Instructor in Medicine
Washington University School of Medicine
Fagan, Anne, Ph.D. and Bruchas, Michael, Ph.D.
In 2000, Dr. Schindler entered the MD/PhD program at Washington University. After her first two years, she began working in the lab of Dr. David Holtzman. Her primary focus was on apolipoprotein E (apoE), which is the major modifier of risk for Alzheimer’s disease. In her last two years of residency training, she identified Dr. Marc Diamond as her scientific mentor. Dr. Diamond studies protein misfolding and mechanisms underlying propagation of protein misfolding. Dr. Schindler began to develop tools to study tau aggregate propagation in vivo and received an award from the American Brain Foundation to fund protected research time during her fellowship. In 2012, she began a combined two-year clinical fellowship in dementia and postdoctoral research fellowship.
Dr. Schindler is a graduate of the MSTP training program here at Washington University where she worked with Dr. David Holtzman on apolipoprotein E (apoE), which is a major genetic risk factor for Alzheimer’s disease. She identified ABCA1 as the major protein that transfers lipids onto apoE and found that alterations in ABCA1 levels affect brain deposition of amyloid-β, a key molecule in Alzheimer’s disease. She completed a neurology residency and fellowship training in dementia, and her current project is to develop a novel optogenetic technique to activate stable gene expression in the mouse brain. Her co-mentor, Dr. Bruchas is an expert in the use of optogenetics for behavioral research in mice. This technique was designed to allow expression of aggregation-prone tau in a focal area of the brain, which would then enable study of tau aggregate spread through the brain.
Awards and Honors
In 2012, awarded the AANF/Robert Katzman Clinical Research Training Fellowship in Alzheimer’s disease. Given by the American Academy of Neurology and Alzheimer’s Association to one junior neurologist every two years to fund further research and training in the area of Alzheimer’s disease.
Trans-synaptic spread of tau aggregates in mouse brain networks and primary neuronal cultures
Tauopathies are neurodegenerative diseases, such as Alzheimer’s disease, characterized by intracellular aggregation of the microtubule associated protein tau within the brain. Each tauopathy affects a distinctive brain network, a pathway of functional and anatomical connections. We hypothesize that different neuropathological and clinical syndromes occur because tau aggregation begins in discrete brain regions and then spreads through specific brain networks via synaptic connections. Various animal models have examined tau spreading, but have been limited by an inability to focally express tau within the brain without the confounds of virus, gene, or protein diffusion. We have developed a novel system utilizing a light-activated Cre recombinase that allows precise spatial gene expression in the mouse brain. We will express tau containing aggregation-prone or aggregation-inhibiting mutations within a small region of the brain and observe whether tau pathology spreads within the associated brain network, rather than diffusing radially. To examine whether tau aggregates spread via synapses, we will study primary cultured neurons expressing aggregation-prone or aggregation-inhibiting mutations. We will activate neurons using Channelrhodopsin and chemical approaches. Tau monomers and tau aggregates will be measured using sensitive ELISAs and a novel assay that detects induction of tau aggregation. We will test whether neuronal activity releases tau monomers and aggregates at the synapse.