Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Amyloid-β oligomers in the nucleus accumbens decrease motivation via insertion of calcium-permeable AMPA receptors

Molecular Psychiatry volume 27, pages 2146–2157 (2022)Cite this article

Subjects

Abstract

It is essential to identify the neuronal mechanisms of Alzheimer’s Disease (AD)-associated neuropsychiatric symptoms, e.g., apathy, before improving the life quality of AD patients. Here, we focused on the nucleus accumbens (NAc), a critical brain region processing motivation, also known to display AD-associated pathological changes in human cases. We found that the synaptic calcium permeable (CP)-AMPA receptors (AMPARs), which are normally absent in the NAc, can be revealed by acute exposure to Aβ oligomers (AβOs), and play a critical role in the emergence of synaptic loss and motivation deficits. Blockade of NAc CP-AMPARs can effectively prevent AβO-induced downsizing and pruning of spines and silencing of excitatory synaptic transmission. We conclude that AβO-triggered synaptic insertion of CP-AMPARs is a key mechanism mediating synaptic degeneration in AD, and preserving synaptic integrity may prevent or delay the onset of AD-associated psychiatric symptoms.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Behavioral effects of intra-NAc delivery of AβOs.
Fig. 2: Involvement of NAc CP-AMPARs in sucrose self-administration in mice with intra-NAc delivery of AβOs.
Fig. 3: Effects of pre-incubation of striatal slices with AβOs on the morphology of VGluT1+ excitatory synapses and the protein levels of AMPAR subunits in the NAc.
Fig. 4: Effects of in vitro AβO pre-incubation of striatal slices on dendritic spine morphology in the NAc, which can be prevented by Naspm.
Fig. 5: Effects of in vitro AβO pre-incubation of NAc slices on synaptic transmission in the mPFC projections to D2 MSNs.

Similar content being viewed by others

References

  1. Bu Z, Huang A, Xue M, Li Q, Bai Y, Xu G. Cognitive frailty as a predictor of adverse outcomes among older adults: a systematic review and meta-analysis. Brain Behav. 2021;11:e01926.

    Article  PubMed  Google Scholar 

  2. Petrovic M, Gehringer P, Eschweiler H, Barcelo D. Radiolytic decomposition of multi-class surfactants and their biotransformation products in sewage treatment plant effluents. Chemosphere. 2007;66:114–22.

    Article  CAS  PubMed  Google Scholar 

  3. Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, et al. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2008;22:246–60.

    Article  CAS  PubMed  Google Scholar 

  4. Guercio BJ, Donovan NJ, Munro CE, Aghjayan SL, Wigman SE, Locascio JJ, et al. The apathy evaluation scale: a comparison of subject, informant, and clinician report in cognitively normal elderly and mild cognitive impairment. J Alzheimers Dis. 2015;47:421–32.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Guercio BJ, Donovan NJ, Ward A, Schultz A, Lorius N, Amariglio RE, et al. Apathy is associated with lower inferior temporal cortical thickness in mild cognitive impairment and normal elderly individuals. J Neuropsychiatry Clin Neurosci. 2015;27:e22–7.

    Article  PubMed  Google Scholar 

  6. Munro CE, Donovan NJ, Guercio BJ, Wigman SE, Schultz AP, Amariglio RE, et al. Neuropsychiatric symptoms and functional connectivity in mild cognitive impairment. J Alzheimers Dis. 2015;46:727–35.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lanctot KL, Amatniek J, Ancoli-Israel S, Arnold SE, Ballard C, Cohen-Mansfield J, et al. Neuropsychiatric signs and symptoms of Alzheimer’s disease: New treatment paradigms. Alzheimer‘s Dement. 2017;3:440–9.

    Google Scholar 

  8. Dietlin S, Soto M, Kiyasova V, Pueyo M, de Mauleon A, Delrieu J et al. Neuropsychiatric symptoms and risk of progression to Alzheimer’s disease among mild cognitive impairment subjects. J Alzheimers Dis. 2019.

