Neurogenesis in Alzheimer's Disease: A-beta, Friend or Foe?

Funding Type: 
SEED Grant
Grant Number: 
RS1-00271
ICOC Funds Committed: 
$0
Disease Focus: 
Parkinson's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Alzheimer's disease (AD), a late-onset disease manifests impairment and loss of neurons over years before the onset of clinical symptoms such as, learning and memory loss. Studies suggest that the brain attempts to replace these nerve cells throughout the course of the disease with new cells, but results are insufficient. It may be that not enough new cells are generated, or that they die due to the disease process itself, and prior to restoration of function. In AD, a major factor of the disease is production of a toxic molecule, the A-beta peptide. We plan to test if this molecule stimulates new nerve cell production, but also eventually is toxic to those cells as they develop more neuron-like functions. As these cells move into the diseased area of the brain, they must assume contact with other existing nerve cells that are essential for memory and learning functions. This step may also not occur in a normal way in AD. Because we cannot test for these activities in the AD-affected patients, and because animal or tissue culture models are inadequate, we propose to use human embryonic stem cells (hESCs) that have been treated to become neural stem cells (NSCs) and expose them to the toxic A-beta peptide and determine if they both increase in numbers and then become more fully like neurons in the brain. This latter function include migration of the new neurons moving towards normal nerve cells that have been previously damaged, for example, exposure to the toxic A-beta peptide. These studies will provide some important information on the ultimate possibility of stem cell replacement of neurons loss during the disease course.
Statement of Benefit to California: 
Alzheimer's disease, a progressive neurological process leading to dementia is devastating to the patient and family. The average duration of disease is 8 years, and is both costly for families and the community, and labor intensive for the caregivers. Our preliminary studies indicate that process of new nerve cell generation is attempted by the brain itself, but insufficient. Possibility of embryonic stem cell biology offers the ultimate possibility of replacement of lost or impaired nerve cells. This proposal attempts to understanding how this replacement can occur and allow the patient to maintain normal function, especially of memory and cognition sufficient for activities of daily living. Defining critical, several steps in neurogenesis can be best accomplished with hESCs. Exposing these cells to the toxic molecule A-beta provides a means to define if the cells become neurons and are maintained or lost due to the A-beta effect itself. If the latter is true, than drugs to block this later step could be tested on these cells. If these cells fail to replace the lost nerve cells, and connect up with remaining cells, then research targeted to promote their integration should be pursued. All of these studies lead to the ultimate goal of repairing the brain and halting the neuron loss or decreasing the rate of loss and the functional decline of the patient.
Progress Report: 
  • A promising approach to alleviating the symptoms of Parkinson's disease is to transplant healthy dopaminergic neurons into the brains of these patients. Due to the large number of transplant neurons required for each patient and the difficulty in obtaining these neurons from human tissue, the most viable transplantation strategy will utilize not fetal dopaminergic neurons but dopaminergic neurons derived from human stem cell lines. While transplantation has been promising, it has had limited success, in part due to the ability of the new neurons to find their correct targets in the brain. This incorrect targeting may be due to the lack of appropriate growth and guidance cues as well as to inflammation in the brain that occurs in response to transplantation, or to a combination of the two. Cytokines released upon inflammation can affect the ability of the new neurons to connect, and thus ultimately will affect their biological function. In out laboratory we have been examining which guidance molecules are required for proper targeting of dopaminergic neurons during normal development and have identified necessary cues. We have now extended these studies to determine that two of the molecules have dramitc effects on dopaminergic neurons made from human embryonic stem cellls and that at least in vitro, cytokines do not mask these effects. Ultimately, an understanding of how the environment of the transplanted brain influences the ability of the healthy new neurons to connect to their correct targets will lead to genetic, and/or drug-based strategies for optimizing transplantation therapy.

© 2013 California Institute for Regenerative Medicine