2024
For proper cellular function, proteins must be moved in cells to their proper locations. One way this occurs is via a system called the endosomal network. This network is like a traffic system to help proteins get to where they need to be or be efficiently degraded if they are no longer needed. Cells use the endosomal network in different ways. For example, neuronal cells use it to express receptors at the right places for electrophysiological function, which is necessary for proper cognition, learning and memory. Other cells in the brain, called microglia, the immune cells of the brain, use it to digest and degrade pathogenic molecules and to secrete factors that mediate immune responses. The endosomal network becomes dysfunctional early in Alzheimer’s disease (AD) before the appearance of amyloid beta plaques or neurofibrillary tangles. We aim to use neurons and microglia–grown from stem cells of individuals with AD genetic risk or controls–to understand how dysfunction in the endosomal network causes problems for these two cell types. We have methods to express factors or use small molecules to enhance this network, hopefully leading to new therapeutic molecules that will be effective for AD prior to irreversible neurodegeneration.