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W2029181104 abstract "Soluble oligomers of the amyloid-β peptide (AβOs) accumulate in the brains of Alzheimer disease (AD) patients and are implicated in synapse failure and early memory loss in AD. AβOs have been shown to impact synapse function by inhibiting long term potentiation, facilitating the induction of long term depression and inducing internalization of both AMPA and NMDA glutamate receptors, critical players in plasticity mechanisms. Because activation of dopamine D1/D5 receptors plays important roles in memory circuits by increasing the insertion of AMPA and NMDA receptors at synapses, we hypothesized that selective activation of D1/D5 receptors could protect synapses from the deleterious action of AβOs. We show that SKF81297, a selective D1/D5 receptor agonist, prevented the reduction in surface levels of AMPA and NMDA receptors induced by AβOs in hippocampal neurons in culture. Protection by SKF81297 was abrogated by the specific D1/D5 antagonist, SCH23390. Levels of AMPA receptor subunit GluR1 phosphorylated at Ser845, which regulates AMPA receptor association with the plasma membrane, were reduced in a calcineurin-dependent manner in the presence of AβOs, and treatment with SKF81297 prevented this reduction. Establishing the functional relevance of these findings, SKF81297 blocked the impairment of long term potentiation induced by AβOs in hippocampal slices. Results suggest that D1/D5 receptors may be relevant targets for development of novel pharmacological approaches to prevent synapse failure in AD. Soluble oligomers of the amyloid-β peptide (AβOs) accumulate in the brains of Alzheimer disease (AD) patients and are implicated in synapse failure and early memory loss in AD. AβOs have been shown to impact synapse function by inhibiting long term potentiation, facilitating the induction of long term depression and inducing internalization of both AMPA and NMDA glutamate receptors, critical players in plasticity mechanisms. Because activation of dopamine D1/D5 receptors plays important roles in memory circuits by increasing the insertion of AMPA and NMDA receptors at synapses, we hypothesized that selective activation of D1/D5 receptors could protect synapses from the deleterious action of AβOs. We show that SKF81297, a selective D1/D5 receptor agonist, prevented the reduction in surface levels of AMPA and NMDA receptors induced by AβOs in hippocampal neurons in culture. Protection by SKF81297 was abrogated by the specific D1/D5 antagonist, SCH23390. Levels of AMPA receptor subunit GluR1 phosphorylated at Ser845, which regulates AMPA receptor association with the plasma membrane, were reduced in a calcineurin-dependent manner in the presence of AβOs, and treatment with SKF81297 prevented this reduction. Establishing the functional relevance of these findings, SKF81297 blocked the impairment of long term potentiation induced by AβOs in hippocampal slices. Results suggest that D1/D5 receptors may be relevant targets for development of novel pharmacological approaches to prevent synapse failure in AD. IntroductionAlzheimer disease (AD) 2The abbreviations used are: AD, Alzheimer disease; AβO, amyloid-β peptide oligomer; fEPSP, field excitatory postsynaptic potential; GluR1, subunit of AMPA receptors; LTD, long term depression; LTP, long term potentiation; PKA, protein kinase A; pS845-GluR1, GluR1 AMPA receptor subunit phosphorylated at serine 845; NR1, subunit of NMDA receptors. is the main cause of dementia among the elderly, and current estimates indicate that it affects around 25 million people worldwide (1Brookmeyer R. Johnson E. Ziegler-Graham K. Arrighi H.M. Alzheimers Dement. 2007; 3: 186-191Abstract Full Text Full Text PDF PubMed Scopus (2393) Google Scholar, 2Kalaria R.N. Maestre G.E. Arizaga R. Friedland R.P. Galasko D. Hall K. Luchsinger J.A. Ogunniyi A. Perry E.K. Potocnik F. Prince M. Stewart R. Wimo A. Zhang Z.X. Antuono P. Lancet Neurol. 