by Xuguang Sui
PHOENIX, the United States, Oct. 16 (Xinhua) -- Scientists have discovered a series of cellular changes that are characteristic of the early stages of Alzheimer's disease (AD), including some not previously seen in animal studies, a newly published study suggested.
"The findings re-affirmed that AD pathology is multifaceted, involving many abnormal processes," Fang Yu, professor at Edson College of Nursing and Health Innovation, Arizona State University, told Xinhua in an interview on Saturday.
"The role of neuroinflammation mediated by glia and astrocytes have been increasingly recognized," said Yu, the lead principal investigator of a clinical trial funded by the U.S. National Institutes of Health on finding the mechanism of physical exercises slowing down memory loss of patients living with AD.
In the study recently published in Cell, a team led by researchers at the Broad Institute of Massachusetts Institute of Technology and Harvard analyzed data from 52 living patients, collection of rare brain tissue samples from patients with varying degrees of AD-related changes in their brains, including 17 individuals who were later clinically diagnosed with AD.
The scientists identified a suite of changes in cells unique to the early stages of Alzheimer's, including some not seen before in animal studies.
Most AD studies in the past on human brain tissue have looked at autopsy samples after death. However, cells, especially neurons, undergo a variety of changes quickly after they are deprived of oxygen after death, which makes it difficult for scientists to discern the earliest events in the brain that might trigger plaque buildup and neuronal death.
Understanding the molecular changes in neurons, glia and other brain cells in the early stages of the disease can help scientists design treatments that work best if they are treated early.
The live human brain tissue samples used in the study came from Dr. Ville Leinonen, a neurosurgeon and professor at the University of Eastern Finland.
He spent more than a decade collecting and studying brain tissue samples from patients undergoing routine surgery for other neurological conditions, and other samples such as hydrocephalus and cerebrospinal fluid from each patient.
Leinonen also followed the patient cohort over time, noting whether each patient later was diagnosis of AD.
Samples from these living patients provide a rare opportunity to observe cells exposed to the early pathological stages of AD.
The research team at the Broad Institute has partnered with Leinonen to use single-nucleus RNA sequencing to analyze those brain tissues and map gene expression in individual cell nuclei.
By cross-checking these data with Leinonen's clinical records and combining them with previous human single-cell autopsy and mouse studies, the researchers identified key changes in various cell types during the early stages of the disease.
The team discovered that a specific group of neurons in the upper layers of the brain are transiently overactive and die early in AD. This hyperactivity can lead to more widespread loss of neurons in patients.
These hyperactive neurons were found to exhibit gene expression signatures associated with amyloid production, consistent with researchers' long-held hypothesis that neurons produce amyloid in AD patients.
They also observed the same signature in oligodendrocytes for the first time.
Future studies that better understand how these cells stimulate plaque growth could help researchers identify new targets for Alzheimer's drugs.
"This was just a really rich opportunity to peer into the actual workings of cells with minimal artifacts and see what they're doing in the context of amyloid," said Evan Macosko, senior author on the study, an institute member at the Broad Institute, and associate professor and attending psychiatrist at the Massachusetts General Hospital.
"It took a decade of neurosurgery, patient involvement, thoughtful analysis, and really useful experiments," said Tushar Kamath and Vahid Gazestani, co-first authors of the study and doctoral students/postdocs in Macosko's lab. "We couldn't have done this research without any of one thing happening."
In the future, a team of researchers led by Macosko and Beth Stevens, an institute member at the Broad Institute and co-author on the study, plan to identify proteins associated with these cellular states in paired blood and cerebrospinal fluid samples, which potentially serve as biomarkers to monitor disease progression.
They also hope that other researchers will be able to use their method to analyze data sets from different types of samples and sequencing methods, which will provide additional crucial insights into the pathogenic process of AD and other diseases of the brain.
