Alzheimer's disease (AD), like many other neurodegenerative diseases, is characterized by nuclear envelope fragmentation. Based on a mouse AD model, nuclear fragmentation is initiated by phosphorylation of nuclear lamins by p25-activated CDK5. The CDK5:p25 complex phosphorylates lamin A (LMNA-1) at serine residues S22 and S392, with S392 being the major CDK5 target site. Nuclear envelope fragmentation increases access of the CDK5:p25 complex to nuclear proteins and precedes neuronal death (Chang et al. 2011).