Enrichment of Presenilin 1 Peptides in Neuronal Large Dense‐Core and Somatodendritic Clathrin‐Coated Vesicles

Abstract

Presenilin 1 is an integral membrane protein specifically cleaved to yield 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 mutations induce the Alzheimer disease neuropathology is not clear. Presenilin 1 is expressed predominantly in neurons, suggesting that the familial Alzheimer disease mutants may compromise or change the neuronal function(s) of the wild‐type protein. To elucidate the function of this protein, we studied its expression in neuronal vesicular systems using as models the chromaffin granules of the neuroendocrine chromaffin cells and the major categories of brain neuronal vesicles, including the small clear‐core synaptic vesicles, the large dense‐core vesicles, and the somatodendritic and nerve terminal clathrin‐coated vesicles. Both the N‐ and C‐terminal presenilin 1 proteolytic fragments were greatly enriched in chromaffin granule and neuronal large dense‐core vesicle membranes, indicating that these fragments are targeted to these vesicles and may regulate the large dense‐core vesicle‐mediated secretion of neuropeptides and neurotransmitters at synaptic sites. The presenilin 1 fragments were also enriched in the somatodendritic clathrin‐coated vesicle membranes, suggesting that they are targeted to the somatodendritic membrane, where they may regulate constitutive secretion and endocytosis. In contrast, these fragments were not enriched in the small clear‐core synaptic vesicle or in the nerve terminal clathrin‐coated vesicle membranes. Taken together, our data indicate that presenilin 1 proteolytic fragments are targeted to specific populations of neuronal vesicles where they may regulate vesicular function. Although full‐length presenilin 1 was present in crude homogenates, it was not detected in any of the vesicles studied, indicating that, unlike the presenilin fragments, full‐length protein may not have a vesicular function.

Presenilin 1 and Cadherins: Stabilization of Cell-Cell Adhesion and Proteolysis-Dependent Regulation of Transcription

“…This explanation is in accordance with previous studies that attribute a role in protein trafficking to PS1 [46,47]. Consistent with this idea, Uemura et al [45] noticed that N-cadherin expression is reduced in cells expressing mutant PS1 (D385A) and the protein has an abnormally higher molecular weight compared to that in control cell lines.…”

Synaptic and Endosomal Localization of Active γ-Secretase in Rat Brain

“…Although the subcellular localization of Aβ in brain tissue has been found to be mainly endosomal [12], [13], it cannot be ruled out that this pool of Aβ was produced in another subcellular compartment and/or endocytosed from the extracellular space. The presenilins were the first γ-secretase components to be discovered and their subcellular localization has been determined in brain [14], [15], [16], [17], [18], [19]. Interestingly, besides the localization to different cell body compartments, presenilin was also found in synaptic compartments [14], [15], [17], [18].…”

Presenilin-1 Holoprotein is an Interacting Partner of Sarco Endoplasmic Reticulum Calcium-ATPase and Confers Resistance to Endoplasmic Reticulum Stress

“…PSEN1 also has γ-secretase-independent activities, such as neuroprotective and apoptotic effects [9][10][11], protein trafficking [12,13], modulation of cell-cell adhesion [14], and, recently, promotion of long-term potentiation (LTP) induced by presynaptic theta-burst stimulation, and glutamatergic neurotransmitter release [15]. It has also been proposed that presenilin holoprotein, but not their fragments, form passive endoplasmic reticulum (ER) calcium leak channels, and that loss of this function causes neurodegeneration that is independent of γ-secretase activity [16].…”