  9. Sabuncu MR, Desikan RS, Sepulcre J, Yeo BT, Liu H, Schmansky NJ, et al. The dynamics of cortical and hippocampal atrophy in Alzheimer disease. Arch Neurol. 2011;68:1040–8.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Beckelman BC, Yang W, Kasica NP, Zimmermann HR, Zhou X, Keene CD, et al. Genetic reduction of eEF2 kinase alleviates pathophysiology in Alzheimer’s disease model mice. J Clin Invest. 2019;129:820–33.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Pini L, Pievani M, Bocchetta M, Altomare D, Bosco P, Cavedo E, et al. Brain atrophy in Alzheimer’s disease and aging. Ageing Res Rev. 2016;30:25–48.

    Article  PubMed  Google Scholar 

  12. Selden N, Geula C, Hersh L, Mesulam MM. Human striatum: chemoarchitecture of the caudate nucleus, putamen and ventral striatum in health and Alzheimer’s disease. Neuroscience. 1994;60:621–36.

    Article  CAS  PubMed  Google Scholar 

  13. Engelhardt E, Laks J. Alzheimer disease neuropathology: understanding autonomic dysfunction. Dement Neuropsychol. 2008;2:183–91.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Yi HA, Fochtman BC, Rizzo RC, Jacobs A. Inhibition of HIV entry by targeting the envelope transmembrane subunit gp41. Curr HIV Res. 2016;14:283–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Parnetti L, Lanari A, Silvestrelli G, Saggese E, Reboldi P. Diagnosing prodromal Alzheimer’s disease: role of CSF biochemical markers. Mech Ageing Dev. 2006;127:129–32.

    Article  CAS  PubMed  Google Scholar 

  16. Selkoe DJ. Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimer‘s Dis. 2001;3:75–80.

    Article  CAS  Google Scholar 

  17. Braak H, Braak E. Alzheimer’s disease: striatal amyloid deposits and neurofibrillary changes. J Neuropathol Exp Neurol. 1990;49:215–24.

    Article  CAS  PubMed  Google Scholar 

  18. Brilliant MJ, Elble RJ, Ghobrial M, Struble RG. The distribution of amyloid beta-protein deposition in the corpus striatum of patients with Alzheimer’s disease. Neuropathol Appl Neurobiol. 1997;23:322–5.

    Article  CAS  PubMed  Google Scholar 

  19. Vazin T, Ball KA, Lu H, Park H, Ataeijannati Y, Head-Gordon T, et al. Efficient derivation of cortical glutamatergic neurons from human pluripotent stem cells: a model system to study neurotoxicity in Alzheimer’s disease. Neurobiol Dis. 2014;62:62–72.

    Article  CAS  PubMed  Google Scholar 

  20. Xu P, Chen A, Li Y, Xing X, Lu H. Medial prefrontal cortex in neurological diseases. Physiol Genom. 2019;51:432–42.

    Article  CAS  Google Scholar 

  21. Roe JM, Vidal-Pineiro D, Sorensen O, Brandmaier AM, Duzel S, Gonzalez HA, et al. Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s disease. Nat Commun. 2021;12:721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature. 2002;416:507–11.

    Article  CAS  PubMed  Google Scholar 

  23. Koffie RM, Meyer-Luehmann M, Hashimoto T, Adams KW, Mielke ML, Garcia-Alloza M, et al. Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci USA. 2009;106:4012–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Klyubin I, Walsh DM, Lemere CA, Cullen WK, Shankar GM, Betts V, et al. Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo. Nat Med. 2005;11:556–61.

