There is an urgent need for a better understanding of how normal neurons in the brain are converted into Alzheimer’s disease neurons, and there is an equally urgent need to identify drugs that can block or even reverse this conversion. We are developing and optimizing new human neuron testing systems that will more faithfully mimic human Alzheimer’s disease and that can be used to rapidly screen for new Alzheimer’s disease drugs. Our new assay systems use cultured adult human neurons (iNeurons), which are converted from human skin cells provided by healthy and Alzheimer’s disease donors. To rapidly advance our iNeuron systems, we are leveraging our established cell culturing systems for embryonic-like human neurons that are also converted from skin cells. We have determined that extracellular cues (i.e., oxygen levels, extracellular proteins) influence how cultured human neurons grow and mature. We have also miniaturized our assay systems so they are compatible with drug screening and can test thousands of drugs simultaneously.
The multitude of failed drug trials for Alzheimer’s disease (AD) emphasizes the urgent need for a better understanding of how normal neurons (nerve cells) in the brain are converted into AD neurons, and how to identify drugs that can block this conversion. To that end, we have defined and are continuing to explore many AD-like features of cultured mouse neurons that have been exposed to small aggregates (oligomers) of amyloid beta. Importantly, amyloid beta oligomers are the soluble building blocks of the poorly soluble amyloid plaques that accumulate in the AD brain, and are far more toxic than the plaques themselves. The AD-like properties of mouse neurons exposed to amyloid beta oligomers include “cell cycle reentry,” which precedes most neuron death in human AD; impaired function of mitochondria, the “power plants” of the cell; cellular senescence; and neuronal DNA damage. It follows naturally that drugs that block these neuronal responses to toxic amyloid beta oligomers might have prophylactic potential for AD. To take our basic science findings to the next step, we will develop and optimize neuron cultures that more faithfully mimic human AD and can be rapidly screened for drug testing. More specifically, we will refine a system in which cultured adult human neurons (iNeurons) are used in place of mouse neurons, and the iNeurons will be grown in three-dimensional matrices instead of on flat, two-dimensional surfaces. Importantly, the adult human neurons will not be obtained from brain tissue, but instead will be differentiated in culture from fibroblasts, which are common cells found throughout the body and are easily and painlessly acquired, and could position the platform for future “personalized medicine” usage. We anticipate initiating pilot drug screening studies near the end of year 1, and continuing those studies on a grander scale during year 2.