Our laboratory studies the molecular basis of neural development and neuronal degeneration using mouse genetics, behavioral, electrophysiological, biochemical, molecular and cell biological approaches. Current investigations focus on the following three areas of research.

First, we are interested in understanding the roles of presenilins (PS1 and PS2) and Notch1 in neural development. Our previous studies of PS1-/- mice revealed a critical role for PS1 in neurogenesis and Notch signaling. We are currently investigating whether presenilins are involved in neuronal migration, dendritic development and synaptogenesis using our recently developed PS1 single and PS1/PS2 double conditional KO mice, in which PS1 or both PS are selectively inactivated in neural progenitor cells or postmitotic neurons. To investigate further the role of Notch signaling in mammalian neural development, we generated cell-type-specific conditional mutant mice and are in the process of determining the effects of elevated Notch signaling or loss of Notch1 function in cortical development.

Second, to understand the pathogenic mechanism of Alzheimer’s disease (AD), we have focused our efforts on the major genes involved in familial AD presenilins and the amyloid precursor protein (APP). Analysis of an additional PS1 conditional KO mouse, in which PS1 is selectively inactivated in pyramidal neurons of the postnatal forebrain, revealed that PS1 is required for normal proteolytic processing of APP and the generation of amyloid peptides. The PS1 conditional KO also exhibits subtle deficits in long-term spatial memory, though synaptic transmission and plasticity are normal. We are furthering our studies by crossing PS1 conditional KO mice to transgenic mice overexpressing mutant APP to determine whether inactivation of PS1 in these APP transgenic mice can effectively eliminate amyloid-related neuropathological changes and memory deficits. We are also assessing the synergistic roles of PS1 and PS2 in the generation of amyloid peptides, learning and memory, synaptic function and neuronal integrity and survival using double conditional KO mice.