2008; 7: 812-826Abstract Full Text Full Text PDF PubMed Scopus (795) Google Scholar). Although much is known about the pathophysiology of AD, there is still no cure or effective treatment capable of slowing the progression of the disease. For this reason, development of novel pharmacological strategies for treatment is of critical importance.Considerable evidence indicates that soluble oligomers of the amyloid-β peptide (AβOs) accumulate in the brains of AD patients and are responsible for synapse dysfunction and memory loss in AD (3Haass C. Selkoe D.J. Nat. Rev. Mol. Cell Biol. 2007; 8: 101-112Crossref PubMed Scopus (3811) Google Scholar, 4Lambert M.P. Barlow A.K. Chromy B.A. Edwards C. Freed R. Liosatos M. Morgan T.E. Rozovsky I. Trommer B. Viola K.L. Wals P. Zhang C. Finch C.E. Krafft G.A. Klein W.L. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 6448-6453Crossref PubMed Scopus (3085) Google Scholar, 5Ferreira S.T. Vieira M.N. De Felice F.G. IUBMB life. 2007; 59: 332-345Crossref PubMed Scopus (288) Google Scholar). Among other deleterious actions, AβOs impair synaptic plasticity, likely leading to memory loss at early stages of the disease. AβOs have been shown to inhibit long term potentiation (LTP) (4Lambert M.P. Barlow A.K. Chromy B.A. Edwards C. Freed R. Liosatos M. Morgan T.E. Rozovsky I. Trommer B. Viola K.L. Wals P. Zhang C. Finch C.E. Krafft G.A. Klein W.L. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 6448-6453Crossref PubMed Scopus (3085) Google Scholar, 6Walsh D.M. Klyubin I. Fadeeva J.V. Cullen W.K. Anwyl R. Wolfe M.S. Rowan M.J. Selkoe D.J. Nature. 2002; 416: 535-539Crossref PubMed Scopus (3662) Google Scholar, 7Townsend M. Shankar G.M. Mehta T. Walsh D.M. Selkoe D.J. J. Physiol. 2006; 572: 477-492Crossref PubMed Scopus (520) Google Scholar), facilitate the induction of long term depression (LTD) (8Li S. Hong S. Shepardson N.E. Walsh D.M. Shankar G.M. Selkoe D. Neuron. 2009; 62: 788-801Abstract Full Text Full Text PDF PubMed Scopus (719) Google Scholar, 9Shankar G.M. Li S. Mehta T.H. Garcia-Munoz A. Shepardson N.E. Smith I. Brett F.M. Farrell M.A. Rowan M.J. Lemere C.A. Regan C.M. Walsh D.M. Sabatini B.L. Selkoe D.J. Nat. Med. 2008; 14: 837-842Crossref PubMed Scopus (2855) Google Scholar), induce internalization of AMPA and NMDA receptors (10Zhao W.Q. Santini F. Breese R. Ross D. Zhang X.D. Stone D.J. Ferrer M. Townsend M. Wolfe A.L. Seager M.A. Kinney G.G. Shughrue P.J. Ray W.J. J. Biol. Chem. 2010; 285: 7619-7632Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 11Hsieh H. Boehm J. Sato C. Iwatsubo T. Tomita T. Sisodia S. Malinow R. Neuron. 2006; 52: 831-843Abstract Full Text Full Text PDF PubMed Scopus (823) Google Scholar, 12Almeida C.G. Tampellini D. Takahashi R.H. Greengard P. Lin M.T. Snyder E.M. Gouras G.K. Neurobiol. Dis. 2005; 20: 187-198Crossref PubMed Scopus (320) Google Scholar, 13Snyder E.M. Nong Y. Almeida C.G. Paul S. Moran T. Choi E.Y. Nairn A.C. Salter M.W. Lombroso P.J. Gouras G.K. Greengard P. Nat. Neurosci. 2005; 8: 1051-1058Crossref PubMed Scopus (1286) Google Scholar, 14Lacor P.N. Buniel M.C. Furlow P.W. Clemente A.S. Velasco P.T. Wood M. Viola K.L. Klein W.L. J. Neurosci. 2007; 27: 796-807Crossref PubMed Scopus (981) Google Scholar), and increase activation of protein phosphatases, such as calcineurin and protein phosphatase-1 (9Shankar G.M. Li S. Mehta T.H. Garcia-Munoz A. Shepardson N.E. Smith I. Brett F.M. Farrell M.A. Rowan M.J. Lemere C.A. Regan C.M. Walsh D.M. Sabatini B.L. Selkoe D.J. Nat. Med. 2008; 14: 837-842Crossref PubMed Scopus (2855) Google Scholar, 10Zhao W.Q. Santini F. Breese R. Ross D. Zhang X.D. Stone D.J. Ferrer M. Townsend M. Wolfe A.L. Seager M.A. Kinney G.G. Shughrue P.J. Ray W.J. J. Biol. Chem. 2010; 285: 7619-7632Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 15Knobloch M. Farinelli M. Konietzko U. Nitsch R.M. Mansuy I.M. J. Neurosci. 2007; 27: 7648-7653Crossref PubMed Scopus (114) Google Scholar, 16Wu H.Y. Hudry E. Hashimoto T. Kuchibhotla K. Rozkalne A. Fan Z. Spires-Jones T. Xie H. Arbel-Ornath M. Grosskreutz C.L. Bacskai B.J. Hyman B.T. J. Neurosci. 