Mutations in presenilin 1 (PS1) are linked to early-onset familial Alzheimer’s disease (FAD). Previous results show that PS1 associates with the neuronal cytoskeleton (Pigino et al., Abs. SFN, 1998;24:470) and that it binds to microtubule-associated proteins Tau and GSK-3ß (Takashima et al., PNAS, 1998, 95:9637). Biochemical analysis of hippocampal cultures revealed that the association of PS1 with the cytoskeleton increased dramatically after the first week in culture. This event correlated closely with an increase in the number of neuronal contacts, increased translocation of Notch 1 intracellular domain (NICD) to neuronal nuclei and a marked reduction of neurite growth. Neurons transfected at day 7 with PS1 mutations M146V, I143T and Δ9 showed a marked reduction in cytoskeletal binding, reduced levels of nuclear NICD and longer processes than PS1wt-transfected cells. In younger neurons (3 DIV) devoid of cellular contacts and bearing fast-growing axons the overexpression of PS1wt significantly increased ...