Faculty Bibliography

Neurofibrillary tangles, composed of tau proteins, are a key lesion observed in sporadic forms of Alzheimer's disease and in familial forms associated with mutations of presenilin-1 (PS1). We have generated a double transgenic mouse line expressing a human tau isoform and a mutated form of PS1 (M146L) in neurons. Increased expression of the PS1 holoprotein was observed in the tau/PS1 transgenic mice and the proteolytic fragments of PS1 did not appear to be modified. A somatodendritic accumulation of the transgenic tau and an increase in tau phosphorylation were observed in both tau- and tau/PS1 transgenic mice. Neurofibrillary tangles were not observed in animals analyzed up to 17 months. Immunoprecipitation of tau from brain homogenates demonstrated its binding with active glycogen synthase kinase-3beta in control, tau- and tau/PS1 transgenic lines. These results suggest that overexpression of this Alzheimer mutant PS1 in vivo is not by itself sufficient to induce the formation of neurofibrillary tangles, even in neurons co-expressing and accumulating a human tau isoform

Immunohistochemical investigation of the post-translational processing of chromogranin A (CgA) to generate WE-14 in the sympathoadrenal cell lineage of the developing porcine fetus (F) detected intense CgA and weak WE-14 immunoreactivity in migrating neuroblast cells of the diffuse sympathetic ganglia adjacent to the dorsal aorta and projecting toward the cortical mass at F24-27. F37-42; WE-14 immunoreactivity was detected in chromaffinoblasts at the periphery of the developing cortex and at F54-56 days gestation WE-14 immunoreactivity was detected in a large population of central medullary cells. From F74 to F76 days and thereafter the number of cells exhibiting intense WE-14 immunostaining decreased, and the majority of chromaffin cells exhibited uniform weak WE-14 immunostaining. At postnatal day 1 (P1) intense WE-14 immunoreactivity was primarily confined to clusters of chromaffin cells with weak immunostaining in the general population. The transitory neuroblasts, chromaffinoblasts, and maturing chromaffin cell population exhibited uniform intense CgA immunostaining through gestation and after birth. Additional observations detected intense CgA and WE-14 immunostaining in extrachromaffin tissue at P1 and in neuronal-like cells in vessels of the aortic arch at F37. This study has demonstrated that CgA is post-translationally processed to generate WE-14 during early fetal development in the migrating progenitor cells of the porcine sympathoadrenal lineage