2010; 30: 2636-2649Crossref PubMed Scopus (286) Google Scholar), finally leading to spine loss (14Lacor P.N. Buniel M.C. Furlow P.W. Clemente A.S. Velasco P.T. Wood M. Viola K.L. Klein W.L. J. Neurosci. 2007; 27: 796-807Crossref PubMed Scopus (981) Google Scholar).Dopamine receptors have been grouped into two families: D1-type and D2-type (17Missale C. Nash S.R. Robinson S.W. Jaber M. Caron M.G. Physiol. Rev. 1998; 78: 189-225Crossref PubMed Scopus (2700) Google Scholar). The D1 family comprises D1 and D5 receptor subtypes, which are mostly coupled to Gαs and stimulate production of the second messenger cyclic AMP, leading to activation of protein kinase A (PKA) (17Missale C. Nash S.R. Robinson S.W. Jaber M. Caron M.G. Physiol. Rev. 1998; 78: 189-225Crossref PubMed Scopus (2700) Google Scholar). D1/D5 receptors play important roles in cognition, mediating plasticity and specific aspects of cognitive function, including working and spatial learning and memory processes (18Dalley J.W. Everitt B.J. Semin. Cell Dev. Biol. 2009; 20: 403-410Crossref PubMed Scopus (83) Google Scholar). Stimulation of D1/D5 receptors promotes the insertion of AMPA receptors into the plasma membrane through phosphorylation of AMPA receptor subunit GluR1 at the PKA target site Ser845 (19Gao C. Sun X. Wolf M.E. J. Neurochem. 2006; 98: 1664-1677Crossref PubMed Scopus (105) Google Scholar, 20Smith W.B. Starck S.R. Roberts R.W. Schuman E.M. Neuron. 2005; 45: 765-779Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar). Because recruitment of new AMPA receptors into the synapse is critical to the establishment of LTP (21Shepherd J.D. Huganir R.L. Annu. Rev. Cell Dev. Biol. 2007; 23: 613-643Crossref PubMed Scopus (751) Google Scholar), this likely accounts for the molecular basis of the effects of dopaminergic neurotransmission on learning and memory.In the present study, we show that SKF81297, a selective D1/D5 receptor agonist, prevents AβO-induced removal of AMPA receptors and NMDA receptors from the dendrites of hippocampal neurons in culture. Results further show that AβOs reduce the levels of GluR1 phosphorylated at Ser845 (pS845-GluR1), which regulates membrane association of AMPA receptors and that this effect can be prevented by SKF81297 and by the calcineurin inhibitor, FK-506. Finally, we show that treatment with SKF81297 prevents AβO-induced impairment of LTP in hippocampal slices, providing functional evidence for the protection of synapse function by D1/D5 receptor activation.DISCUSSIONDriven by previous reports showing that Aβ oligomers impair synapse function (30Yamin G. J. Neurosci. Res. 2009; 87: 1729-1736Crossref PubMed Scopus (112) Google Scholar, 31Parameshwaran K. Dhanasekaran M. Suppiramaniam V. Exp. Neurol. 2008; 210: 7-13Crossref PubMed Scopus (177) Google Scholar) and that activation of dopamine D1/D5 receptors enhances excitatory transmission and facilitates synaptic plasticity (18Dalley J.W. Everitt B.J. Semin. Cell Dev. Biol. 2009; 20: 403-410Crossref PubMed Scopus (83) Google Scholar, 32Wolf M.E. Mangiavacchi S. Sun X. Ann. N. Y. Acad. Sci. 2003; 1003: 241-249Crossref PubMed Scopus (108) Google Scholar), the present study was designed to investigate whether pharmacological manipulation of D1/D5 receptors could represent a novel mechanism to protect synapses from damage instigated by Aβ oligomers.Among several aspects of synapse function reported to be affected by AβOs is the internalization of AMPA and NMDA receptors. Both receptors exhibit reduced surface levels upon in vitro exposure of neurons to different AβO preparations and reduced total levels in transgenic mouse models of AD and in AD brains (10Zhao W.Q. Santini F. Breese R. Ross D. Zhang X.D. Stone D.J. Ferrer M. Townsend M. Wolfe A.L. Seager M.A. Kinney G.G. Shughrue P.J. Ray W.J. J. Biol. Chem. 2010; 285: 7619-7632Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 11Hsieh H. Boehm J. Sato C. Iwatsubo T. Tomita T. Sisodia S. Malinow R. Neuron. 