Developmental Regulation of Presenilin-1 Processing in the Brain Suggests a Role in Neuronal Differentiation

Abstract

Most cases of early-onset familial Alzheimer's disease are caused by mutations in the presenilin genes. Presenilin-1 (PS1) is subject to proteolytic cleavage resulting in the accumulation of N- and C-terminal fragments. In this report, we show that the proteolytic cleavage of PS1 is developmentally regulated in the brain. Low levels of full-length PS1 and higher levels of 30-kDa N-terminal and 20-kDa C-terminal fragments are identified at all developmental stages in the rat brain. However, in the adult brain, additional 36-kDa N-terminal and 14-kDa C-terminal fragments appear and become major PS1 species. Alternative N-terminal PS1 fragments also appear in the adult human brain, but are more heterogenous than in the rat brain. The alternative PS1 fragments are not detected at significant levels in rat or human peripheral tissues that express PS1. The alternative cleavage of PS1 is also detected in primary cultures of rat hippocampal neurons, but not in astrocytes, and is induced by neuronal differentiation. Furthermore, alternative PS1 cleavage is detected in rat PC12 cells and human neuroblastoma SH-SY5Y cells following induction of neuronal differentiation. These results suggest that an alternative pathway of PS1 proteolytic processing is induced in the brain by neuronal differentiation. PS1 may therefore play an important role in brain development and neuronal function, which may relate to the brain-specific pathological effects of PS1 mutations.