The knowledge about liquid biomarkers for the detection and prognosis of Alzheimer’s disease has exploded over the last few years. Also, inflammatory responses associated with the disease has been known for a while and results from experimental work indicate a role in early disease development. Still, investigating subtle inflammatory changes inside the living human brain has not been possible, so far. But modern, sensitive technology opens for the detection of even low amounts of proteins in the cerebrospinal fluid surrounding the brain.
“We detected elevated levels of the inflammatory protein Galectin-3 in the cerebrospinal fluid from patients with Alzheimer’s disease. Our work highlights the importance of the inflammatory response mediated by Galectin-3 and that it can potentially be used as a biomarker for the sporadic form of the disease,” tells an enthusiastic Antonio Boza Serrano, post-doc at Seville University and Lund University and first-author of the study.
Our work highlights the importance of the inflammatory response mediated by Galectin-3 and that it can potentially be used as a biomarker for the sporadic form of the disease,” tells Antonio Boza Serrano.
The primary source of Galectin-3 inside the brain is the microglia, the brain’s own immune cells. This inflammatory protein is not present in detectable levels in the healthy brain, but can increase quickly when the microglial cells react to pathological events.
A collaboration between research groups in Lund, Seville, and Barcelona, and Kaj Blennow at Gothenburg University, made it possible to investigate the links between pathological levels of well-known Alzheimer’s-related proteins and inflammatory proteins such as Galectin-3. Their study contains cerebrospinal fluid samples from 155 individuals, whereof 119 have gotten an Alzheimer’s disease diagnosis. In addition, the researchers analyzed brain tissue from 28 patients and 13 non-demented controls. In the hippocampus and cerebral cortex, two brain regions specifically affected in Alzheimer’s disease, they found an interaction between Galectin-3 and phosphorylated tau in the senile plaques.
Galectin-3 and pathological tau goes hand in hand
Taking a closer look at the brain tissue, the researchers could see that microglial cells expressing Galectin-3 were situated nearby neurons containing inclusions of tau. And higher levels of Galectin-3 in the cerebrospinal fluid correlate with higher levels of pathological tau that are established as biomarkers for early detection of Alzheimer’s disease.
“To elucidate if Galectin-3 is a suitable biomarker for early detection of neuroinflammation linked to Alzheimer’s disease, we initiated a longitudinal study following the evolution of this protein levels together with other hallmarks of Alzheimer’s pathology over time,” tells Antonio Boza Serrano.
More than just an inflammatory protein
The research team has previously shown that activated microglia around Alzheimer’s-specific senile plaques express Galectin-3 in both mice and human brain samples and that this contributes to pathology (Read more about this finding here).
“To be able to validate our previous findings about microglial involvement in Alzheimer’s disease in patient samples is very rewarding,” says Tomas Deierborg, Professor, leader of the Experimental Neuroinflammation Laboratory at Lund University, and the last author of the study.
“To be able to validate our previous findings about microglial involvement in Alzheimer’s disease in patient samples is very rewarding,” says Tomas Deierborg.
Galectin-3 does not seem to be the only inflammatory protein that is involved in Alzheimer’s pathology. Advanced statistical analysis shows that it is associated with other proteins involved in brain inflammatory responses. And other large, genome-wide association studies have indicated that genes linked to inflammation affect the risk of developing Alzheimer’s disease. Even though Galectin-3 alone may not be sensitive enough to detect this disease, it may be one of several biomarkers covering the neuroinflammatory aspects of the pathology.
“Our finding opens up for expanding the panel of biomarkers for Alzheimer’s disease, to capture unknown pathological aspects that could play a critical role for some patients. And if we are lucky, this may even pinpoint new potential therapeutic targets. Other research groups have confirmed our previous results and a clinical study targeting Galectin-3 has been initiated. This is very inspiring,” summarizes Tomas Deierborg.