2006; 52: 831-843Abstract Full Text Full Text PDF PubMed Scopus (823) Google Scholar, 12Almeida C.G. Tampellini D. Takahashi R.H. Greengard P. Lin M.T. Snyder E.M. Gouras G.K. Neurobiol. Dis. 2005; 20: 187-198Crossref PubMed Scopus (320) Google Scholar, 13Snyder E.M. Nong Y. Almeida C.G. Paul S. Moran T. Choi E.Y. Nairn A.C. Salter M.W. Lombroso P.J. Gouras G.K. Greengard P. Nat. Neurosci. 2005; 8: 1051-1058Crossref PubMed Scopus (1286) Google Scholar, 14Lacor P.N. Buniel M.C. Furlow P.W. Clemente A.S. Velasco P.T. Wood M. Viola K.L. Klein W.L. J. Neurosci. 2007; 27: 796-807Crossref PubMed Scopus (981) Google Scholar, 33Roselli F. Tirard M. Lu J. Hutzler P. Lamberti P. Livrea P. Morabito M. Almeida O.F. J. Neurosci. 2005; 25: 11061-11070Crossref PubMed Scopus (259) Google Scholar, 34Yasuda R.P. Ikonomovic M.D. Sheffield R. Rubin R.T. Wolfe B.B. Armstrong D.M. Brain Res. 1995; 678: 161-167Crossref PubMed Scopus (67) Google Scholar, 35Ikonomovic M.D. Mizukami K. Warde D. Sheffield R. Hamilton R. Wenthold R.J. Armstrong D.M. Exp. Neurol. 1999; 160: 194-204Crossref PubMed Scopus (50) Google Scholar). AMPA and NMDA receptors are essential for glutamatergic synaptic transmission and play key roles in LTP and LTD, cellular mechanisms of plasticity thought to underlie learning, memory, and cognition (36Malenka R.C. Bear M.F. Neuron. 2004; 44: 5-21Abstract Full Text Full Text PDF PubMed Scopus (2901) Google Scholar). Current results show that activation of D1/D5 receptors by SKF81297 prevents AβO-induced loss of GluR1 and NR1 from dendrites. The fact that total levels of GluR1 and NR1 were unaffected by exposure to AβOs suggests that changes in their surface levels are a consequence of altered regulation of trafficking rather than changes in expression or stability of these receptors.It is well established that NMDA receptors and D1/D5 receptors interact physically and functionally in the brain (37Castner S.A. Williams G.V. Brain Cognition. 2007; 63: 94-122Crossref PubMed Scopus (0) Google Scholar, 38Missale C. Fiorentini C. Busi C. Collo G. Spano P.F. Curr. Top. Med. Chem. 2006; 6: 801-808Crossref PubMed Scopus (65) Google Scholar). This interaction accounts for several aspects of dopaminergic regulation of cognitive function, including reward, addiction, and working memory (37Castner S.A. Williams G.V. Brain Cognition. 2007; 63: 94-122Crossref PubMed Scopus (0) Google Scholar). Activation of D1/D5 receptors enhances PKA-mediated phosphorylation of NR1 at Ser897, which signals synaptic insertion of NMDA receptors (39Chen B.S. Roche K.W. Neuropharmacology. 2007; 53: 362-368Crossref PubMed Scopus (298) Google Scholar, 40Snyder G.L. Fienberg A.A. Huganir R.L. Greengard P. J. Neurosci. 1998; 18: 10297-10303Crossref PubMed Google Scholar), resulting in increased NMDA currents and synaptic potentiation (41Granado N. Ortiz O. Suárez L.M. Martín E.D. Ceña V. Solís J.M. Moratalla R. Cereb. Cortex. 2008; 18: 1-12Crossref PubMed Scopus (158) Google Scholar). Preventing the removal of NMDA receptors from synaptic membranes, as accomplished by D1/D5 receptor activation, is thus critical for the integrity of synaptic plasticity.AMPA receptors are the major excitatory neurotransmitter receptors in the brain, and their levels at synapses are highly dynamic and regulated (42Malenka R.C. Ann. N. Y. Acad. Sci. 2003; 1003: 1-11Crossref PubMed Scopus (266) Google Scholar). AMPA receptor trafficking is critically engaged in modulating synaptic strength; for example, recruitment of new AMPA receptors occurs during LTP (43Park M. Penick E.C. Edwards J.G. Kauer J.A. Ehlers M.D. Science. 