Using a recreation of homeostatically expanded CD8 T cells, researchers are investigating causes of sporadic Alzheimer's and also new treatments for the disease. In experiments, these cells assume characteristics of aberrant T cells that accumulate with aging in some individuals. Aberrant T cells are unique because of their functional abilities and conditions favoring their formation with age and traumatic brain injury.
Recipients of these aberrant T cells show signs of pathological hallmarks of Alzheimer's, including Aβ plaques, neurofibrillary tangles, neuronal and synaptic loss, progressive brain atrophy, and profound cognitive impairment. In an effort to determine the functional properties of aberrant T cells promoting this neuropathology, we also recreate homeostatic expansion using T cells deficient in their two major effector functions: target cell lysis (perforin deficiency) and pro-inflammatory cytokine production (IFN-gamma deficiency). These T cells expand normally, but they either fail to persist in the brain, causing neuropathology (deficient T cells), or they enter the brain but promote only limited neuropathology without clinical symptoms.
Our findings suggest that aberrant T cells linked to at least two major risk factors induce the major hallmarks of sporadic Alzheimer's. These T cells may therefore be linked to development of Alzheimer's in patients, a possibility we are seeking to validate. Our research also provides a unique model to further examine sporadic pathoetiology of Alzheimer's, neurodegeneration and therapy, as well as the general contribution of immune aging to diseases.
- Principal Investigator: Christopher Wheeler, PhD