A new, landmark study launches Alzheimer’s research forward by identifying the neurons in the brain most-vulnerable to degeneration in the disease’s earliest stages, often preceding symptoms. Published in Nature Neuroscience, the study investigates why some brain cells suffer disproportionate degeneration due to Alzheimer’s, while others surrounding them don’t.
The findings, scientists say, can help inform treatments to boost the brain’s resilience against Alzheimer’s and aid diagnosis in the disease’s early years, when symptoms have not yet appeared.
Scientists already know how Alzheimer’s manifests in the brain — in the form of toxic tangles consisting of the protein tau, which is known to kill brain cells and cause symptoms such as dementia or memory loss. “The belief in the field has been that once these trash proteins are there, it’s always ‘game over’ for the cell, but our lab has been finding that that is not the case,” the study’s senior author Lea Grinberg, a professor at the University of California, San Francisco’s Memory and Aging Centre, said in a statement. “Some cells end up with high levels of tau tangles well into the progression of the disease, but for some reason don’t die. 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 researchers identified two main areas of the brain, known to be the first ones to succumb to Alzheimer’s degeneration, in which vulnerable neurons were found. In the entorhinal cortex, a region associated with memory, a set of neurons — called excitatory neurons — were found to reduce by nearly 50% in the early stages of Alzheimer’s. Scientists found a unique factor in this set of vulnerable neurons: the presence of high quantities of the protein RORB (retinoid-related orphan receptor alpha). RORB is known to control the expression of other proteins in cells, which means it has the ability to control whether or not a particular cell becomes susceptible to tau tangles, and therefore, disease.
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The scientists then looked for excitatory neurons in another early Alzheimer’s-affected region in the brain — the superior frontal gyrus, which is associated with self-awareness. There, they found a similar type of neuron vulnerability in the early stages of the disease, also determined by high levels of RORB.
While scientists are unclear if the mere presence of the RORB protein is causing the cells’ selective susceptibility, they are positive the new molecular connection they discovered can help shed light upon one more layer of Alzheimer’s progression and possibly help innovate ways in which such degeneration can be reversed.
The deeper, more targeted scientists get in determining how Alzheimer’s wreaks havoc in the brain, the more targeted, specific they can hold future investigations into preventative treatment, scientists added, in the fight to slow the disease.