2004; 305: 1972-1975Crossref PubMed Scopus (572) Google Scholar), whereas they are removed by endocytosis from synaptic membranes upon induction of LTD (42Malenka R.C. Ann. N. Y. Acad. Sci. 2003; 1003: 1-11Crossref PubMed Scopus (266) Google Scholar). From its insertion into the synaptic membrane to receptor endocytosis, AMPA receptor subunits are regulated mainly by two mechanisms: phosphorylation at specific sites and interaction with scaffolding proteins, which confer stability to the receptor at the postsynaptic membrane (44Groc L. Choquet D. Cell Tiss. Res. 2006; 326: 423-438Crossref PubMed Scopus (134) Google Scholar). Among the four distinct subunits that may form AMPA receptors, GluR1 is the one whose trafficking depends directly on neuronal activity, whereas GluR2 is more prone to undergo constitutive, activity-independent recycling (45Bredt D.S. Nicoll R.A. Neuron. 2003; 40: 361-379Abstract Full Text Full Text PDF PubMed Scopus (919) Google Scholar). Membrane insertion of GluR1 is regulated by two phosphorylation sites in the intracellular C-terminal tail: Ser845 and Ser831, targets of PKA and calcium/calmodulin-dependent kinase II, respectively (46Song I. Huganir R.L. Trends Neurosci. 2002; 25: 578-588Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar). When phosphorylated, Ser845 signals AMPA receptor insertion at extrasynaptic sites, and Ser831 signals subsequent translocation to synaptic sites (21Shepherd J.D. Huganir R.L. Annu. Rev. Cell Dev. Biol. 2007; 23: 613-643Crossref PubMed Scopus (751) Google Scholar, 47He K. Song L. Cummings L.W. Goldman J. Huganir R.L. Lee H.K. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 20033-20038Crossref PubMed Scopus (153) Google Scholar, 48Lee H.K. Takamiya K. He K. Song L. Huganir R.L. J. Neurophysiol. 2010; 103: 479-489Crossref PubMed Scopus (188) Google Scholar). Phosphorylation of GluR1 Ser845 is required for the induction of LTP (49Lee H.K. Takamiya K. Han J.S. Man H. Kim C.H. Rumbaugh G. Yu S. Ding L. He C. Petralia R.S. Wenthold R.J. Gallagher M. Huganir R.L. Cell. 2003; 112: 631-643Abstract Full Text Full Text PDF PubMed Scopus (630) Google Scholar), whereas its dephosphorylation is essential for NMDA receptor-dependent LTD (48Lee H.K. Takamiya K. He K. Song L. Huganir R.L. J. Neurophysiol. 2010; 103: 479-489Crossref PubMed Scopus (188) Google Scholar).Our finding that AβOs induce loss of surface AMPA receptors and a parallel reduction in pS845-GluR1 levels is consistent with the fact that AβOs facilitate LTD and induce long lasting depression of synaptic activity (8Li S. Hong S. Shepardson N.E. Walsh D.M. Shankar G.M. Selkoe D. Neuron. 2009; 62: 788-801Abstract Full Text Full Text PDF PubMed Scopus (719) Google Scholar, 50Cerpa W. Farías G.G. Godoy J.A. Fuenzalida M. Bonansco C. Inestrosa N.C. Mol. Neurodegen. 2010; 5: 3Crossref PubMed Scopus (98) Google Scholar). This impact of AβOs may be part of the underlying mechanism by which AβOs facilitate/induce LTD, inhibit LTP, and cause synapse failure. Giving further support to this notion is the observation that reduction in pS845-GluR1 levels induced by AβOs was blocked by a calcineurin inhibitor, FK-506. It is well established that dephosphorylation of GluR1 by calcineurin and other phosphatases, such as protein phosphatases-1 and -2A, cause removal of AMPA receptors from the plasma membrane (51Lee H.K. Pharmacol. Ther. 2006; 112: 810-832Crossref PubMed Scopus (159) Google Scholar). Calcineurin can also act indirectly, through the relief of protein phosphatase-1 inhibition by DARPP-32 (52Greengard P. Allen P.B. Nairn A.C. Neuron. 1999; 23: 435-447Abstract Full Text Full Text PDF PubMed Scopus (638) Google Scholar). Specifically, previous works have shown that calcineurin may be involved in the deleterious synaptic effects of AβOs, including LTP impairment, LTD facilitation, and induction of AMPA receptor endocytosis (8Li S. Hong S. Shepardson N.E. Walsh D.M. Shankar G.M. Selkoe D. Neuron. 2009; 62: 788-801Abstract Full Text Full Text PDF PubMed Scopus (719) Google Scholar, 10Zhao W.Q. Santini F. Breese R. Ross D. Zhang X.D. Stone D.J. Ferrer M. Townsend M. Wolfe A.L. Seager M.A. Kinney G.G. Shughrue P.J. Ray W.J. J. Biol. Chem. 2010; 285: 7619-7632Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 16Wu H.Y. Hudry E. Hashimoto T. Kuchibhotla K. Rozkalne A. Fan Z. Spires-Jones T. Xie H. Arbel-Ornath M. Grosskreutz C.L. Bacskai B.J. Hyman B.T. J. Neurosci. 