1. Understanding tau in the developing brain to better understand the pathogenesis of adult neurodegenerative diseases.

Figure 1

The tau protein is the main component of abnormal protein aggregates in diseases ranging including myotonic dystrophy, Alzheimers disease and chronic traumatic encephalopathy. It exists in several forms of different lengths and can be phosphorylated at multiple sites. In adults, isoform imbalance and tau phosphorylation can trigger formation of toxic aggregates, but we have found that the developing human brain expresses short-isoform and hyperphosphorylated tau without any apparent adverse effects. Understanding why this shift happens and what prevents toxic aggregate formation will help us better understand the role of tau in neurodegenerative disease. I collaborate closely with Dr. John Crary of the Mount Sinai School of Medicine who studies regulation of tau expression in splicing in neurodegenerative disease.

2. Comparative neuropathology of Alzheimer disease.

Figure 2

Although some animals, such as dogs, marmosets and some apes and monkeys, can form β-amyloid aggregates, most do not form tangles like those seen in humans with Alzheimer disease. We and others have found that aging domestic cats show both β-amyloid and tau aggregates. Due to the difficulty in collecting large numbers of cases and in translating methods developed for human neuropathology into different non-model species, most such studies have been limited in size and scope. In collaboration with Dr. Jodi Smith of the Iowa State College of Veterinary Medicine we are conducting a systematic study of the neuropathology of aging in domestic cats and hope to expand this to other domestic animal species. We hope that these studies will lead to new models for Alzheimer disease research and will help us better understand the mechanisms that trigger development of β-amyloid and tau aggregation in Alzheimer disease.

3. The mechanisms by which neonatal hypoxic-ischemic injury causes long term cognitive deficits and how this can be prevented.

Figure 3

Because of rapid advances in neonatal medicine, children born prematurely and those with congenital heart defects or birth injury are surviving in ever greater numbers. Many will have long-term cognitive deficits including learning disabilities and autism. My laboratory is interested in understanding risk factors and mechanisms by which these deficits occur and how to prevent them. These studies include work with human brain tissue at the University of Iowa and with piglet models done in collaboration with Dr. Todd Kilbaugh and his group at Children’s Hospital of Philadelphia.