Release of Alzheimer Amyloid Precursor Derivatives Stimulated by Activation of Muscarinic Acetylcholine Receptors

Nitsch, Roger M.; Slack, Barbara E.; Wurtman, Richard J.; Growdon, John H.

doi:10.1126/science.1411529

Cited by 873 publications

(519 citation statements)

References 31 publications

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“…Expression of increasing amounts of 5-HT 4 R did not significantly affect total APP (APP band intensity/actin band intensity = 97 ± 4% of control, 96 ± 7%, 108 ± 13%, or 89 ± 18% for 25, 100, 250, or 500 ng of 5-HT 4 R cDNA respectively, n ≥ 3 per each group) or ADAM10 expression (intensity of ADAM10 bands/actin band intensity = 104 ± 5% of control, 96 ± 11%, 113 ± 18%, or 87 ± 21% for 25, Figure 1C) without affecting APP and ADAM10 levels (APP band intensity/ actin band intensity = 88 ± 19% of control, intensity of ADAM10 bands/actin band intensity = 111 ± 14% for 2.500 ng of 5-HT4R cDNA n ≥ 3 per each group). Expression of similar amounts of PAC 1 or muscarinic M 3 receptor, which both increase sAPPα release upon activation by their respective agonists, 22,23 failed to enhance sAPP release in HEK-293 cells in the absence of agonist ( Figure 1D). Moreover, comparative levels of overexpressed 5-HT6 receptor, another serotonin receptor positively coupled to the Gs/cAMP pathway, did not induce sAPP production ( Figure 1D).…”

mentioning

confidence: 96%

5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

Cochet

Donneger

Cassier

et al. 2012

ACS Chem. Neurosci.

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In addition to the amyloidogenic pathway, amyloid precursor protein (APP) can be cleaved by α-secretases, producing soluble and neuroprotective APP alpha (sAPPα) (nonamyloidogenic pathway) and thus preventing the generation of pathogenic amyloid-β. However, the mechanisms regulating APP cleavage by α-secretases remain poorly understood. Here, we showed that expression of serotonin type 4 receptors (5-HT 4 Rs) constitutively (without agonist stimulation) induced APP cleavage by the α-secretase ADAM10 and the release of neuroprotective sAPPα in HEK-293 cells and cortical neurons. This effect was independent of cAMP production. Interestingly, we demonstrated that 5-HT 4 receptors physically interacted with the mature form of ADAM10. Stimulation of 5-HT 4 receptors by an agonist further increased sAPPα secretion, and this effect was mediated by cAMP/Epac signaling. These findings describe a new mechanism whereby a GPCR constitutively stimulates the cleavage of APP by α-secretase and promotes the nonamyloidogenic pathway of APP processing. KEYWORDS: Alpha-secretase, Alzheimer's disease, sAPP alpha, serotonin A ccording to the amyloid hypothesis, alteration in synaptic transmission and neuronal loss observed in Alzheimer's disease (AD) mainly result from the formation of toxic amyloid-β (Aβ) oligomers followed by the extracellular accumulation of Aβ aggregates. Aβ is produced by the successive cleavage of a transmembrane amyloid precursor protein (APP) by β-secretase and γ-secretase. 1 In addition to this amyloidogenic pathway, APP can be cleaved by α-secretases, a set of membrane-bound proteases of the ADAM (A disintegrin and metalloprotease) family, generating the soluble APP ectodomain (sAPPα) and a membrane-bound carboxy-terminal fragment (nonamyloidogenic pathway). As α-secretases cleave APP within the Aβ sequence, APP shedding by α-secretases prevents the generation of the pathogenic Aβ peptide. 2,3 Therefore, enhancing α-secretase expression or activity has been considered as a valuable strategy for inhibiting Aβ formation. For instance, it has recently been shown that activation of the transcription of the gene encoding the α-secretase ADAM10, by retinoic acid and sirtuin 1 (SIRT1), reduces Aβ production. 4−6 Previous reports have shown that G protein-coupled receptors (GPCRs) can differentially affect Aβ peptide production by either modulating the cellular trafficking of APP or by influencing the activity and trafficking of α-, β-and γ-secretases. Moreover, both the expression and the stimulation of GPCRs can affect APP metabolism. 7 GPCRs that enhance sAPPα production by stimulating α-secretase activities include the muscarinic M 1 -M 3 receptors, mGlu2 metabotropic glutamate receptor, serotonin 2A (5-HT 2A ) and 5-HT 2C receptors, corticotropin-releasing factor (CRF) receptor 1, purinergic receptor P2X 7 and pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 (PAC 1 ) receptor. 7 These GPCRs are supposed to have a beneficial effect, because sAPPα exerts neuroprotective and neurotro...