2010; 30: 2636-2649Crossref PubMed Scopus (286) Google Scholar, 53Chen Q.S. Wei W.Z. Shimahara T. Xie C.W. Neurobiol. Learn. Mem. 2002; 77: 354-371Crossref PubMed Scopus (164) Google Scholar). Based on the present data, we propose that AβOs cause a reduction in pS845-GluR1 levels mediated by activation of calcineurin, triggering AMPA receptor removal and synapse failure.Current results show that activation of D1/D5 receptors prevents the reduction in pS845-GluR1 and loss of surface GluR1 induced by AβOs. D1/D5 receptor activation leads to increased cyclic AMP levels and increased PKA activity (17Missale C. Nash S.R. Robinson S.W. Jaber M. Caron M.G. Physiol. Rev. 1998; 78: 189-225Crossref PubMed Scopus (2700) Google Scholar), favoring phosphorylation of GluR1 (54Chao S.Z. Lu W. Lee H.K. Huganir R.L. Wolf M.E. J. Neurochem. 2002; 81: 984-992Crossref PubMed Scopus (86) Google Scholar) and AMPA receptor insertion into extrasynaptic sites (19Gao C. Sun X. Wolf M.E. J. Neurochem. 2006; 98: 1664-1677Crossref PubMed Scopus (105) Google Scholar). This may explain why D1/D5-selective agonists prevent LTD (55Mockett B.G. Guévremont D. Williams J.M. Abraham W.C. J. Neurosci. 2007; 27: 2918-2926Crossref PubMed Scopus (38) Google Scholar) and facilitate the induction of LTP (41Granado N. Ortiz O. Suárez L.M. Martín E.D. Ceña V. Solís J.M. Moratalla R. Cereb. Cortex. 2008; 18: 1-12Crossref PubMed Scopus (158) Google Scholar). PKA activity is known to be affected by Aβ (29Vitolo O.V. Sant'Angelo A. Costanzo V. Battaglia F. Arancio O. Shelanski M. Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 13217-13221Crossref PubMed Scopus (456) Google Scholar), and this is likely the kinase involved in mediating the protective effect of SKF81297 on the surface levels of AMPA receptor. However, other kinases thought to be involved in AD pathogenesis, including GSK3β (56Decker H. Lo K.Y. Unger S.M. Ferreira S.T. Silverman M.A. J. Neurosci. 2010; 30: 9166-9171Crossref PubMed Scopus (176) Google Scholar), have been implicated in Aβ effects on AMPA receptor trafficking (57Rui Y. Gu J. Yu K. Hartzell H.C. Zheng J.Q. Mol. Brain. 2010; 3: 10Crossref PubMed Scopus (49) Google Scholar). Therefore, the possible roles of GSK3β and other kinases in the regulation of AMPA receptor trafficking by D1/D5 receptors merits further investigation.Finally, we found that SKF81297 prevented AβO-induced impairment of LTP in hippocampal slices, further substantiating the notion that activation of D1/D5 receptors prevents synapse dysfunction induced by AβOs. LTP is a central event in learning and memory processes, and it is known to be compromised in AD (30Yamin G. J. Neurosci. Res. 2009; 87: 1729-1736Crossref PubMed Scopus (112) Google Scholar). It is generally accepted that synaptic recruitment of AMPA receptors is necessary for LTP (45Bredt D.S. Nicoll R.A. Neuron. 2003; 40: 361-379Abstract Full Text Full Text PDF PubMed Scopus (919) Google Scholar). Phosphorylation of GluR1 at Ser845 is required for delivery of new AMPA receptors into perisynaptic sites (36Malenka R.C. Bear M.F. Neuron. 2004; 44: 5-21Abstract Full Text Full Text PDF PubMed Scopus (2901) Google Scholar), which precedes full expression of LTP (58Yang Y. Wang X.B. Frerking M. Zhou Q. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 11388-11393Crossref PubMed Scopus (120) Google Scholar). Thus, D1/D5 receptor-mediated extrasynaptic insertion of AMPA receptors (19Gao C. Sun X. Wolf M.E. J. Neurochem. 2006; 98: 1664-1677Crossref PubMed Scopus (105) Google Scholar) via Ser845 phosphorylation of GluR1 by PKA (59Man H.Y. Sekine-Aizawa Y. Huganir R.L. