Towards A Cell Biology of Alzheimer’s Disease

In many neurodegenerative disorders, including Alzheimer's Disease (AD), the dysfunction of multiple cell types causes neuronal cell death, but the precise cellular processes involved remain incompletely understood for any neurodegenerative disease. Strikingly, synapses are often affected early during pathogenesis, probably because presynaptic terminals are distant outstations of neurons that are the most vulnerable part of a neuron. In AD, multiple mutations in APP and presenilin genes cause rare familial cases, while the ApoE4 variant of the ApoE gene represents the strongest genetic risk factor for sporadic AD in the general population. APP and presenilin gene mutations are thought to induce AD pathogenesis by overproducing pathogenic Abeta variants, and ApoE4 is thought to influence Abeta clearance, but how Abeta might incite AD pathogenesis and how ApoE4 might predispose to AD pathogenesis remains incompletely understood. Moreover, compelling evidence implicates microglial and possibly astrocytic dysfunction in AD pathogenesis. In my lab, we have taken a cell-biological approach to these questions with a focus on synapses because of their prominent role in AD, recognizing that synapse impairments in AD may also be secondary to microglial dysfunction. We have examined how pathogenic APP mutations, chronic impairments of presenilin function, or ApoE4 may act on synapses, using human neurons trans-differentiated from ES and iPS cells as a model. In my presentation, I will discuss the current status of this project which is far from providing a definitive account of AD pathogenesis but may offer a basis for understanding the most basic processes underlying such pathogenesis.