Researchers have identified a molecular signature that links together different cell populations in the brain that are selectively vulnerable to the neurodegenerative condition Alzheimer’s disease (AD).
A characteristic feature of the path of destruction left in the brain by the progression of AD is that, amongst the wreckage of cells left scarred by amyloid plaques or tau neurofibrillary tangles, certain cell subtypes remain relatively unaffected until the very late stages of the disease. What makes certain cell types vulnerable or resilient to neurodegeneration? The answer to that question has been brought further into focus by new findings from a team primarily based at the University of California San Francisco (UCSF).
The work is published in Nature Neuroscience.1
"Some cells end up with high levels of tau tangles well into the progression of the disease, but for some reason don't die,” said Lea Grinberg, an associate professor in the UCSF Memory and Aging Center and co-senior author of the study in a press release. “It has become a pressing question for us to understand the specific factors that make some cells selectively vulnerable to Alzheimer's pathology, while other cells appear able to resist it for years, if not decades."
The team examined brain samples obtained from the UCSF Neurodegenerative Disease Brain Bank and the Brazilian BioBank for Aging Studies, assembling a group of 10 sets of tissue taken from donors matched for sex and APOE genotype, a key determinant of Alzheimer’s risk.
What makes neurons vulnerable to Alzheimer's?
Using an exhaustive sequencing technique called single-nucleus RNA sequencing (snRNA-seq), which examined the individual genetic material of cells in these post-mortem brains, Grinberg’s team were able to look for distinct molecular profiles that identified cells affected early on in the disease pathology.
Excitatory neurons have been previously reported to be more vulnerable in AD. Searching through nine subtypes of these neurons, the teams noted that certain clusters of neurons exhibited rapid depletion early on in disease pathology, in some cases losing over 50% of their relative abundance.
Looking at the gene expression patterns of these vulnerable subtypes, the researchers noted that they distinctly expressed the transcription factor protein RORB. Whilst their initial data set was underpowered for further analysis, the team then looked at a larger set of 26 brains and used histopathological techniques to mark out cells that expressed RORB.
What is a transcription factor?Transcription factors are proteins that control the transcription of genes. Transcription is the first step in turning a gene coded on DNA into a protein that can exert functions within a cell.
Transcription factors hunt through the genome, binding at certain points where they are able to either activate or deactivate transcription. Sometimes, TFs can bind to non-specific regions of DNA as well.
These cells were shown to express tau tangles and degenerate more quickly than other types of neuron, confirming the team’s findings from their first data set.
Does RORB play a causal role in this process? The team noted that whilst certain other cortical neuronal populations that expressed RORB were not vulnerable, RORB’s important role in establishing neuronal subtype identity may suggest that gene programs written by RORB contribute to their later vulnerability.
This finding represents the first study in a wider investigation into the disease progress of AD, a project that could have important outcomes. "If we understood why these neurons are so vulnerable, maybe we could identify interventions that could make them, and the brain as a whole, more resilient to the disease,” said co-senior author Martin Kampmann, an associate professor in the UCSF Institute for Neurodegenerative Diseases.
Leng K. Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease. Nature Neuroscience.:31.