Identification and neuron specific expression of the S182/presenilin I protein in human and rodent brains

Elder, Gregory A.; Tezapsidis, Nikolaos; Carter, J.; Shioi, Junichi; Bouras, Constantin; Li, H.-C.; Johnston, Jane M.; Efthimiopoulos, Spiros; Friedrich, Victor L.; Robakis, Nikolaos K.

doi:10.1002/(sici)1097-4547(19960801)45:3<308::aid-jnr13>3.0.co;2-#

Cited by 93 publications

(43 citation statements)

References 18 publications

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“…Rat brain preparations of SCCSVs or NTCCVs were not enriched in the PSi fragments, suggesting that PSi peptides are not targeted to these vesides. In contrast, these fragments were present in rat PCi2 CCVs, suggesting that PSi peptides are specifically targeted to neuronal somatodendritic vesicles, in agreement with previous work from this (Elder et al, 1996) and other laboratories (Cook et al, 1996;Busciglio et al, 1997;Weber et al, 1997), showing that PSi antigens are expressed in the somatodendritic compartment of neurons. We did not detect full-length PS 1 in any of these vesicular preparations, although full-length PSi was clearly detected in crude homogenates (Fig.…”

Section: Discussionsupporting

confidence: 91%

“…7). This suggestion is supported further by the high PSi reactivity in the somatodendritic neuronal area and the low PS 1 reactivity in axons (Elder et al, 1996). Combined, these observations suggest that APP and PSi may interact on the somatodendritic neuronal surface and/or in the somatodendritic endocytic vesicles rather than on the axons or in presynaptic terminals.…”

Section: Discussionmentioning

confidence: 70%

“…PSi is neither glycosylated nor sulfated; however, there is some evidence that it is phosphorylated (De Strooper et al, 1997). Several groups reported the existence of a fulllength PSi peptide in brain tissue (Elder et al, 1996;Mercken et al, i996;Busciglio 1997;Weber et al, 1997;Wisiniewski et al, i997), although other investigators detected only PSi proteolytic fragments in this tissue (Thinakaran et al,i996;Seeger et al,i997). It has been hypothesized that PSi fragments have specific functions distinct from that of full-length PS!, and that the PSi FAD mutations may cause AD by altering the proteolytic processing of the full-length protein .…”

mentioning

confidence: 98%

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

Efthimiopoulos

Floor

Georgakopoulos

et al. 1998

Journal of Neurochemistry

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 70%

mentioning

confidence: 98%

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

Efthimiopoulos

Floor

Georgakopoulos

et al. 1998

Journal of Neurochemistry

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“…On the other hand, we reported that transgenic mice expressing the FAD-linked PS1ΔE9 and PS1M146L variants driven by the ubiquitously active PrP-promoter, fail to exhibit EE-induced AHNPC proliferation or differentiation towards neuronal lineage, with no noticeable changes in these parameters in SH conditions compared to mice expressing hPS1WT [12]. In this regard, PS1 has been shown to be expressed endogenously in AHNPCs [24], neurons [25], cerebral vasculature [26], glia and oligodendrocytes [12,27]. Thus, while it seems reasonable that ubiquitous, PrP promoter-driven of mutant PSEN1 transgenes reflects the expression patterns of endogenous PSEN1 , there remain concerns regarding expression levels and regulation in specific CNS cell types.…”

Section: Discussionmentioning

confidence: 99%

Endogenous expression of FAD-linked PS1 impairs proliferation, neuronal differentiation and survival of adult hippocampal progenitors

