Presenilins in the developing, adult, and aging cerebral cortex

Mutations in presenilins are the major cause of familial Alzheimer disease. The involvement of presenilins in the pathogenesis of Alzheimer disease, therefore, has been the subject of intense investigation during the past decade. Genetic analysis of phenotypes associated with presenilin mutations in invertebrate and vertebrate systems has greatly advanced our understanding of the in vivo functions of presenilins. In this review, the authors will summarize the current understanding of presenilin function, with an emphasis on the mammalian cerebral cortex. During development, presenilins play crucial roles in the maintenance of neural progenitor cell proliferation, the temporal control of neuronal differentiation, the survival of Cajal-Retzius neurons, and proper neuronal migration in the developing cerebral cortex. Analysis of presenilin function in the adult cerebral cortex has revealed essential roles for presenilins in synaptic plasticity, long-term memory, and neuronal survival. The authors will also discuss the molecular mechanisms through which presenilins may mediate these functions, including the Notch, CREB, and NMDA receptor-mediated signaling pathways. These diverse functions of presenilins in cortical development and function and neuronal survival have important implications for the pathogenesis of neurodegenerative dementia.