One of the major problems with brain aging and neurodegenerative diseases is the cognitive impairment caused by the destabilization of neurites and synaptic connections followed by the degeneration and loss of neurons. Thus, elucidating the molecular mechanisms that regulate the growth and stabilization of neurites and synapses may not only help us better understand these events, but may also provide information for developing new preventive and therapeutic approaches. Recent evidence obtained in several laboratories, including ours, has implicated contact- dependent signaling via the Notch receptors, which has been traditionally associated only with embryonic development, in the growth and stabilization of neurites and synaptic connections in the cerebral cortex. We have also demonstrated that endogenous Notch activity in both developing and mature cortical neurons can be modulated by exogenously applying the Notch ligands Delta and Jagged, and the intracellular proteins Numb, Numb-like, and Deltex. In addition, numerous mutations causing early-onset Alzheimer's Disease (AD) have been identified in the presenilin (PS) genes, which have been shown to be necessary not only for gamma-secretase-mediated processing of amyloid precursor protein (APP), but also for the trafficking, endoproteolytic processing, and activity of the Notch receptors. Our working hypothesis is that in aging and many neurodegenerative disorders, the degradation of neuronal connections is associated with changes in the expression and activity of the Notch signaling pathway genes, which may directly-or indirectly contribute to the underlying pathogenesis. If so, then finding a way to control Notch signaling, either upstream, via ligands, or downstream, via intracellular proteins, could provide a means to slow down or change the outcome of aging and memory disorders in the cerebral cortex. We propose three logistically related Specific Aims: (I) The expression and subcellular localization of Notch signaling molecules in the normal and abnormal adult cerebral cortex; (II) The effect of manipulating Notch activity on the stability and modifiability of cortical neurites and synapses; and (III) The role of preseniiins in the expression, endoproteolytic processing, and activity of Notch receptors in the cortical neurons. We have promising preliminary data and our expectation is that research of this scope and methodological diversity will provide insight into the pathogenesis of neurodegeneration and possibly generate the means to alleviate or slow its progression.
