Cholinergic agonists stimulate secretion of soluble full-length amyloid precursor protein in neuroendocrine cells.

Efthimiopoulos, Spiros; Vassilacopoulou, Dido; Ripellino, James A.; Tezapsidis, Nikolaos; Robakis, Nikolaos K.

doi:10.1073/pnas.93.15.8046

Cited by 62 publications

(58 citation statements)

References 46 publications

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“…The release of full-length APP was also demonstrated to be stimulated by cholinergic agonists (52). These data, together with the data from this study, show that APP and its catabolites can be released associated with exosomes and that this process is likely modulated by several parameters.…”

Section: Discussionsupporting

confidence: 48%

“…These APP fragments are also co-sedimented with markers of exosomes at a sucrose density corresponding to that described for exosomes (50,51). The presence of soluble full-length APP in the medium was demonstrated previously in cells transfected with APP, but remained unexplained (52,53). Secretion of APP within exosomes is con- sistent with these observations and could be an explanation.…”

Section: Discussionmentioning

confidence: 95%

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Alkalizing Drugs Induce Accumulation of Amyloid Precursor Protein By-products in Luminal Vesicles of Multivesicular Bodies

Vingtdeux

Hamdane

Loyens

et al. 2007

Journal of Biological Chemistry

178

166

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Amyloid precursor protein (APP) metabolism is central to the pathogenesis of Alzheimer disease. We showed recently that the amyloid intracellular domain (AICD), which is released by ␥-secretase cleavage of APP C-terminal fragments (CTFs), is strongly increased in cells treated with alkalizing drugs (Vingtdeux, V., Hamdane, M., Bégard, S., Loyens, A., Delacourte, A., Beauvillain, J.-C., Buée, L., Marambaud, P., and Sergeant, N. Amyloid precursor protein (APP)3 metabolism is central to Alzheimer disease etiopathogenesis. Extracellular amyloid deposits, a neuropathological hallmark of Alzheimer disease, are composed of amyloid-␤ (A␤) peptides that derive from APP catabolism. APP is a type I transmembrane glycoprotein processed by an ␣-or a ␤-secretase to produce C-terminal fragments (CTFs) (for review, see Ref. 1). ␥-Secretase further processes APP-CTFs (2, 3), releasing A␤ from ␤-CTF and the amyloid intracellular domain (AICD or ⑀-CTF) from all APP-CTFs (2, 4 -8). Several lines of evidence suggest that AICD is a trans-regulating factor of gene expression (neprilysin, KAI1, APP, and glycogen synthase kinase-3␤) (9 -12). However, AICD is rapidly degraded and thus seldom detected (13). We showed recently that AICD is strongly increased upon treatment with alkalizing drugs, suggesting that the endosomal/lysosomal pathway regulates AICD degradation (14).The endosomal/lysosomal pathway is essential for A␤ production and APP catabolism. For instance, BACE-1 (beta-site APP-cleaving enzyme 1) resides within endosomes, and endocytosis of BACE-1 and APP is a prerequisite for generating A␤ (15-17). An acidic pH is necessary for optimal BACE-1 protease activity (18), and BACE-1 is degraded in lysosomes (19). The ␥-secretase activity has been localized at the endosomal/ lysosomal membrane (20 -23). Treatment with drugs that prevent endosomal/lysosomal acidification (24 -26) or deletion of the APP internalization motif (27, 28) dramatically reduces A␤ secretion.The endosomal/lysosomal system is likely to be altered in Alzheimer disease (for review, see Ref. 29). Several APP derivatives accumulate in multivesicular bodies (MVBs), in transgenic animal models of amyloidosis (30, 31), in Alzheimer disease (30), and in cell models (32). MVBs belong to the endocytic pathway (33); are at the crossroad of several cellular mechanisms such as membrane receptor recycling and protein degradation; and can release their intraluminal vesicles, known as exosomes (for review, see Refs. 34 -36). More recently, exosomes were demonstrated to contain A␤ peptides (37). Taken together, a growing body of evidence suggests that APP processing takes place mainly between the plasma membrane and late endosomal compartments such as multivesicular endosomes. Herein, we studied the localization of APP and its derivatives in SY5Y neuroblastoma cells stably overexpressing human APP and demonstrate that APP, APP-CTFs, and AICD accumulate in the luminal vesicles of multivesicular endosomes and are also found in exosomes.