Veeraraghavalu

Choi

Zhang

et al. 2013

Mol Neurodegeneration

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BackgroundAlzheimer’s disease (AD) is characterized by progressive memory loss and impaired cognitive function. Early-onset familial forms of the disease (FAD) are caused by inheritance of mutant genes encoding presenilin 1 (PS1) variants. We have demonstrated that prion promoter (PrP)-driven expression of human FAD-linked PS1 variants in mice leads to impairments in environmental enrichment (EE)-induced adult hippocampal neural progenitor cell (AHNPC) proliferation and neuronal differentiation, and have provided evidence that accessory cells in the hippocampal niche expressing PS1 variants may modulate AHNPC phenotypes, in vivo. While of significant interest, these latter studies relied on transgenic mice that express human PS1 variant transgenes ubiquitously and at high levels, and the consequences of wild type or mutant PS1 expressed under physiologically relevant levels on EE-mediated AHNPC phenotypes has not yet been tested.ResultsTo assess the impact of mutant PS1 on EE-induced AHNPC phenotypes when expressed under physiological levels, we exposed adult mice that constitutively express the PSEN1 M146V mutation driven by the endogenous PSEN1 promoter (PS1 M146V “knock-in” (KI) mice) to standard or EE-housed conditions. We show that in comparison to wild type PS1 mice, AHNPCs in mice carrying homozygous (PS1M146V/M146V) or heterozygous (PS1M146V/+) M146V mutant alleles fail to exhibit EE-induced proliferation and commitment towards neurogenic lineages. More importantly, we report that the survival of newborn progenitors are diminished in PS1 M146V KI mice exposed to EE-conditions compared to respective EE wild type controls.ConclusionsOur findings reveal that expression at physiological levels achieved by a single PS1 M146V allele is sufficient to impair EE-induced AHNPC proliferation, survival and neuronal differentiation, in vivo. These results and our finding that microglia expressing a single PS1 M146V allele impairs the proliferation of wild type AHNPCs in vitro argue that expression of mutant PS1 in the AHNPC niche impairs AHNPCs phenotypes in a dominant, non-cell autonomous manner.

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“…Several immunohistochemical studies of human, mouse, rat, and monkey brains show that PS is mainly recognized as cytoplasmic granular structures in neurons (Busciglio et al 1997;Calenda et al 1996;Chui et al 1998;Elder et al 1996;Giannakopoulos et al 1997;Kim et al 1997;Kimura et al 2001;Lah et al 1997;Uchihara et al 1996). These structures are associated with membranous organelles, such as endoplasmic reticulum and Golgi apparatus (Cook et al 1996;De Strooper et al 1997;Lah et al 1997;Murphy et al 1996;Walter et al 1996).…”

Section: Introductionmentioning

confidence: 99%

Presenilin-2 in the cynomolgus monkey brain: investigation of age-related changes

et al. 2004

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Localization of presenilin-2 (PS-2), a transmembrane protein implicated in early onset familial Alzheimer's disease, was examined in the brains of 30 cynomolgus monkeys aged 4 to 36 years. Anti-PS-2 antibody N20, which recognizes PS-2 amino acid residues 2-20, and anti-PS-2 antibody C20, which recognizes PS-2 amino acid residues 535-554, stained mainly the cytoplasm of large pyramidal neurons and large neurites. This finding was also confirmed by double immunohistochemical investigations using N20 or C20 and anti-NeuN antibody. In the brain of the oldest monkey, swollen neurites containing senile plaques were immunostained with C20, but not with N20. Western blot analyses of microsomal fractions isolated from the brains of three adult monkeys revealed that much less PS-2 was present compared to presenilin-1 (PS-1). Age-related assessment of PS-2 in brain homogenates from young and adult monkeys showed that PS-2 levels and PS-2 subcellular localization were unchanged with increasing age. Because PS-2 expression was much less robust than that of PS-1, we conclude that PS-2 mainly localizes to large neurons and does not show so drastic age-related changes as PS-1.

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Identification and neuron specific expression of the S182/presenilin I protein in human and rodent brains

Cited by 93 publications

References 18 publications

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

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

Endogenous expression of FAD-linked PS1 impairs proliferation, neuronal differentiation and survival of adult hippocampal progenitors

Presenilin-2 in the cynomolgus monkey brain: investigation of age-related changes

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