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confidence: 96%

5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

Cochet

Donneger

Cassier

et al. 2012

ACS Chem. Neurosci.

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“…Findings from these experiments show (i) APP may have neurite-promoting properties and acts as a neuroprotective molecule that can down-regulate intracellular calcium levels in cultured rat and human neurons (Mattson et al 1993b) and (ii) secreted fAP and probably intracellular amyloidogenic APP C-terminal fragments, which are present as membrane bound form Golde et al 1992), may be neurotoxic by disturbing calcium homeostasis (Mattson et al 1993a). Moreover, several reports suggest the properties of APP derivatives are closely related to Ca2+ and K+ ion channels Lahiri et al 1992;Nitsch et al 1992;Arispe et al 1993;Etcheberrigaray et al 1994;Weiss et al 1994). This could be related to the dysfunction of both channels in fibroblasts and lymphocytes which has been found in the patients of Alzheimer's disease Eckert et al 1993;Etcheberrigaray et al 1993;McCoy et al 1993;.…”

Section: Pkc Content and Its Activitymentioning

confidence: 99%

“…Since /3AP has a tendency to aggregate itself, increment of /3-pathway may be causative of deposition by associated with immunological events in the brain. Recent reports showed the activation of muscarinic acetylcholine receptor ml and/or the protein kinase C signal transduction pathway down-regulate /3AP generation and accelerate sAPP formation on non-neuronal cells or cell lines (Buxbaum et al 1990Caporaso et al 1992; Gillespie et al 1992; Nitsch et al 1992; Gabuzda et al 1993). Moreover, several reports suggest flAP and amyloidogenic C-terminal fragments are neurotoxic (Yankner et al 1990; Pike et al 1991; Kowall et al 1992; Mattson et al 1992; Yoshikawa et al 1992).…”

mentioning

confidence: 99%

The Decrement of Muscarinic Receptor-Mediated Calcium Influx by Overexpression of APP in a Mouse Cholinergic Cell Line.

Kunishita¹,

Ikeda²,

Araki³

et al. 1994

Tohoku J. Exp. Med.

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The effects of f3-amyloid precursor protein (APP) overexpressing on cell metabolisms of cholinergic neuronal hybridoma cell line (SN49) were examined. The cells stably overexpressing APP contained higher amount of GTP binding protein Go and cytosolic inactive protein kinase Ce, and showed less Ca2+ influx through muscarinic acetylcholine receptor ml compared to original and mock cells which had been transfected with a vector alone. The contents of sn-1, 2-diacylglycerol and cycilc AMP were also reduced in the APP transfectants, although the similar changes were observed in the mock cells. These findings strongly suggest that the overexpression of APP affect the transient receptor-mediated ion channel and calcium-related cell metabolisms in neuronal cells.APP overexpression; cholinergic cell line; muscarinic receptor; protein kinase C; GTP binding protein Deposition of f3-amyloid protein (fAP), which is composed of 39-42 of amino acids, in the brain was one of the major pathological hall-marks in Alzheimer's disease and aged Down's syndrome. fAP is generated by the cleavage of its precursor protein (APP 695, 751 and 770), 100-140 KDa integral mambrane proteins produced by three of alternative spliced mRNA from a gene on human chromosome 21. Proteolytic cleavage between residues 595 and 596 of APP695 forms amyloidogenic C-terminal fragments containing /3AP , while it between residue 612 and 163 produces non-amyloidogenic C-terminal fragments containing P3 (Haass et al. 1993). At least three of APP fragments are normally released to extra-cellular space by either so called c -or f3-secretary pathway. That is, secreted APPS (sAPP) and P3 are processed by a-pathway

