Alzheimer's disease-associated presenilin 1 in neuronal cells: Evidence for localization to the endoplasmic reticulum-Golgi intermediate compartment

Culvenor, Janetta G.; Maher, Frances A.; Evin, Geneviève; Malchiodi-Albedi, Fiorella; Cappai, Roberto; Underwood, John R.; Davis, John B.; Karran, Eric; Roberts, Gareth W.; Beyreuther, Konrad; Masters, Colin L.

doi:10.1002/(sici)1097-4547(19970915)49:6<719::aid-jnr6>3.0.co;2-a

Cited by 72 publications

(46 citation statements)

References 48 publications

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“…Immunofluorescence labeling indicated localization of PS1 to endoplasmic reticulum-Golgi apparatus compartments and at the plasma membrane ( Fig. 2A), a finding consistent with previous reports by us and others (11,26,31). AChE staining appeared contiguous with that of PS1, being very intense in the perinuclear region and at the plasma membrane, and diffuse throughout the cytoplasm (Fig.…”

Section: Resultssupporting

confidence: 91%

Presenilin 1 Interacts with Acetylcholinesterase and Alters Its Enzymatic Activity and Glycosylation

Silveyra

Evin

Montenegro

et al. 2008

Molecular and Cellular Biology

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Presenilin 1 (PS1) plays a critical role in the ␥-secretase processing of the amyloid precursor protein to generate the ␤-amyloid peptide, which accumulates in plaques in the pathogenesis of Alzheimer's disease (AD). Mutations in PS1 cause early onset AD, and proteins that interact with PS1 are of major functional importance. We report here the coimmunoprecipitation of PS1 and acetylcholinesterase (AChE), an enzyme associated with amyloid plaques. Binding occurs through PS1 N-terminal fragment independent of the peripheral binding site of AChE. Subcellular colocalization of PS1 and AChE in cultured cells and coexpression patterns of PS1 and AChE in brain sections from controls and subjects with sporadic or familial AD indicated that PS1 and AChE are located in the same intracellular compartments, including the perinuclear compartments. A PS1-A246E pathogenic mutation expressed in transgenic mice leads to decreased AChE activity and alteration of AChE glycosylation and the peripheral binding site, which may reflect a shift in protein conformation and disturbed AChE maturation. In both the transgenic mice and humans, mutant PS1 impairs coimmunoprecipitation with AChE. The results indicate that PS1 can interact with AChE and influence its expression, supporting the notion of cholinergic-amyloid interrelationships.Alzheimer's disease (AD) is characterized by the presence of large numbers of amyloid plaques and neurofibrillary tangles in the brain (56). The major constituent of the amyloid plaques is the ␤-amyloid protein (A␤), a polypeptide generated by processing of a much larger amyloid precursor protein (APP) through the successive action of two proteolytic enzymes, ␤-secretase and ␥-secretase (71). ␥-Secretase is a membrane protease complex comprising presenilin 1 (PS1) as a catalytic subunit (76). The importance of PS was first highlighted by genetic studies of AD. Families bearing mutations in the PS1 gene, or in the highly homologous presenilin 2 (PS2) gene, invariably develop an aggressive form of early-onset AD with an accelerated rate of A␤ deposition (75).The accumulation of A␤ peptide in the brain is thought to be an important step in the pathogenesis of AD, leading to a number of neurodegenerative changes (19). In particular, there is a decrease in cholinergic activity in the basal forebrain of AD patients, which affects activity of the acetylcholinesynthesizing enzyme, choline acetyltransferase, as well as the acetylcholine-hydrolyzing enzyme, acetylcholinesterase (AChE) (13, 53). The altered expression of AChE in the AD-affected brain (AD brain) is of particular interest. Despite an overall decrease in the AD brain, the activity of AChE is increased around the amyloid plaques (42,78). This may be a direct consequence of amyloid deposition, since A␤ peptides influence AChE levels in cell cultures (25,69) and in the brains of transgenic mice that produce human A␤ (70). Conversely, AChE may play a role in A␤ fibrillogenesis (27,60). Finally, several investigations have argued for a strict interrelation b...

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Section: Resultssupporting

confidence: 91%

Presenilin 1 Interacts with Acetylcholinesterase and Alters Its Enzymatic Activity and Glycosylation

Silveyra

Evin

Montenegro

et al. 2008

Molecular and Cellular Biology

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“…This could also indicate the presence of PSs at the cell surface (Ray et al, 1999a;Kaether et al, 2002). By contrast, several groups have demonstrated that the bulk of PS immunoreactivity is distributed in the ER, intermediate compartment and to a certain extent into the early Golgi Culvenor et al, 1997;Lah et al, 1997). Since γ-secretase activity is believed to occur mainly in endosomes, Golgi and at the cell surface, some discrepancy still exists between the subcellular distribution of PS, which is the putative catalytic subunit, and the γ-secretase activity, agreeing with the 'spatial paradox' .…”

