ENRICHMENT OF PRESENILIN-1 PEPTIDES IN NEURONAL LARGE DENSE-CORE AND SOMATODENDRITIC CLATHRIN-COATED VESICLES

Presenilin 1 is an integral membrane protein specifically cleaved to y ield an N-terminal and a C-terminal fragment, both membrane-associated . More than 40 presenilin 1 mutations have been linked to early-onset familial Alzheimer disease, although the mechanism by which these muta tions induce the Alzheimer disease neuropathology is not clear. Presen ilin 1 is expressed predominantly in neurons, suggesting that the fami lial Alzheimer disease mutants may compromise or change the neuronal f unction(s) of the wild-type protein. To elucidate the function of this protein, we studied its expression in neuronal vesicular systems usin g as models the chromaffin granules of the neuroendocrine chromaffin c ells and the major categories of brain neuronal vesicles, including th e small clear-core synaptic vesicles, the large dense-core vesicles, a nd the somatodendritic and nerve terminal clathrin-coated vesicles. Bo th the N- and C-terminal presenilin 1 proteolytic fragments were great ly enriched in chromaffin granule and neuronal large dense-core vesicl e membranes, indicating that these fragments are targeted to these ves icles and may regulate the large dense-core vesicle-mediated secretion of neuropeptides and neurotransmitters at synaptic sites, The preseni lin 1 fragments were also enriched in the somatodendritic clathrin-coa ted vesicle membranes, suggesting that they are targeted to the somato dendritic membrane, where they may regulate constitutive secretion and endocytosis. In contrast, these fragments were not enriched in the sm all clear-core synaptic vesicle or in the nerve terminal clathrin-coat ed vesicle membranes. Taken together, our data indicate that presenili n 1 proteolytic fragments are targeted to specific populations of neur onal vesicles where they may regulate vesicular function. Although ful l-length presenilin 1 was present in crude homogenates, it was not det ected in any of the vesicles studied, indicating that, unlike the pres enilin fragments, full-length protein may not have a vesicular functio n.