    Article  CAS  PubMed  Google Scholar 

  25. Bjorklund NL, Reese LC, Sadagoparamanujam VM, Ghirardi V, Woltjer RL, Taglialatela G. Absence of amyloid beta oligomers at the postsynapse and regulated synaptic Zn2+ in cognitively intact aged individuals with Alzheimer’s disease neuropathology. Mol Neurodegener. 2012;7:23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yoo SJ, Son G, Bae J, Kim SY, Yoo YK, Park D, et al. Longitudinal profiling of oligomeric Abeta in human nasal discharge reflecting cognitive decline in probable Alzheimer’s disease. Sci Rep. 2020;10:11234.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Li X, Bao X, Wang R. Experimental models of Alzheimer’s disease for deciphering the pathogenesis and therapeutic screening (Review). Int J Mol Med. 2016;37:271–83.

    Article  CAS  PubMed  Google Scholar 

  28. Beal MF. Role of excitotoxicity in human neurological disease. Curr Opin Neurobiol. 1992;2:657–62.

    Article  CAS  PubMed  Google Scholar 

  29. Guo C, Ma YY. Calcium permeable-AMPA receptors and excitotoxicity in neurological disorders. Front Neural Circuits. 2021;15:711564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bukke VN, Archana M, Villani R, Romano AD, Wawrzyniak A, Balawender K et al. The dual role of glutamatergic neurotransmission in Alzheimer’s disease: from pathophysiology to pharmacotherapy. Int J Mol Sci. 2020; 21.

  31. Kashyap G, Bapat D, Das D, Gowaikar R, Amritkar RE, Rangarajan G, et al. Synapse loss and progress of Alzheimer’s disease—a network model. Sci Rep. 2019;9:6555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bezprozvanny I, Hayden MR. Deranged neuronal calcium signaling and Huntington disease. Biochemical Biophys Res Commun. 2004;322:1310–7.

    Article  CAS  Google Scholar 

  33. Tong BC, Wu AJ, Li M, Cheung KH. Calcium signaling in Alzheimer’s disease & therapies. Biochim Biophys Acta Mol Cell Res. 2018;1865:1745–60.

    Article  CAS  PubMed  Google Scholar 

  34. Popugaeva E, Bezprozvanny I. Can the calcium hypothesis explain synaptic loss in Alzheimer’s disease? Neurodegener Dis. 2014;13:139–41.

    Article  CAS  PubMed  Google Scholar 

  35. Roselli V, Guo C, Huang D, Wen D, Zona D, Liang T, et al. Prenatal alcohol exposure reduces posterior dorsomedial striatum excitability and motivation in a sex- and age-dependent fashion. Neuropharmacology. 2020;180:108310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shan L, Galaj E, Ma Y-Y. Nucleus accumbens shell small conductance potassium channels underlie adolescent ethanol exposure-induced anxiety. Neuropsychopharmacology. 2019.

  37. Luo YX, Huang D, Guo C, Ma YY. Limited versus extended cocaine intravenous self-administration: Behavioral effects and electrophysiological changes in insular cortex. CNS Neurosci Ther. 2021;27:196–205.

    Article  CAS  PubMed  Google Scholar 

  38. Ma YY, Cepeda C, Chatta P, Franklin L, Evans CJ, Levine MS. Regional and cell-type-specific effects of DAMGO on striatal D1 and D2 dopamine receptor-expressing medium-sized spiny neurons. ASN neuro. 2012; 4.

  39. Ma YY, Lee BR, Wang X, Guo C, Liu L, Cui R, et al. Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections. Neuron. 2014;83:1453–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ma YY, Wang X, Huang Y, Marie H, Nestler EJ, Schluter OM, et al. Re-silencing of silent synapses unmasks anti-relapse effects of environmental enrichment. Proc Natl Acad Sci USA. 2016;113:5089–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Galaj E, Guo C, Huang D, Ranaldi R, Ma YY. Contrasting effects of adolescent and early-adult ethanol exposure on prelimbic cortical pyramidal neurons. Drug Alcohol Depend. 2020;216:108309. https://doi.org/10.1016/j.drugalcdep.2020.108309. Epub 2020 Sep 21.