Section: Discussionmentioning

confidence: 96%

“…In any case, PSs are not capable of cleaving APP substrates without additional cofactors. For instance, while PSs are abundantly present in the endoplasmic reticulum (ER), the intermediate compartment and the cisGolgi Culvenor et al, 1997;Lah et al, 1997), they do not efficiently cleave an APP substrate that is specifically retained in these compartments (Cupers et al, 2001a;Maltese et al, 2001). Only after addition of brefeldin A are the APP substrates proteolyzed, indicating that other proteins or specific post-translational modifications of the γ-secretase complex in the Golgi apparatus are needed to trigger this proteolytic activity (Cupers et al, 2001a).…”

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confidence: 99%

γ-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation

Herreman

Gassen

Bentahir

et al. 2003

Journal of Cell Science

179

194

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Nicastrin and presenilin are two major components of the γ-secretase complex, which executes the intramembrane proteolysis of type I integral membrane proteins such as the amyloid precursor protein (APP) and Notch. Nicastrin is synthesized in fibroblasts and neurons as an endoglycosidase-H-sensitive glycosylated precursor protein (immature nicastrin) and is then modified by complex glycosylation in the Golgi apparatus and by sialylation in the trans-Golgi network (mature nicastrin). These modifications are not observed with exogenously overexpressed nicastrin. Under normal cell culture conditions, only mature nicastrin is expressed at the cell surface and binds to the presenilin heterodimers. Mature nicastrin has a half-life of more than 24 hours. In the absence of presenilin 1 and 2,nicastrin remains entirely endoglycosidase H sensitive, is retained in the endoplasmic reticulum and is slowly degraded. Single presenilin 1 or presenilin 2 deficiency affects glycosylation of nicastrin to a lesser extent than the combined presenilin deficiencies, suggesting a correlation between either the transport of nicastrin out of the endoplasmic reticulum or the concomitant complex glycosylation of nicastrin, and γ-secretase activity. However, when complex glycosylation of nicastrin was inhibited using mannosidase I inhibitors, γ-secretase cleavage of APP or Notch was not inhibited and the immature nicastrin still associates with presenilin and appears at the cell surface. Complex glycosylation of nicastrin is therefore not needed for γ-secretase activity. Because the trafficking of nicastrin to the Golgi apparatus is dependent on presenilins, our data point to a central role of presenilin in nicastrin maturation/localization, which could help to partially resolve the `spatial paradox'.

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“…A␤ also binds to the ERGIC marker protein ERGIC-53, which is involved in the calcium-dependent transport of glycoproteins such as APP from the ER to the Golgi intermediate compartment (111), where presenilin is located (112). Thus, ERGIC-53, like sortilin, may serve a transport function.…”

Section: Discussionmentioning

confidence: 99%

Protection against β-Amyloid-induced Apoptosis by Peptides Interacting with β-Amyloid

Nelson

Alkon

2007

Journal of Biological Chemistry

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␤-Amyloid peptide produces apoptosis in neurons at micromolar concentrations, but the mechanism by which ␤-amyloid exerts its toxic effect is unknown. The normal biological function of ␤-amyloid is also unknown. We used phage display, coprecipitation, and mass spectrometry to examine the proteinprotein interactions of ␤-amyloid in normal rabbit brain in order to identify the biochemical receptors for ␤-amyloid. ␤-Amyloid was found to bind primarily to proteins involved in low density lipoprotein and cholesterol transport and metabolism, including sortilin, endoplasmic reticulum-Golgi intermediate compartment 2 (ERGIC2), ERGIC-53, steroid 5␣-reductase, and apolipoprotein B. ␤-Amyloid also bound to the C-reactive protein precursor, a protein involved in inflammation, and to 14-3-3, a protein that regulates glycogen synthase kinase-3␤, the kinase involved in tau phosphorylation. Of eight synthetic peptides identified as targets of ␤-amyloid, three were found to be effective blockers of the toxic effect of ␤-amyloid on cultured neuronal cells. These peptides bound to the hydrophobic region (residues 17-21) or to the nearby protein kinase C pseudo-phosphorylation site (residues 26 -30) of ␤-amyloid, suggesting that these may be the most critical regions for ␤-amyloid effector action and for aggregation. Peptides or other small molecules that bind to this region may protect against ␤-amyloid toxic effect by competitively blocking its ability to bind ␤-amyloid effector proteins such as sortilin and 14-3-3.

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Alzheimer's disease-associated presenilin 1 in neuronal cells: Evidence for localization to the endoplasmic reticulum-Golgi intermediate compartment

Cited by 72 publications

References 48 publications

Presenilin 1 Interacts with Acetylcholinesterase and Alters Its Enzymatic Activity and Glycosylation

Presenilin 1 Interacts with Acetylcholinesterase and Alters Its Enzymatic Activity and Glycosylation

γ-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation

Protection against β-Amyloid-induced Apoptosis by Peptides Interacting with β-Amyloid

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