefore, we decided to conduct a large-scale proteomics study of cerebrospinal fluid, because we know that CSF is a good representation of the pathology of this disease. Because it is.”

Kuruchaga explained that similar studies rely on brain tissue taken post-mortem, so they can only provide information about the later stages of Alzheimer's disease. Other studies have looked at plasma, which is not specific to tissues affected by the disease.

In the past 15 years of Alzheimer's disease research, scientists have increased the number of genomic regions known to be associated with Alzheimer's disease from 10 to nearly 80. But knowing which genes and DNA regions are associated with Alzheimer's disease is just the first step. By combining an individual's proteomic profile, which proteins are active and how active, with genetic information, a complete picture of cellular activity in the brain is established. By comparing CSF samples from people with and without Alzheimer's disease, researchers were able to identify which cellular pathways were malfunctioning.

“There may be many genes within regions of DNA known to be associated with Alzheimer's disease, but we do not know which of these genes causes the condition,” Professor Kuruchaga said. . “By adding proteins to our analysis, we can identify the genes driving the association, identify the molecular pathways they are involved in, and identify new protein-protein interactions that would not be possible using other methods. ”

Cruchaga and his collaborators had access to a rich database of information through the Knight-ADRC and Dominant Inherited Alzheimer Network (DIAN), both based at WashU Medicine, and through other studies by his collaborators. These studies were also able to provide genetic information and CSF samples from 3,506 people, including both healthy donors and patients with Alzheimer's disease.

The research team cross-referenced proteomics data from CSF samples with existing studies that have identified genomic regions that correlate with Alzheimer's disease. From this process, they narrowed it down to 1,883 proteins out of 6,361 in the CSF Proteome Atlas. The researchers used three different established statistical analyzes that can reliably identify genes and proteins that are part of biological pathways that lead to disease. Using this technique, they determined that 38 proteins likely have a causal role in the progression of Alzheimer's disease. Of those, 15 could be drugs.

“The novelty and strength of this analysis is that we have defined proteins that modify risk,” Kuruchaga said. “Now that we know the causal steps, we can figure out where those steps connect in the brain.”

While this research will have a direct impact on the understanding and development of treatments for Alzheimer's disease, Professor Kuruchaga said CSF proteomics is a treasure trove of information about many neurological conditions, from Parkinson's disease to schizophrenia. He said he believes it has the potential to bring about

“That's the power of this approach. If you have an atlas of genetic variation and an atlas of protein levels, you can apply this to any disease,” he says.

Proteins are not the only key to understanding these conditions found in CSF. Kulchaga is also investigating the possibility of metabolites, substances released by cells when they break down other compounds as part of their daily processes (also found in CSF). In a separate paper, also published in Nature Genetics, he and his colleagues demonstrated the promise of this approach, reporting links between certain metabolites and conditions such as Parkinson's disease, diabetes, and dementia. .