  42. Luo YX, Galaj E, Ma YY. Differential alterations of insular cortex excitability after adolescent or adult chronic intermittent ethanol administration in male rats. J Neurosci Res. 2021;99:649–61.

    Article  CAS  PubMed  Google Scholar 

  43. Lee BR, Ma YY, Huang YH, Wang X, Otaka M, Ishikawa M, et al. Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving. Nat Neurosci. 2013;16:1644–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Stuber GD, Sparta DR, Stamatakis AM, van Leeuwen WA, Hardjoprajitno JE, Cho S, et al. Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature. 2011;475:377–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cheng J, Wang J, Ma X, Ullah R, Shen Y, Zhou YD. Anterior paraventricular thalamus to nucleus accumbens projection is involved in feeding behavior in a novel environment. Front Mol Neurosci. 2018;11:202.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Bobadilla AC, Garcia-Keller C, Heinsbroek JA, Scofield MD, Chareunsouk V, Monforton C, et al. Accumbens mechanisms for cued sucrose seeking. Neuropsychopharmacology. 2017;42:2377–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Koh DS, Burnashev N, Jonas P. Block of native Ca(2+)-permeable AMPA receptors in rat brain by intracellular polyamines generates double rectification. J Physiol. 1995;486:305–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lim BK, Huang KW, Grueter BA, Rothwell PE, Malenka RC. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature. 2012;487:183–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zapata A, Minney VL, Shippenberg TS. Shift from goal-directed to habitual cocaine seeking after prolonged experience in rats. J Neurosci. 2010;30:15457–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ostlund SB, Balleine BW. On habits and addiction: an associative analysis of compulsive drug seeking. Drug Discov Today Dis Models. 2008;5:235–45.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Commons KG, Cholanians AB, Babb JA, Ehlinger DG. The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem Neurosci. 2017;8:955–60.

    Article  CAS  PubMed  Google Scholar 

  52. Bellocchio EE, Hu H, Pohorille A, Chan J, Pickel VM, Edwards RH. The localization of the brain-specific inorganic phosphate transporter suggests a specific presynaptic role in glutamatergic transmission. J Neurosci. 1998;18:8648–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fremeau RT Jr., Troyer MD, Pahner I, Nygaard GO, Tran CH, Reimer RJ, et al. The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron. 2001;31:247–60.

    Article  CAS  PubMed  Google Scholar 

  54. Fremeau RT Jr., Kam K, Qureshi T, Johnson J, Copenhagen DR, Storm-Mathisen J, et al. Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites. Science. 2004;304:1815–9.

    Article  CAS  PubMed  Google Scholar 

  55. Xu W. PSD-95-like membrane associated guanylate kinases (PSD-MAGUKs) and synaptic plasticity. Curr Opin Neurobiol. 2011;21:306–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Herms J, Dorostkar MM. Dendritic spine pathology in neurodegenerative diseases. Annu Rev Pathol. 2016;11:221–50.

    Article  CAS  PubMed  Google Scholar 

  57. Kourrich S, Rothwell PE, Klug JR, Thomas MJ. Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens. J Neurosci. 2007;27:7921–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Conrad KL, Tseng KY, Uejima JL, Reimers JM, Heng LJ, Shaham Y, et al. Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature. 2008;454:118–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Durand GM, Kovalchuk Y, Konnerth A. Long-term potentiation and functional synapse induction in developing hippocampus. Nature. 1996;381:71–5.

    Article  CAS  PubMed  Google Scholar 

  60. Soares-Cunha C, de Vasconcelos NAP, Coimbra B, Domingues AV, Silva JM, Loureiro-Campos E, et al. Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion. Mol Psychiatry. 2020;25:3241–55.

    Article  CAS  PubMed  Google Scholar 

  61. Francelle L, Galvan L, Brouillet E. Possible involvement of self-defense mechanisms in the preferential vulnerability of the striatum in Huntington’s disease. Front Cell Neurosci. 2014;8:295.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Bergonzoni G, Doring J, Biagioli M. D1R- and D2R-medium-sized spiny neurons diversity: insights into striatal vulnerability to huntington’s disease mutation. Front Cell Neurosci. 2021;15:628010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Schneider LS, Dagerman KS, Higgins JP, McShane R. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. 2011;68:991–8.

