Though researchers can’t pinpoint why individuals have different presentations of Alzheimer's disease, one thing most people experience at the onset is short-term memory problems.
It isn't clear what causes certain regions of the brain to be affected first by the disease while many other parts seemingly are still functioning normally. Yet, as Alzheimer’s disease progresses into the advanced stages, all affected individuals end up with widespread brain disease.
A team of molecular biologists and neuropathologists gathered from the University of California San Francisco Weill Institute for Neuroscience to identify for the first time the neurons, or nerve cells, that are among the first victims of the disease — accumulating toxic “tangles” and dying off earlier than the neighboring cells.
In a study published in Nature Neuroscience in January, the researchers commented: “We know which neurons are first to die in other neurodegenerative diseases like Parkinson’s disease and ALS, but not Alzheimer’s,” said co-senior author Martin Kampmann, an associate professor in the UCSF Institute for Neurodegenerative Diseases and Chan Zuckerberg Biohub Investigator. “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.”
Much research has been done on why certain cells are more prone to producing the toxic tangles of the protein known as tau, which spread through the brain and drive widespread cell death, resulting in progressive memory loss, dementia and other symptoms.
However, researchers have not thoroughly investigated whether all cells are equally vulnerable to the toxic effects of these protein accumulations. What baffles researchers is that some cells end up with high levels of tau tangles well into the progression of the disease, but, for unknown reasons, don’t die.
The question becomes what makes some cells vulnerable to Alzheimer’s pathology, while other cells appear to resist the destruction of the tau proteins for years.
The team at UCSF studied brain tissue from people who had died from different stages of Alzheimer’s disease.
In a brain region called the entorhinal cortex, located in the medial temporal lobe, which is one of the first areas attacked by Alzheimer’s, the researchers identified a certain subset of neurons that began to dissipate very early on in the disease. In the later course of the disease, researchers found that a similar group of neurons were also first to die when degeneration reached the brain’s superior frontal gyrus.
In both regions, these vulnerable cells were distinguished by a protein called RORB.
“Our discovery of RORB for these selectively vulnerable cells gives us the opportunity to study in detail exactly why they succumb to tau pathology, and what could be done to make them more resilient,” said researcher Kun Leng, of the Department of Neurology in the UCSF Weill Institute for Neurosciences.
Though it is not clear whether RORB itself causes vulnerability in some cells, it provides a new molecular handle for future studies to understand what makes these cells succumb to Alzheimer’s pathology.