More About Our Research

Molecular Neurobiology of Central Nervous System Diseases
Neurological diseases that result in the degeneration of neuronal circuits in the brain can culminate in severe impairments of cognitive functions and behavioral disturbances. These dementing illnesses represent increasing medical and socioeconomic problems and raise a wide range of fundamental neuroscientific questions. We are particularly interested in clinically relevant aspects that can be assessed in human patients and manipulated experimentally in related disease models. For example, spatial learning and memory and curiosity are critical to the survival and success of many species. What processes underlie these functions and how are they disrupted in disease? Why do neuronal subpopulations differ so much in their susceptibility to distinct neurodegenerative disorders?

Transgenic mice genetically engineered to produce human proteins or altered levels of mouse proteins are used to study the effects of potential disease-provoking factors on the central nervous system (CNS). Pathogenic pathways are dissected further in nerve cell cultures to help pinpoint critical targets for therapeutic interventions. The relevance of results obtained in experimental models is assessed by comparative analyses of human postmortem tissues and clinical specimens. We also use mouse models to examine the efficacy and safety of novel treatment strategies to prevent or reduce CNS impairments.

Homologues of molecules affected by genetic alterations in human neurodegenerative disorders are expressed at high abundance in the CNS of diverse species and appear to be involved in synaptic plasticity and neural regeneration after injury. Examples include the amyloid protein precursor (APP) and apolipoprotein E (apoE). Using a multidisciplinary approach, we try to determine the roles these molecules play in normal and abnormal CNS biology. How do APP missense mutations lead to early-onset Alzheimer's disease (AD)? How do APP and the APP-derived Aβ peptide affect synaptic transmission and neuronal survival? Why do apoE3 and apoE4, which differ by only a single amino acid, have such different effects on AD risk and clinical outcome after head injury? What can we learn from neurological disease processes about normal CNS function? Can the increased knowledge of pathological cascades that emerges from our studies be used to develop better treatments for incurable neurological diseases? We sure hope so.