    Article  PubMed  Google Scholar 

  64. van Marum RJ. Update on the use of memantine in Alzheimer’s disease. Neuropsychiatr Dis Treat. 2009; 5.

  65. Huang YH, Schluter OM, Dong Y. Cocaine-induced homeostatic regulation and dysregulation of nucleus accumbens neurons. Behav Brain Res. 2011;216:9–18.

    Article  CAS  PubMed  Google Scholar 

  66. Jia Y, Jeng JM, Sensi SL, Weiss JH. Zn2+ currents are mediated by calcium-permeable AMPA/kainate channels in cultured murine hippocampal neurones. J Physiol. 2002;543:35–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Redman PT, Hartnett KA, Aras MA, Levitan ES, Aizenman E. Regulation of apoptotic potassium currents by coordinated zinc-dependent signalling. J Physiol. 2009;587:4393–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Sensi SL, Yin HZ, Carriedo SG, Rao SS, Weiss JH. Preferential Zn2+ influx through Ca2+-permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production. Proc Natl Acad Sci USA. 1999;96:2414–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Whitehead G, Regan P, Whitcomb DJ. Cho K. Ca(2+)-permeable AMPA receptor: a new perspective on amyloid-beta mediated pathophysiology of Alzheimer’s disease. Neuropharmacology. 2017;112:221–7.

    Article  CAS  PubMed  Google Scholar 

  70. Avila J, Llorens-Martin M, Pallas-Bazarra N, Bolos M, Perea JR, Rodriguez-Matellan A, et al. Cognitive decline in neuronal aging and Alzheimer’s disease: role of NMDA receptors and associated proteins. Front Neurosci. 2017;11:626.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Foster TC, Kyritsopoulos C, Kumar A. Central role for NMDA receptors in redox mediated impairment of synaptic function during aging and Alzheimer’s disease. Behav Brain Res. 2017;322:223–32.

    Article  CAS  PubMed  Google Scholar 

  72. Liu J, Chang L, Song Y, Li H, Wu Y. The role of NMDA receptors in Alzheimer’s disease. Front Neurosci. 2019;13:43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Malinow R. New developments on the role of NMDA receptors in Alzheimer’s disease. Curr Opin Neurobiol. 2012;22:559–63.

    Article  CAS  PubMed  Google Scholar 

  74. Wang R, Reddy PH. Role of glutamate and NMDA receptors in Alzheimer’s disease. J Alzheimer‘s Dis. 2017;57:1041–8.

    Article  CAS  Google Scholar 

  75. Noh KM, Yokota H, Mashiko T, Castillo PE, Zukin RS, Bennett MV. Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death. Proc Natl Acad Sci USA. 2005;102:12230–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Malkin SL, Amakhin DV, Veniaminova EA, Kim K, Zubareva OE, Magazanik LG, et al. Changes of AMPA receptor properties in the neocortex and hippocampus following pilocarpine-induced status epilepticus in rats. Neuroscience. 2016;327:146–155.

    Article  CAS  PubMed  Google Scholar 

  77. Kwak S, Weiss JH. Calcium-permeable AMPA channels in neurodegenerative disease and ischemia. Curr Opin Neurobiol. 2006;16:281–7.

    Article  CAS  PubMed  Google Scholar 

  78. Spaethling JM, Klein DM, Singh P, Meaney DF. Calcium-permeable AMPA receptors appear in cortical neurons after traumatic mechanical injury and contribute to neuronal fate. J Neurotrauma. 2008;25:1207–16.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Marcello E, Epis R, Saraceno C, Gardoni F, Borroni B, Cattabeni F, et al. SAP97-mediated local trafficking is altered in Alzheimer disease patients’ hippocampus. Neurobiol Aging. 2012;33:422 e421–10.

