Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

Racchi, Marco; Mazzucchelli, Michela; Pascale, Alessia; Sironi, M; Govoni, Stefano

doi:10.1038/sj.mp.4001204

Cited by 39 publications

(41 citation statements)

References 36 publications

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“…7A and B). As expected, an increased sAPP␣ secretion was observed when PKC was activated by phorbol-12-myristate-13 acetate (PMA) (35). These results suggest that the ␦OR-Cys27 expression-induced, agonist-independent, increase in the APP C83 levels is related to disturbances in a constitutive cellular process(es) rather than to PKC-dependent or -independent induction of the nonamyloidogenic APP processing described for several other GPCRs upon agonist-mediated activation (8,29,30).…”

Section: Resultssupporting

confidence: 52%

Cysteine 27 Variant of the δ-Opioid Receptor Affects Amyloid Precursor Protein Processing through Altered Endocytic Trafficking

Sarajärvi

Tuusa

Haapasalo

et al. 2011

Molecular and Cellular Biology

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Agonist-induced activation of the ␦-opioid receptor (␦OR) was recently shown to augment ␤-and ␥-secretase activities, which increased the production of ␤-amyloid peptide (A␤), known to accumulate in the brain tissues of Alzheimer's disease (AD) patients. Previously, the ␦OR variant with a phenylalanine at position 27 (␦OR-Phe27) exhibited more efficient receptor maturation and higher stability at the cell surface than did the less common cysteine (␦OR-Cys27) variant. For this study, we expressed these variants in human SH-SY5Y and HEK293 cells expressing exogenous or endogenous amyloid precursor protein (APP) and assessed the effects on APP processing. Expression of ␦OR-Cys27, but not ␦OR-Phe27, resulted in a robust accumulation of the APP C83 C-terminal fragment and the APP intracellular domain, while the total soluble APP and, particularly, the ␤-amyloid 40 levels were decreased. These changes upon ␦OR-Cys27 expression coincided with decreased localization of APP C-terminal fragments in late endosomes and lysosomes. Importantly, a long-term treatment with a subset of ␦OR-specific ligands or a c-Src tyrosine kinase inhibitor suppressed the ␦OR-Cys27-induced APP phenotype. These data suggest that an increased constitutive internalization and/or concurrent signaling of the ␦OR-Cys27 variant affects APP processing through altered endocytic trafficking of APP.Alzheimer's disease (AD) is the most common neurodegenerative disorder in the aging population. It is neuropathologically characterized by well-known hallmarks, such as extracellular amyloid plaques and intraneuronal neurofibrillary tangles, composed of ␤-amyloid peptide (A␤) and hyperphosphorylated tau, respectively. A␤ is generated from the amyloid precursor protein (APP) after sequential cleavages by ␤ (BACE1)-and ␥-secretases. It is a well-established fact that the molecular mechanisms underlying AD pathogenesis involve alterations in APP processing which lead to increased A␤ production or, alternatively, decreased enzymatic degradation and clearance of A␤ (39). To facilitate the design of novel intervention approaches for AD, it is important to identify and functionally characterize genetic alterations which play a role in AD pathogenesis. A plausible candidate in this context is the OPRD1 gene, encoding the ␦-opioid receptor (␦OR), which was recently shown to form a complex with ␤-and ␥-secretases (28, 40). Following agonist-induced activation, ␦OR mediates coendocytic sorting of this complex to late endosomes and lysosomes (LEL) (28,40), in which compartments A␤ production primarily takes place. Conversely, ␤-and ␥-secretase activities as well as A␤ levels were found to be significantly reduced in transgenic APP/PS1⌬E9 mice (overexpressing human APP with the Swedish mutation together with human presenilin-1 harboring the exon 9 deletion) treated with a selective nonpeptide antagonist for ␦OR (40). These results suggest that the amyloidogenic processing of APP is enhanced upon ␦OR activation and that the selective antagonist-mediated modulation of ␦OR ma...

