title: Oligomeric amyloid-{beta} inhibits the proteolytic conversion of brain-derived neurotrophic factor (BDNF), AMPA receptor trafficking, and classical conditioning.
abstract: Amyloid-β (Aβ) peptide is thought to have a significant role in the progressive memory loss observed in patients with Alzheimer disease and inhibits synaptic plasticity in animal models of learning. We previously demonstrated that brain-derived neurotrophic factor (BDNF) is critical for synaptic AMPA receptor delivery in an in vitro model of eyeblink classical conditioning. Here, we report that acquisition of conditioned responses was significantly attenuated by bath application of oligomeric (200 nm), but not fibrillar, Aβ peptide. Western blotting revealed that BDNF protein expression during conditioning is significantly reduced by treatment with oligomeric Aβ, as were phosphorylation levels of cAMP-response element-binding protein (CREB), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV), and ERK. However, levels of PKA and PKCζ/λ were unaffected, as was PDK-1. Protein localization studies using confocal imaging indicate that oligomeric Aβ, but not fibrillar or scrambled forms, suppresses colocalization of GluR1 and GluR4 AMPA receptor subunits with synaptophysin, indicating that trafficking of these subunits to synapses during the conditioning procedure is blocked. In contrast, coapplication of BDNF with oligomeric Aβ significantly reversed these findings. Interestingly, a tolloid-like metalloproteinase in turtle, tTLLs (turtle tolloid-like protein), which normally processes the precursor proBDNF into mature BDNF, was found to degrade oligomeric Aβ into small fragments. These data suggest that an Aβ-induced reduction in BDNF, perhaps due to interference in the proteolytic conversion of proBDNF to BDNF, results in inhibition of synaptic AMPA receptor delivery and suppression of the acquisition of conditioning.
authors.affiliation: From the Neuroscience Group, Division of Basic Biomedical Sciences, University of South Dakota, Sanford School of Medicine, Vermillion, South Dakota 57069.
authors.forename: Zhaoqing
authors.initials: Z
authors.lastname: Zheng
authors.forename: Boris
authors.initials: B
authors.lastname: Sabirzhanov
authors.forename: Joyce
authors.initials: J
authors.lastname: Keifer
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D007858:Learning / Q000502:physiology*; D008954:Models, Biological; D011493:Protein Kinase C / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D014426:Turtles
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D011498:Protein Precursors; D018091:Receptors, AMPA; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4
references.citation: J Neurosci. 1995 Jul;15(7 Pt 1):5036-48
references.pmid: 7623132
references.citation: Neuroscience. 2008 Oct 28;156(4):872-84
references.pmid: 18809472
references.citation: J Neurosci. 2001 Apr 1;21(7):2434-41
references.pmid: 11264317
references.citation: Neurobiol Dis. 2005 Nov;20(2):187-98
references.pmid: 16242627
references.citation: Neuroscience. 2008 Aug 26;155(3):686-97
references.pmid: 18639615
references.citation: J Neurophysiol. 2007 Sep;98(3):1278-86
references.pmid: 17596423
references.citation: Genomics. 2007 Sep;90(3):397-406
references.pmid: 17629449
references.citation: J Neurosci. 2000 Jun 1;20(11):3937-46
references.pmid: 10818128
references.citation: J Neurochem. 2004 Oct;91(2):349-61
references.pmid: 15447668
references.citation: J Neurophysiol. 2004 Nov;92(5):2853-8
references.pmid: 15212428
references.citation: Brain Res Mol Brain Res. 2000 Mar 29;76(2):347-54
references.pmid: 10762711
references.citation: J Neurochem. 2005 Jun;93(6):1412-21
references.pmid: 15935057
references.citation: Nat Med. 2009 Mar;15(3):331-7
references.pmid: 19198615
references.citation: J Neurosci. 2009 Nov 25;29(47):14956-64
references.pmid: 19940191
references.citation: J Neurophysiol. 2009 May;101(5):2539-49
references.pmid: 19261706
references.citation: J Biol Chem. 2003 Jul 25;278(30):27971-80
references.pmid: 12738769
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13069-74
references.pmid: 14557544
references.citation: Neurobiol Dis. 2005 Feb;18(1):75-82
references.pmid: 15649697
references.citation: J Neurochem. 2006 May;97(4):1104-10
references.pmid: 16573645
references.citation: J Biol Chem. 2002 Aug 30;277(35):32046-53
references.pmid: 12058030
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3410-5
references.pmid: 16492745
references.citation: J Biol Chem. 2006 Jul 21;281(29):20315-25
references.pmid: 16714296
references.citation: J Biol Chem. 2009 Apr 17;284(16):10639-49
references.pmid: 19240035
references.citation: Neurobiol Learn Mem. 2008 Nov;90(4):596-603
references.pmid: 18707012
references.citation: J Neurosci. 2007 Mar 7;27(10):2628-35
references.pmid: 17344400
references.citation: J Biol Chem. 2007 Nov 16;282(46):33305-33312
references.pmid: 17855343
references.citation: J Biol Chem. 2007 Apr 27;282(17):12619-28
references.pmid: 17337442
references.citation: Brain Res Mol Brain Res. 1997 Oct 3;49(1-2):71-81
references.pmid: 9387865
references.citation: Brain Res Rev. 2008 Nov;59(1):201-20
references.pmid: 18708092
references.citation: Physiol Rev. 2010 Apr;90(2):465-94
references.pmid: 20393191
references.citation: J Neurophysiol. 1999 Mar;81(3):1242-50
references.pmid: 10085351
references.citation: FEBS Lett. 2007 May 15;581(10):2047-54
references.pmid: 17482902
references.citation: J Neurosci Methods. 2006 Oct 30;157(2):218-24
references.pmid: 16740315
references.citation: Neurobiol Learn Mem. 2009 Mar;91(3):243-9
references.pmid: 18977306
references.citation: Int J Mol Med. 2004 Nov;14(5):917-24
references.pmid: 15492866
references.citation: J Biol Chem. 2006 Aug 25;281(34):24566-74
references.pmid: 16787929
references.citation: Neuron. 2006 Dec 7;52(5):831-43
references.pmid: 17145504
references.citation: Mol Neurodegener. 2009 Nov 23;4:48
references.pmid: 19930651