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Cell Cycle Re-entry in 3-D Human Neuron Cultures

Funding year(s): 
2015 to 2016
Funding to date: 

The well-known behavioral symptoms of Alzheimer’s disease (AD) are caused by the loss of connections, or synapses, among neurons that control memory and cognition, and by the death of those neurons. A major goal of our labs is to unravel the seminal molecular pathways that convert normal healthy neurons into neurons that will die long before the AD patients themselves. To that end, we recently made major strides toward understanding what may be the most common pathway for neuron death in AD: cell cycle re-entry (CCR), which represents the aberrant reactivation of innate processes for neuronal cell division. Whereas normal, fully differentiated neurons never attempt to divide, up to 5 to 10 percent of the neurons in brain regions affected by AD show signs of CCR over the course of many years. These neurons, which typically have duplicated much of their DNA, evidently never divide, but instead eventually die, and may account for as much as 90 percent of the massive neuron loss that occurs in AD. During the past few years we have defined many features of a complex biochemical signaling web that causes CCR. This process is initiated by soluble amyloid-beta oligomers (AβOs), which are the building blocks of the insoluble amyloid plaques that accumulate in AD brain, and requires soluble forms of tau, the protein that aggregates inside AD neurons to form insoluble neurofibrillary tangles.

Our principal strategy so far has been to model CCR in two-dimensional (2-D) cultures of mouse brain cells, and to test the in vivo relevance of our findings through parallel studies of transgenic AD model mice and human brain tissue samples. Now we would like to test the hypothesis that AβO-induced, tau-dependent CCR can be observed in human neurons grown in three-dimensional (3-D) culture. Such cultures recently were shown to accumulate plaques and Abeta-dependent tangles, and thereby recapitulate human AD features that have not been achieved by any other cultured cell model. If successful, this effort will establish 3-D cultures of human neurons as a viable platform for screening potential drugs that block CCR and for revealing new diagnostic markers for this seminal process in AD pathogenesis.