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 3579-3584Crossref PubMed Scopus (239) Google Scholar) is likely the mechanism involved in prevention of AβO-induced LTP impairment by SKF81297.In conclusion, we have established a novel connection between dopaminergic signaling and AD by demonstrating that activation of D1/D5 receptors prevents pathological changes in synapse composition and function induced by AβOs. One of the implications of this connection is that dopamine D1/D5 receptors may constitute a target for the development of novel approaches to combat synapse failure in AD. Also of interest is that dopaminergic neurotransmission, which is reduced with aging (60de Keyser J. De Backer J.P. Vauquelin G. Ebinger G. Brain Res. 1990; 528: 308-310Crossref PubMed Scopus (85) Google Scholar), plays important roles in nonpharmacological strategies aimed to improve age-related cognitive decline, such as environmental enrichment and physical exercise (61van Praag H. Kempermann G. Gage F.H. Nat. Rev. Neurosci. 2000; 1: 191-198Crossref PubMed Scopus (1904) Google Scholar). Previous works have suggested that such strategies could be beneficial to ameliorate AD symptoms (62Schaeffer E.L. Novaes B.A. da Silva E.R. Skaf H.D. Mendes-Neto A.G. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2009; 33: 1087-1102Crossref PubMed Scopus (48) Google Scholar). Thus, investigating the relationship between dopamine D1/D5 receptor activation and relief of AD symptoms achieved by either pharmacological tools or nonpharmacological approaches may be an interesting avenue for future investigations. IntroductionAlzheimer disease (AD) 2The abbreviations used are: AD, Alzheimer disease; AβO, amyloid-β peptide oligomer; fEPSP, field excitatory postsynaptic potential; GluR1, subunit of AMPA receptors; LTD, long term depression; LTP, long term potentiation; PKA, protein kinase A; pS845-GluR1, GluR1 AMPA receptor subunit phosphorylated at serine 845; NR1, subunit of NMDA receptors. is the main cause of dementia among the elderly, and current estimates indicate that it affects around 25 million people worldwide (1Brookmeyer R. Johnson E. Ziegler-Graham K. Arrighi H.M. Alzheimers Dement. 2007; 3: 186-191Abstract Full Text Full Text PDF PubMed Scopus (2393) Google Scholar, 2Kalaria R.N. Maestre G.E. Arizaga R. Friedland R.P. Galasko D. Hall K. Luchsinger J.A. Ogunniyi A. Perry E.K. Potocnik F. Prince M. Stewart R. Wimo A. Zhang Z.X. Antuono P. Lancet Neurol. 2008; 7: 812-826Abstract Full Text Full Text PDF PubMed Scopus (795) Google Scholar). Although much is known about the pathophysiology of AD, there is still no cure or effective treatment capable of slowing the progression of the disease. For this reason, development of novel pharmacological strategies for treatment is of critical importance.Considerable evidence indicates that soluble oligomers of the amyloid-β peptide (AβOs) accumulate in the brains of AD patients and are responsible for synapse dysfunction and memory loss in AD (3Haass C. Selkoe D.J. Nat. Rev. Mol. Cell Biol. 2007; 8: 101-112Crossref PubMed Scopus (3811) Google Scholar, 4Lambert M.P. Barlow A.K. Chromy B.A. Edwards C. Freed R. Liosatos M. Morgan T.E. Rozovsky I. Trommer B. Viola K.L. Wals P. Zhang C. Finch C.E. Krafft G.A. Klein W.L. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 6448-6453Crossref PubMed Scopus (3085) Google Scholar, 5Ferreira S.T. Vieira M.N. De Felice F.G. IUBMB life. 2007; 59: 332-345Crossref PubMed Scopus (288) Google Scholar). Among other deleterious actions, AβOs impair synaptic plasticity, likely leading to memory loss at early stages of the disease. AβOs have been shown to inhibit long term potentiation (LTP) (4Lambert M.P. Barlow A.K. Chromy B.A. Edwards C. Freed R. Liosatos M. Morgan T.E. Rozovsky I. Trommer B. Viola K.L. Wals P. Zhang C. Finch C.E. Krafft G.A. Klein W.L. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 6448-6453Crossref PubMed Scopus (3085) Google Scholar, 6Walsh D.M. Klyubin I. Fadeeva J.V. Cullen W.K. Anwyl R. Wolfe M.S. Rowan M.J. Selkoe D.J. Nature. 2002; 416: 535-539Crossref PubMed Scopus (3662) Google Scholar, 7Townsend M. Shankar G.M. Mehta T. Walsh D.M. Selkoe D.J. J. Physiol. 2006; 572: 477-492Crossref PubMed Scopus (520) Google Scholar), facilitate the induction of long term depression (LTD) (8Li S. Hong S. Shepardson N.E. Walsh D.M. Shankar G.M. Selkoe D. Neuron. 