Apoptosis may represent a prominent form of neuronal death in chronic neurodegenerative disorders, such as Alzheimer’s disease. Although apoptosis under mitochondrial control has received considerable attention, mechanisms used within the endoplasmic reticulum (ER) and nucleus in mediating apoptotic signals are not well understood. A growing body of evidence is emerging from different studies which suggests an active role for the ER in regulating apoptosis. Disturbances of ER function have been shown to trigger two different apoptotic pathways; one involves cross-talk with mitochondria and is regulated by the antiapoptotic Bcl-2, and the second is characterized by the activation of caspase-12. Also, stress in the ER has been suggested to result in the activation of a number of proteins, such as gadd 153 and NF-k, and in the downregulation of the antiapoptotic protein, Bcl-2. In the present study, the intracisternal injection in aged rabbits of either the neurotoxin aluminum maltolate or of Ab(1-42), has been found to induce nuclear translocation of gadd 153 and the inducible transcription factor, NF-kB. Translocation of these two proteins is accompanied by decreased levels of Bcl-2 in both the ER and the nucleus. Aluminum maltolate, but not Ab, induces caspase-12 activation which is a mediator of ER-specific apoptosis; this is the first report of the in vivo activation of caspase-12. These findings indicate that the ER may play a role in regulating apoptosis in vivo, and could be of significance in the pathology of neurodegeneration and related disorders.