Expression of presenilin-1 and notch-1 receptor in human embryonic CNS

In vitro studies have shown that the Alzheimer's disease-related presenilin -1 protein can mediate Notch-1 receptor cleavage during signalling. In the present study, we compared the distribution of presenilin-1 and Notch-1 rec eptor immunoreactivities in human embryonic CNS tissue during the first tri mester of development. Our aim was to gain insight into whether these prote ins are likely to interact functionally during human fetal brain developmen t. CNS material was obtained from routine abortions, cryosectioned and stud ied by means of immunohistochemistry with antibodies to presenilin-1 and No tch-1. At very early stages of embryonic development (four to five gestatio nal weeks) intensive presenilin-1 immunoreactivity could be seen predominan tly in neurites in the ventral horn of the spinal cord, where it overlapped with 200-kDa neurofilament immunoreactivity. Presenilin-1 immunoreactivity was also seen in neuroblasts of the ventricular zone of the tel- and mesen cephalon, as well as of the brainstem. Notch-1 receptor appeared in neurona l and ependymal cells throughout the CNS. Seven- to eight-week CNS tissue s howed similar patterns of presenilin-1 and Notch-1 receptor expression in t he spinal cord and cerebral cortex as was seen at five weeks. Both proteins were localised in the neuroepithelial cell layer lining the ventricles, as well as in the cortical plate layer, where immunoreactivity was seen in th e cell bodies. In addition, presenilin-1 immunoreactivity was seen in thin neurites in the subplate of the developing cortex. At 10 weeks, presenilin- 1 immunoreactivity was reduced in the spinal cord. These results show that, although presenilin-1 and Notch-1 receptor are localised to the same diffe rentiating cell populations in the human cerebral cortex, making a direct i nteraction possible, these proteins are otherwise confined to different neu rons or neuronal compartments, suggesting a role for presenilin-1 during ea rly CNS differentiation that does not involve Notch-1 receptor processing. Double staining for presenilin-1 in the endoplasmic reticulum and presenili n-1 in the Golgi showed overlap to some extent in investigated CNS regions, but not in neurites. This suggests that presenilin-1 function during neuro genesis is not exclusively correlated to protein processing within the endo plasmic reticulum and Golgi, but that presenilin-1 may also be involved in other processes, such as axonal and dendritic outgrowth or synaptic formati on. In summary, our findings provide supportive evidence that the presenilin-1 protein is involved in the development and maturation of;he human fetal CNS . The presence of presenilin-1 immunoreactivity in both the cell bodies and neurites of developing neurons strongly suggests divergent mechanisms of f unction for presenilin-1 during human brain development. These may include interactions with any of the Notch receptor proteins, as well as Notch-inde pendent mechanisms. (C) 2001 IBRO. Published by Elsevier Science Ltd. All r ights reserved.