The neuropeptide PACAP promotes ?‐secretase pathway for processing Alzheimer amyloid precursor protein

Kojro, Elżbieta; Postina, Rolf; Buro, Corinna; Meiringer, Christoph; Gehrig‐Burger, Katja; Fahrenholz, Falk

doi:10.1096/fj.05-4812fje

Cited by 108 publications

(102 citation statements)

References 66 publications

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“…26). ERK activation has been shown to modulate APP processing and Aβ generation (24,25,36). M1 muscarinic acetylcholine receptors activate the ERK signaling pathway (37), which is at least in part responsible for their regulation of APP processing (38).…”

Section: Discussionmentioning

confidence: 99%

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Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Cirrito

Disabato²,

Restivo³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

290

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Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonindependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.microdialysis | selective serotonin reuptake inhibitor antidepressants | late-life depression A myloid-β (Aβ) dysregulation appears to initiate the pathogenesis of Alzheimer's disease (AD) with a cascade of downstream factors that exacerbate and propagate neuronal injury (1). Aβ can accumulate as toxic plaques and soluble oligomers in the brains of individuals with AD a decade or more before the initial symptoms are identified (2). The concentration of Aβ is a critical factor determining if and when it will aggregate into these toxic structures; high concentrations of Aβ are more prone to convert from its normal soluble form into these multimeric conformations (3). Aβ is formed within neurons by sequential cleavage of the amyloid precursor protein (APP) by two enzymes, β-secretase and then γ-secretase. Alternatively, α-secretase can cleave APP within the Aβ sequence, which precludes the peptide from being formed at all. The enzymes and mechanisms that produce Aβ have been well characterized; however, the mechanisms that regulate Aβ production and levels are only partly understood. Understanding the cellular processes that regulate Aβ levels may provide greater insight into disease pathogenesis and suggest new avenues to treat or prevent AD.Synaptic activity is one key regulator of brain Aβ production. Depolarization and subsequent synaptic transmission causes Aβ to be produced presynaptically and then secreted into the brain extracel...

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Section: Discussionmentioning

confidence: 99%

“…ERK, a mitogen-activated protein kinase (MAPK), has been shown to suppress Aβ production in vitro and in vivo by altering secretase activity (24,25). Extracellular ligands bind to a GPCR on the cell surface, which leads to sequential activation of Raf, MEK (MAPK kinase), and then ERK.…”

Section: Serotonergic Regulation Of Isf Aβ Does Not Require Actionmentioning

confidence: 99%

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Cirrito

Disabato²,

Restivo³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

290

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“…Immunoblot analysis of secreted sAβPPα and sAβPPβ was performed as described [29]. Briefly, for sAβPPα detection, membranes were probed with antibody 6E10 and for sAβPPβ with an anti-sAβPPβ antibody (Signet), followed by a 35 S-labeled or peroxidasecoupled anti-mouse or anti-rabbit antibody.…”

Section: Immunoblot Analysis Of Secreted Saβppα and Saβppβmentioning

confidence: 99%

Statins and the Squalene Synthase Inhibitor Zaragozic Acid Stimulate the Non-Amyloidogenic Pathway of Amyloid-β Protein Precursor Processing by Suppression of Cholesterol Synthesis

Kojro

Füger

Prinzen

et al. 2010

JAD

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Abstract. Cholesterol-lowering drugs such as statins influence the proteolytic processing of the amyloid-β protein precursor (AβPP) and are reported to stimulate the activity of α-secretase, the major preventive secretase of Alzheimer's disease. Statins can increase the α-secretase activity by their cholesterol-lowering properties as well as by impairment of isoprenoids synthesis. In the present study, we elucidate the contribution of these pathways in α-secretase activation. We demonstrate that zaragozic acid, a potent inhibitor of squalene synthase which blocks cholesterol synthesis but allows synthesis of isoprenoids, also stimulates α-secretase activity. Treatment of human neuroblastoma cells with 50 µM zaragozic acid resulted in a ∼3 fold increase of α-secretase activity and reduced cellular cholesterol by ∼30%. These effects were comparable to results obtained from cells treated with a low lovastatin concentration (2 µM). Zaragozic acid-stimulated secretion of α-secretase cleaved soluble AβPP was dose dependent and saturable. Lovastatin-or zaragozic acid-stimulated increase of α-secretase activity was completely abolished by a selective ADAM10 inhibitor. By targeting the α-secretase ADAM10 to lipid raft domains via a glycosylphosphatidylinositol anchor, we demonstrate that ADAM10 is unable to cleave AβPP in a cholesterol-rich environment. Our results indicate that inhibition of cholesterol biosynthesis by a low lovastatin concentration is sufficient for α-secretase activation.

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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).…”

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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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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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The neuropeptide PACAP promotes ?‐secretase pathway for processing Alzheimer amyloid precursor protein

Cited by 108 publications

References 66 publications

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Statins and the Squalene Synthase Inhibitor Zaragozic Acid Stimulate the Non-Amyloidogenic Pathway of Amyloid-β Protein Precursor Processing by Suppression of Cholesterol Synthesis

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

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The neuropeptide PACAP promotes ?‐secretase pathway for processing Alzheimer amyloid precursor protein

Cited by 108 publications

References 66 publications

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Statins and the Squalene Synthase Inhibitor Zaragozic Acid Stimulate the Non-Amyloidogenic Pathway of Amyloid-β Protein Precursor Processing by Suppression of Cholesterol Synthesis

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

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