Major neurodegenerative diseases differ in the types of neurons and brain regions they destroy. Why some brain cells accumulate proteins while other, neighboring cells do not has remained a fundamental question in the field of Alzheimer’s research.
In a review published in Nature Neuroscience, Dr. Karen Duff, member of the Cure Alzheimer’s Fund Research Leadership Group, and her colleagues discuss the recent advances published in the area of selective neuronal vulnerability. The review explores the reasons why certain neurons become diseased while others only teeter on the brink of a catastrophic cliff. The group reports that the difference is due, in large part, to clearance mechanisms in the cells that keep misfolded or aggregated proteins in line. Neurons that are vulnerable to pathological proteins and are lost early in the disease include those present in the entorhinal cortex, the subiculum, the CA1 region of the hippocampus, and cholinergic neurons in the basal forebrain. Importantly, some cell types are vulnerable in the initial stage of the disease, while others are only affected later.
The paper is published in Nature Neuroscience: https://www.nature.com/articles/s41593-018-0221-2
Neurodegenerative diseases have two general characteristics that are so fundamental we usually take them for granted. The first is that the pathology associated with the disease only affects particular neurons (‘selective neuronal vulnerability’); the second is that the pathology worsens with time and impacts more regions in a stereotypical and predictable fashion. The mechanisms underpinning selective neuronal and regional vulnerability have been difficult to dissect, but the recent application of whole-genome technologies, the development of mouse models that reproduce spatial and temporal features of the pathology, and the identification of intrinsic morphological, electrophysiological, and biochemical properties of vulnerable neurons are beginning to shed some light on these fundamental features of neurodegenerative diseases. Here we detail our emerging understanding of the underlying biology of selective neuronal vulnerability and outline some of the areas in which our understanding is incomplete.