Targeting Cell Cycle Re-entry Using 3-D Neuron Cultures

2018

Our laboratories have been attempting to unravel the key molecular pathways that convert normal, healthy neurons into dysfunctional neurons. We have made progress toward understanding what may be the most common pathway for neuronal death in Alzheimer’s disease: cell cycle re-entry, or CCR. CCR refers to the abnormal reactivation of a process normally reserved for neuronal cell replication. Whereas normal neurons in most of the brain never attempt to divide, up to 5 percent to 10 percent of the neurons in brain regions affected by Alzheimer’s disease show signs of CCR over the course of many years. Instead of dividing, these CCR neurons eventually die, and may account for as much as 90 percent of the neuronal loss seen in AD. We have found that CCR is initiated by soluble amyloid beta oligomers, which are the building blocks of the insoluble amyloid plaques that accumulate in AD brain, and that it requires soluble forms of tau, the protein that aggregates inside AD neurons, to form insoluble neurofibrillary tangles. In the next funding period, we will exploit innovative 3-D models to screen “libraries” of small molecules for compounds that can inhibit CCR, and thus have the potential to become drugs that prevent or slow progression of AD.

2017

The loss of connections among neurons that control memory and cognition, and the death of those neurons, account for the well-known behavioral symptoms of Alzheimer’s disease. Our laboratories have been attempting to unravel the seminal molecular pathways that convert normal healthy neurons into neurons destined to die long before the AD patients themselves. In the past two years, in large part due to the generous support of Cure Alzheimer’s Fund, we made major progress 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 replication.

Whereas normal neurons in most of the brain never attempt to divide, up to 5 percent to 10 percent of the neurons in brain regions affected by AD show signs of CCR over the course of many years. Ironically, instead of dividing, these CCR neurons eventually die, and may account for as much as 90 percent of the neuronal loss seen in AD. We have found that CCR is initiated by soluble amyloid beta oligomers, which are the building blocks of the insoluble amyloid plaques that accumulate in AD brain, and that it requires soluble forms of tau, the protein that aggregates inside AD neurons to form insoluble neurofibrillary tangles.

In the previous funding period, we established the conditions for maximal CCR in human and mouse neurons that grow in three dimensions (3-D) and model many features of AD neurons in human brain. We have successfully identified several protein modifications and molecular pathways that participate in CCR in these cells. In the next funding period, we will exploit these innovative 3-D models to screen “libraries” of small molecules for compounds that can inhibit CCR, and thus have the potential to become drugs that prevent or slow progression of AD.