Age-related CD8 T cells in the inhibition of endogenous and iPS-derived neurogenesis
The objective of this proposal is to understand how immune aging diminishes the ability of stem cells to make new brain cells. We found that when a certain type of immune cell (T cell) was missing, stem cells in aged brains produced more new nerve cells, and this depended on certain T cell molecules and surface receptors. This could help us promote new nerve cell production in the aged, if we knew it that just aged T cells and not other things in aging brain were responsible for decreasing neuron production, exactly how aged T cells might keep neurons from forming from stem cells, and . Aim #1 will determine if just aged T cells are responsible for decreasing neuron production, by seeing how well neurons are made in young and old animals bearing T cells aged outside their bodies. Aim #2 will determine how well neurons form from stem cells, in the presence of aged or normal T cells, and with and without drugs that block certain T cell functions. Aim #3 will determine if aged T cells prevent transplanted stem cells meant to treat diseases from making new nerve cells in the brain, and will use information gained from the previous Aims to determine how nerve cell production can be enhanced with T cells. Our studies take advantage of a unique way we developed to age T cells outside the body, and previous studies of T cell plus stem cells in culture together. They thus promise to best determine how to promote new nerve cell production in the aged, and in diseases of the elderly.
Central nervous system disorders of aging that could potentially benefit from enhanced neurogenesis (i.e., through engraftment of iPS-derived neural stem cells) include neurodegenerative conditions such as Amyotrophic Lateral Sclerosis, Alzheimer’s, Parkinson’s, and Huntington’s diseases; vascular conditions such as stroke and cerebral amyloid angiopathy; and increased risk of neurotrauma secondary to falls. In aggregate, these conditions place a very large burden on state resources through lost work, caregiver time, and hospital equipment. It is estimated that the cost of caring for a single Alzheimer’s (AD) patient, for example, is $56,800 per year. Multiplied by the over 588,000 patients in the state currently living with AD, plus costs of other conditions, and the burden is truly staggering. Engrafting iPS-derived neural stem cells into patients promises to improve such conditions, but this technology needs to be more efficient and reliable in the elderly in particular. This project aims to exploit aspects of immune cell aging to enhance neurogenesis and iPS-derived graft function in the aged. As the first study to examine the effects of the most common form of immune aging on neurogenesis it will make California a center of excellence for aging and Regenerative Medicine research. It will also attract scientists and companies interested in this area of medicine to California thus increasing state revenue and state prestige in these rapidly growing fields.