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Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 95%

Alkalizing Drugs Induce Accumulation of Amyloid Precursor Protein By-products in Luminal Vesicles of Multivesicular Bodies

Vingtdeux

Hamdane

Loyens

et al. 2007

Journal of Biological Chemistry

178

166

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“…Although it is clear that M1 and M3 receptors (muscarinic acetylcholine receptors) activate protein kinase C (PKC), augment production of nonamyloidogenic fragments of APP, and inhibit A␤ production, some studies have shown that nAChRs can also influence APP metabolism and toxicity (for review see Roberson and Harrell, 1997;Auld et al, 1998). Activation of nAChRs has been shown to increase the secretion of nonamyloidogenic fragments of APP from PC12 cells, an effect that requires extracellular Ca 2ϩ (Efthimiopoulos et al, 1996;Kim et al, 1997). It is therefore possible that cholinergic transmission influences APP metabolism via both muscarinic and nicotinic receptors.…”

Section: Neuronal Nachrs and Neuroprotectionmentioning

confidence: 99%

Nicotinic receptors in aging and dementia

2002

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Activation of neuronal nicotinic acetylcholine receptors (nAChRs) has been shown to maintain cognitive function following aging or the development of dementia. Nicotine and nicotinic agonists have been shown to improve cognitive function in aged or impaired subjects. Smoking has also been shown in some epidemiological studies to be protective against the development of neurodegenerative diseases. This is supported by animal studies that have shown nicotine to be neuroprotective both in vivo and in vitro. Treatment with nicotinic agonists may therefore be useful in both slowing the progression of neurodegenerative illnesses, and improving function in patients with the disease. While increased nicotinic function has been shown to be beneficial, loss of cholinergic markers is often seen in patients with dementia, suggesting that decreased cholinergic function could contribute to both the cognitive deficits, and perhaps the neuronal degeneration, associated with dementia. In this article we will review the literature on each of these areas. We will also present hypotheses that might address the mechanisms underlying the ability of nAChR function to protect against neurodegeneration or improve cognition, two potentially distinct actions of nicotine.

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“…A single chain antibody fragment engineered from a catalytic V L domain degraded APP (31), highlighting the risk of interference in APP function. Intact, fulllength APP is found physiologically in two forms: the membrane-bound form and the soluble, secreted form (32,33). nIgV 2E6 did not digest the purified soluble APP substrate detectably (Fig.…”

Section: Igv 2e6 Hydrolytic Properties-recombinantmentioning

confidence: 99%

Specific Amyloid β Clearance by a Catalytic Antibody Construct

Planque

Nishiyama

Sonoda

et al. 2015

Journal of Biological Chemistry

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Background: Naturally occurring catalytic antibodies (catabodies) can hydrolyze peptide bonds. Results: A catabody engineered from innate immunity principles hydrolyzed amyloid ␤ (A␤) specifically, dissolved A␤ aggregates, and cleared brain A␤ deposits without evident toxicity. Conclusion:The catabody could potentially be developed as a therapy for Alzheimer disease. Significance: The innate catabody repertoire may be a source of useful catabodies to toxic amyloids.

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Cholinergic agonists stimulate secretion of soluble full-length amyloid precursor protein in neuroendocrine cells.

Cited by 62 publications

References 46 publications

Alkalizing Drugs Induce Accumulation of Amyloid Precursor Protein By-products in Luminal Vesicles of Multivesicular Bodies

Alkalizing Drugs Induce Accumulation of Amyloid Precursor Protein By-products in Luminal Vesicles of Multivesicular Bodies

Nicotinic receptors in aging and dementia

Specific Amyloid β Clearance by a Catalytic Antibody Construct

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