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“…The media (7.5 ml) were desalted and concentrated on a PD-10 column (modified from [16]). The column eluates were frozen in liquid N 2 and dried under vacuum, and then dissolved in SDS-sample buffer.…”

Section: Measurement O/' App~ Releasementioning

confidence: 99%

“…It has been shown that the metabolism of APP is highly regulated not only by extracellular signals, such as hormones, but also by intracellular second messengers [11,16,17]. Especially, the activation of PKC by treatment with phorbol ester can increase the secretion of APP~ [1][2][3] and reduce the production of amyloidogenic fragments containing Aft and Aft itself [18,19].…”

Section: Introductionmentioning

confidence: 99%

Conventional protein kinase C (PKC)‐α and novel PKCε, but not ‐δ, increase the secretion of an N‐terminal fragment of Alzheimer's disease amyloid precursor protein from PKC cDNA transfected 3Y1 fibroblasts

et al. 1995

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A large soluble N-terminal fragment of Alzheimer's disease amyloid precursor protein (secreted form of APP: APPs) is produced by constitutive processing in the middle of the amyloid E-protein portion of APP. Recent studies indicate that the activation of endogenous protein kinase C (PKC) with phorbol ester raises the rate of secretion of APP,. We constructed rat fibroblast 3Y1 cells that stably overexpress PKC isoenzymes a, ~, or c, and analyzed the amount of APPs released from these PKC transfectants. The levels of APP~ released from 3Y1 cells overexpressing PKCa and -e were higher than those from PKC0-transfected and control cells expressing vector only. These results suggest that specific isoforms of PKC regulate the secretion of APP~ through a signaling pathway.Key words: Alzheimer's disease; Amyroid precursor protein; Amyloid fl-protein; Protein kinase C; Phorbol ester; Secretion novel PKC (nPKC), and atypical PKC (aPKC)) are reported in mammalian tissues [20]. It is still unknown which PKC group(s) mediates the secretion of APP,. Thus, in order to analyze which PKC species is responsible for the secretion of APPs, we selected three PKC isoenzymes with different activation profiles by phorbol esters (e.g. 12-O-tetradecanoylphorbol 13-acetate (TPA), phorbol dibutylate (PDBu)) [21], and examined the secretion of APPs from rat fibroblast 3YI cells after transfection with their full-length cDNA [4]. cPKC members show Ca2+-dependency for activity [21], while the activation of nPKC and aPKC do not require Ca 2+. We chose cPKCc~ because it is widely distributed in most tissues, especially in brain [22]. nPKC~ was also selected because of its universal distribution among most tissues [23 25]. Finally we introduced brainspecific nPKCe cDNA into 3YI fibroblasts. We measured the level of APPs in the medium of PKC-transfected 3Y1 cells in the presence and absence of TPA.

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Release of Alzheimer Amyloid Precursor Derivatives Stimulated by Activation of Muscarinic Acetylcholine Receptors

Cited by 873 publications

References 31 publications

5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

The Decrement of Muscarinic Receptor-Mediated Calcium Influx by Overexpression of APP in a Mouse Cholinergic Cell Line.

Conventional protein kinase C (PKC)‐α and novel PKCε, but not ‐δ, increase the secretion of an N‐terminal fragment of Alzheimer's disease amyloid precursor protein from PKC cDNA transfected 3Y1 fibroblasts

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Release of Alzheimer Amyloid Precursor Derivatives Stimulated by Activation of Muscarinic Acetylcholine Receptors

Cited by 873 publications

References 31 publications

5-HT4 Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

5-HT4 Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

The Decrement of Muscarinic Receptor-Mediated Calcium Influx by Overexpression of APP in a Mouse Cholinergic Cell Line.

Conventional protein kinase C (PKC)‐α and novel PKCε, but not ‐δ, increase the secretion of an N‐terminal fragment of Alzheimer's disease amyloid precursor protein from PKC cDNA transfected 3Y1 fibroblasts

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5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10