    Article  Google Scholar 

  80. Whitcomb DJ, Hogg EL, Regan P, Piers T, Narayan P, Whitehead G, et al. Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus. Sci Rep. 2015;5:10934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci. 2007;27:2866–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med. 2008;14:837–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Cheng IH, Scearce-Levie K, Legleiter J, Palop JJ, Gerstein H, Bien-Ly N, et al. Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem. 2007;282:23818–28.

    Article  CAS  PubMed  Google Scholar 

  84. Cline EN, Bicca MA, Viola KL, Klein WL. The amyloid-beta oligomer hypothesis: beginning of the third decade. J Alzheimer‘s Dis. 2018;64:S567–S610.

    Article  CAS  Google Scholar 

  85. Kreutzer AG, Nowick JS. Elucidating the structures of amyloid oligomers with macrocyclic beta-hairpin peptides: insights into Alzheimer’s disease and other amyloid diseases. Acc Chem Res. 2018;51:706–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Walsh DM, Selkoe DJ. A beta oligomers—a decade of discovery. J Neurochem. 2007;101:1172–84.

    Article  CAS  PubMed  Google Scholar 

  87. Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, et al. A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci. 2010;30:4845–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. van Dyck CH. Anti-amyloid-beta monoclonal antibodies for Alzheimer’s disease: pitfalls and promise. Biol Psychiatry. 2018;83:311–9.

    Article  PubMed  Google Scholar 

  89. Wolf ME. The Bermuda Triangle of cocaine-induced neuroadaptations. Trends Neurosci. 2010;33:391–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006;26:10129–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Walker JM, Fowler SW, Miller DK, Sun AY, Weisman GA, Wood WG, et al. Spatial learning and memory impairment and increased locomotion in a transgenic amyloid precursor protein mouse model of Alzheimer’s disease. Behav Brain Res. 2011;222:169–75.

    Article  CAS  PubMed  Google Scholar 

  92. Karisetty BC, Bhatnagar A, Armour EM, Beaver M, Zhang H, Elefant F. Amyloid-beta Peptide Impact on Synaptic Function and Neuroepigenetic Gene Control Reveal New Therapeutic Strategies for Alzheimer’s Disease. Front Mol Neurosci. 2020;13:577622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tenreiro S, Eckermann K, Outeiro TF. Protein phosphorylation in neurodegeneration: friend or foe? Front Mol Neurosci. 2014;7:42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Pan X, Kaminga AC, Wen SW, Wu X, Acheampong K, Liu A. Dopamine and dopamine receptors in Alzheimer’s disease: a systematic review and network meta-analysis. Front Aging Neurosci. 2019;11:175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grants (R01AA025784, R01AG072897, and R21NS108128).

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Changyong Guo, Di Wen, Yihong Zhang, Richie Mustaklem, Basil Mustaklem & Yao-Ying Ma

  2. Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, 91766, USA

    Miou Zhou

  3. Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27101, USA

    Tao Ma

  4. Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, 27101, USA

    Tao Ma

  5. Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, NC, 27101, USA

    Tao Ma

  6. Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Yao-Ying Ma

Authors
  1. Changyong Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Di Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yihong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richie Mustaklem
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Basil Mustaklem
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Miou Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tao Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yao-Ying Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Experimental design: CG, MZ, TM, YM. Data collection: CG, DW, YZ, RM, BM, YM. Data analysis: CG, DW, YZ, YM. Paper writing: CG, DW, TM, YM.

Corresponding author

Correspondence to Yao-Ying Ma.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, C., Wen, D., Zhang, Y. et al. Amyloid-β oligomers in the nucleus accumbens decrease motivation via insertion of calcium-permeable AMPA receptors. Mol Psychiatry 27, 2146–2157 (2022). https://doi.org/10.1038/s41380-022-01459-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-022-01459-0

Search

Advanced search

Quick links