2009; 62: 788-801Abstract Full Text Full Text PDF PubMed Scopus (719) Google Scholar, 9Shankar G.M. Li S. Mehta T.H. Garcia-Munoz A. Shepardson N.E. Smith I. Brett F.M. Farrell M.A. Rowan M.J. Lemere C.A. Regan C.M. Walsh D.M. Sabatini B.L. Selkoe D.J. Nat. Med. 2008; 14: 837-842Crossref PubMed Scopus (2855) Google Scholar), induce internalization of AMPA and NMDA receptors (10Zhao W.Q. Santini F. Breese R. Ross D. Zhang X.D. Stone D.J. Ferrer M. Townsend M. Wolfe A.L. Seager M.A. Kinney G.G. Shughrue P.J. Ray W.J. J. Biol. Chem. 2010; 285: 7619-7632Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 11Hsieh H. Boehm J. Sato C. Iwatsubo T. Tomita T. Sisodia S. Malinow R. Neuron. 2006; 52: 831-843Abstract Full Text Full Text PDF PubMed Scopus (823) Google Scholar, 12Almeida C.G. Tampellini D. Takahashi R.H. Greengard P. Lin M.T. Snyder E.M. Gouras G.K. Neurobiol. Dis. 2005; 20: 187-198Crossref PubMed Scopus (320) Google Scholar, 13Snyder E.M. Nong Y. Almeida C.G. Paul S. Moran T. Choi E.Y. Nairn A.C. Salter M.W. Lombroso P.J. Gouras G.K. Greengard P. Nat. 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Kuchibhotla K. Rozkalne A. Fan Z. Spires-Jones T. Xie H. Arbel-Ornath M. Grosskreutz C.L. Bacskai B.J. Hyman B.T. J. Neurosci. 2010; 30: 2636-2649Crossref PubMed Scopus (286) Google Scholar), finally leading to spine loss (14Lacor P.N. Buniel M.C. Furlow P.W. Clemente A.S. Velasco P.T. Wood M. Viola K.L. Klein W.L. J. Neurosci. 2007; 27: 796-807Crossref PubMed Scopus (981) Google Scholar).Dopamine receptors have been grouped into two families: D1-type and D2-type (17Missale C. Nash S.R. Robinson S.W. Jaber M. Caron M.G. Physiol. Rev. 1998; 78: 189-225Crossref PubMed Scopus (2700) Google Scholar). The D1 family comprises D1 and D5 receptor subtypes, which are mostly coupled to Gαs and stimulate production of the second messenger cyclic AMP, leading to activation of protein kinase A (PKA) (17Missale C. Nash S.R. Robinson S.W. Jaber M. Caron M.G. Physiol. Rev. 1998; 78: 189-225Crossref PubMed Scopus (2700) Google Scholar). D1/D5 receptors play important roles in cognition, mediating plasticity and specific aspects of cognitive function, including working and spatial learning and memory processes (18Dalley J.W. Everitt B.J. Semin. Cell Dev. Biol. 2009; 20: 403-410Crossref PubMed Scopus (83) Google Scholar). Stimulation of D1/D5 receptors promotes the insertion of AMPA receptors into the plasma membrane through phosphorylation of AMPA receptor subunit GluR1 at the PKA target site Ser845 (19Gao C. Sun X. Wolf M.E. J. Neurochem. 2006; 98: 1664-1677Crossref PubMed Scopus (105) Google Scholar, 20Smith W.B. Starck S.R. Roberts R.W. Schuman E.M. Neuron. 2005; 45: 765-779Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar). Because recruitment of new AMPA receptors into the synapse is critical to the establishment of LTP (21Shepherd J.D. Huganir R.L. Annu. Rev. Cell Dev. Biol. 2007; 23: 613-643Crossref PubMed Scopus (751) Google Scholar), this likely accounts for the molecular basis of the effects of dopaminergic neurotransmission on learning and memory.In the present study, we show that SKF81297, a selective D1/D5 receptor agonist, prevents AβO-induced removal of AMPA receptors and NMDA receptors from the dendrites of hippocampal neurons in culture. Results further show that AβOs reduce the levels of GluR1 phosphorylated at Ser845 (pS845-GluR1), which regulates membrane association of AMPA receptors and that this effect can be prevented by SKF81297 and by the calcineurin inhibitor, FK-506. Finally, we show that treatment with SKF81297 prevents AβO-induced impairment of LTP in hippocampal slices, providing functional evidence for the protection of synapse function by D1/D5 receptor activation." @default.
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W2029181104 title "Activation of D1/D5 Dopamine Receptors Protects Neurons from Synapse Dysfunction Induced by Amyloid-β Oligomers" @default.
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