CELLULAR EXPRESSION AND PROTEOLYTIC PROCESSING OF PRESENILIN PROTEINSIS DEVELOPMENTALLY-REGULATED DURING NEURONAL DIFFERENTIATION

We have determined the expression of the Alzheimer's disease-associate d proteins presenilin-1 and presenilin-2 in primary cultures of rat hi ppocampal neurons. Neurons highly express presenilin-1 and presenilin- 2, whereas both proteins were not detected in astrocytes. Further, we have analyzed the subcellular localization and expression in rat hippo campal neurons during development. Although presenilin proteins were l ocalized predominantly to the endoplasmic reticulum in nonneuronal cel ls transfected with presenilin cDNAs, in neurons, presenilin proteins were also found in compartments not staining with antibodies to grp78( BiP). Presenilin-1 and presenilin-2 were predominantly detected in ves icular structures within the somatodendritic compartment with much les s expression in axons. Polarized distribution of presenilin-1 and pres enilin-2 differs slightly, with more presenilin-2 expressed in axons c ompared with presenilin-1. Presenilin expression was found to be devel opmentally regulated. Presenilin expression strongly increased during neuronal differentiation until full morphological polarization and the n declined. No full-length presenilin-1 or presenilin-2 could be detec ted within cell lysates. At early developmental stages the expected si milar to 34-kDa N-terminal proteolytic fragment of presenilin-1 and th e similar to 38-kDa fragment of presenilin-2 were detected. Later duri ng differentiation we predominantly detected a similar to 38-kDa fragm ent for presenilin-1 and a similar to 42-kDa fragment for presenilin-2 . By epitope mapping, we show that these slower migrating peptides rep resent N-terminal proteolytic fragments, cleaved C-terminal to the con ventional site of processing. it is noteworthy that both presenilin-1 and presenilin-2 undergo alternative proteolytic cleavage at the same stage of neuronal differentiation. Regulation of presenilin expression and proteolytic processing might have implications for the pathologic al as well as the biological function of presenilins during aging in t he human brain.