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Section: Resultssupporting

confidence: 52%

Cysteine 27 Variant of the δ-Opioid Receptor Affects Amyloid Precursor Protein Processing through Altered Endocytic Trafficking

Sarajärvi

Tuusa

Haapasalo

et al. 2011

Molecular and Cellular Biology

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“…On the other hand, GM1 has been reported to have an inhibitory action on PKC and sAPPa is positively regulated by PKC activation. [40][41][42] GM1 may inhibit sAPPa secretion by inhibiting the PKC activity. Both hypotheses require and deserve further experimental work.…”

Section: Discussionmentioning

confidence: 99%

GM1 ganglioside regulates the proteolysis of amyloid precursor protein

et al. 2004

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Plaques containing amyloid b-peptides (Ab) are a major feature in Alzheimer's disease (AD), and GM1 ganglioside is an important component of cellular plasma membranes and especially enriched in lipid raft. GM1-bound Ab (GM1/Ab), found in brains exhibiting early pathological changes of AD including diffuse plaques, has been suggested to be involved in the initiation of amyloid fibril formation in vivo by acting as a seed. However, the role of GM1 in amyloid bprotein precursor (APP) processing is not yet defined. In this study, we report that exogenous GM1 ganglioside promotes Ab biogenesis and decreases sAPPa secretion in SH-SY5Y and COS7 cells stably transfected with human APP695 cDNA without affecting full-length APP and the sAPPb levels. We also observe that GM1 increases extracellular levels of Ab in primary cultures of mixed rat cortical neurons transiently transfected with human APP695 cDNA. These findings suggest a regulatory role for GM1 in APP processing pathways. Molecular Psychiatry (2004) 9, 946-952.

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“…Direct and indirect receptor-mediated activation of PKC has been shown to increase the release of sAPPα and reduce the secretion of β-amyloid peptides. Experimental evidence suggests that specific isoforms of PKC, such as PKCα and PKCε, are involved in the regulation of APP metabolism [4]. Moreover, PKC messenger pathways have been shown to be involved in regulating the non-amyloidogenic processing of APP [34,35], although not through APP phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…Many recent findings have demonstrated that there is a strong relationship between the protein kinase C (PKC) isozyme-signalling deficits and the transduction mechanisms related to the regulation of the amyloid precursor protein (APP) metabolism [4,5]. Furthermore, several reports seem to indicate that AChEIs may affect the secretory processes of APP via activation of both PKC, especially PKCα, and mitogen-activated protein kinase (MAPK) [6,7,8].…”

Section: Introductionmentioning

confidence: 99%

Huprine X and Huperzine A Improve Cognition and Regulate Some Neurochemical Processes Related with Alzheimer’s Disease in Triple Transgenic Mice (3xTg-AD)

et al. 2012

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Background: Different studies have established that cholinergic neurodegeneration could be a major pathological feature of Alzheimer’s disease (AD). Thus, enhancement of the central cholinergic neurotransmission has been regarded as one of the most promising strategies for the symptomatic treatment of AD, mainly by means of reversible acetylcholinesterase inhibitors (AChEIs). The cognitive-enhancing properties of both huprine X, a new AChEI, and the structurally related huperzine A, as well as their effects on the regulation of several neurochemical processes related to AD have been studied in triple transgenic mice (3xTg-AD). Methods: Seven-month-old homozygous 3xTg-AD male mice, which received chronic intraperitoneal treatment with either saline, huprine X (0.12 µmol·kg^–1) or huperzine A (0.8 µmol·kg^–1) were subjected to a battery of behavioural tests after 3 weeks of treatment and thereafter the brains were dissected to study the neurochemical effects induced by the two AChEIs. Results: Treatments with huprine X and huperzine A improved learning and memory in the Morris water maze and some indicators of emotionality without inducing important adverse effects. Moreover, huprine X and huperzine A activate protein kinase C/mitogen-activated protein kinase pathway signalling, α-secretases (ADAM 10 and TACE) and increase the fraction of phospho-glycogen synthase kinase 3-β. Conclusion: Results obtained herein using a sample of 3xTg-AD animals strongly suggest that the treatment with the two AChEIs not only improves the cognitive performance of the animals but also induces some neurochemical changes that could contribute to the beneficial effects observed.

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Role of protein kinase Cα in the regulated secretion of the amyloid precursor protein

Cited by 39 publications

References 36 publications

Cysteine 27 Variant of the δ-Opioid Receptor Affects Amyloid Precursor Protein Processing through Altered Endocytic Trafficking

Cysteine 27 Variant of the δ-Opioid Receptor Affects Amyloid Precursor Protein Processing through Altered Endocytic Trafficking

GM1 ganglioside regulates the proteolysis of amyloid precursor protein

Huprine X and Huperzine A Improve Cognition and Regulate Some Neurochemical Processes Related with Alzheimer’s Disease in Triple Transgenic Mice (3xTg-AD)

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