Noninvasive Neurostimulation to Reduce Pathology in a Female Mouse Model of Alzheimer's Disease

Veterans Health Administration, Decatur PA

Investigators

Abstract

Over half a million U.S. veterans have Alzheimer’s disease (AD). With AD diagnoses increasing each year, treatments are urgently needed. Despite this need, no clear effective treatment exists for AD and interventions tested in nonhuman models often fail to translate to successful clinical trials. As women are more likely to develop AD than men, AD treatments must address sex as determining factor when evaluating treatments prior to clinical use. Optimized treatments that have the potential to reverse AD neuropathology and mitigate cognitive impairment at prodromal stages, prior to neural degeneration and cell death, are required. Exposure to noninvasive audiovisual neurostimulation at 40Hz (gamma flicker) stimulates neural activity in brain regions first affected by AD pathology that are important for learning and memory, including the hippocampus (HPC) and prefrontal cortex (PFC). Gamma flicker recruits microglia, the primary immune cell of the brain, in the HPC and visual cortex in male 5XFAD mouse models of amyloidosis, as well as cytokine expression in WT male mice. Neurotransmitters like dopamine and norepinephrine modulate the activation, proliferation, and cytokine release from immune cells. Further, AD pathology includes disrupted expression of brain-derived neurotrophic factor (BDNF), an important trophic factor for learning and memory. These neuromodulators are reduced as AD progresses, revealing potential therapeutic targets for treating neural dysfunction and disease. Despite known sex differences in AD pathology, there is a knowledge gap on how flicker noninvasively elicits changes in the immune response, neuromodulators, and cognition in females. Preliminary data in female 5XFAD mouse models of aggressive amyloid accumulation in AD suggest that different frequencies could be key to optimally tuning neurostimulation for each sex. Thus, the central goal of this proposal is to test the hypothesis that specific frequencies of audiovisual flicker are optimal for altering the neuroimmune response of microglia and neuromodulators in brain regions important for learning and memory affected by neurodegenerative disease for each sex. Through the CDA2 proposed research, male and female 5XFAD mice will be exposed to chronic audiovisual flicker (1hr/ day for 7 days), then flicker’s effects on 1) the spectrum of glia reactivity across stimulation frequencies, 2) trophic factors and neurotransmitters that alter glia reactivity, cognition, and neuroplasticity, and 3) working memory performance, will be measured. The proposed research will take place over the proposed 5-year timeline of the CDA2 at the Center for Visual and Neurocognitive Rehabilitation (CVNR) of the Atlanta VA. The resources available include the Atlanta CVNR, Emory University’s Goizueta Alzheimer’s Disease Research Center, the Department of Biomedical Engineering at Georgia Tech, and Emory’s Proteomics and Microscopy cores. The mentoring team and the CVNR will support training in research techniques, lab management, and grant writing to provide Dr. Prichard with a strong foundation to achieve her goals of independence through the submission of a VA Merit Award. Through her unique training at Emory University and Georgia Tech, combined with the training through the CDA2, Dr. Prichard will ultimately pursue a career in research and mentoring as a tenure-track professor and VA researcher in her future comparative cognition and neuropathology lab. She will utilize rodent models for assessment of flicker’s effects on AD pathology and apply this to noninvasive studies of pet dogs with canine cognitive dysfunction, a naturally occurring form of human-like AD pathology. The first step in this career path is to train at the Atlanta VA to establish the effects of flicker on the immune response and neuromodulators, explicitly addressing sex as an important factor in disease etiology, progressing toward treatment in higher-order animal models and ultimately clinical trials. Upon completion of the fellowship, she will have learned valuable research techniques in cell morphology, neuroimmune responses, and protein analyses, developed a strong background in aging research and disease pathology, and built a network of VA mentors and collaborators.