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Cited by 98Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroscience and Neuropharmacology Research

Absence of amyloid β oligomers at the postsynapse and regulated synaptic Zn2+ in cognitively intact aged individuals with Alzheimer’s disease neuropathology

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Bjorklund, Nicole L, Reese, Lindsay C, Sadagoparamanujam, V-M, Ghirardi, Valeria, Woltjer, Randall L, Taglialatela, Giulio·2012·Molecular Neurodegeneration
DOI 10.1186/1750-1326-7-23PMC PMC3403985
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Abstract

Background: Early cognitive impairment in Alzheimer Disease (AD) is thought to result from the dysfunctional effect of amyloid beta (Aβ) oligomers targeting the synapses. Some individuals, however, escape cognitive decline despite the presence of the neuropathologic features of AD (Aβ plaques and neurofibrillary tangles). We term this group Non-Demented with AD Neuropathology or NDAN. The present study illustrates one putative resistance mechanism involved in NDAN cases which may suggest targets for the effective treatment of AD. Results: Here we describe the localization of Aβ oligomers at the postsynapse in hippocampi from AD cases. Notably, however, we also found that while present in soluble fractions, Aβ oligomers are absent from hippocampal postsynapses in NDAN cases. In addition, levels of phosphorylated (active) CREB, a transcription factor important for synaptic plasticity, are normal in NDAN individuals, suggesting that their synapses are functionally intact. Analysis of Zn 2+showed that levels were increased in both soluble fractions and synaptic vesicles in AD hippocampi, paralleled by a decrease of expression of the synaptic vesicle Zn 2+transporter, ZnT3. Conversely, in NDAN individuals, levels of Zn 2+in soluble fractions were significantly lower than in AD, whereas in synaptic vesicles the levels of Zn 2+were similar to AD, but accompanied by preserved expression of the ZnT3. Conclusions: Taken together, these data illustrate that despite substantial AD neuropathology, Aβ oligomers, and increased synaptic vesicle Zn 2+, susceptible brain tissue in these aged NDAN individuals features, as compared to symptomatic AD subjects, significantly lower total Zn 2+levels and no association of Aβ oligomers with the postsynapse, which collectively may promote the maintenance of intact cognitive function.

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  • AsymAD cases exhibit an overall deficiency in oligomeric and soluble phospho-tau species, indicating fewer pathological tau species in these cases than in AD cases.

    “Consistent with our findings, previous studies have shown that AsymAD cases exhibit an overall deficiency in oligomeric and soluble phospho-tau species, indicating fewer pathological tau species in these cases than in AD cases [8, 73, 83].”

    From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [8]

    The Discussion says hippocampal neurofibrillary tangles and hyperphosphorylated tau were comparable between AD and cognitively intact NDAN cases, contrary to the claimed overall deficiency of pathological tau. The paper does not report a comparison of oligomeric or soluble phospho-tau species; its oligomer measurements concern amyloid β. (LLM, conf=0.82)

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  • AsymAD brains exhibit no signs of notorious synaptic or neuronal deterioration.

    “studies have demonstrated that AsymAD brains exhibit no signs of notorious synaptic or neuronal deterioration [8, 42, 73]”

    From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [8]

    The Discussion (page unavailable) says preserved neuronal pCREB levels suggest that synaptic functional integrity is maintained in NDAN, the paper’s term for cognitively intact individuals with AD neuropathology. But this is an inference from specific synaptic measures, not a demonstration that the brains show no synaptic or neuronal deterioration generally; the paper also reports substantial AD neuropathology. (LLM, conf=0.84)

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Research works printed but not linked: 57

  1. Alzheimer’s A Alzheimer’s disease facts and figures Alzheimer’s & Dementia 2010 2010 6 20298981
  2. Kramer PL Xu H Woltjer RL Westaway SK Clark D Erten-Lyons D Kaye JA Welsh-Bohmer KA Troncoso JC Markesbery WR Alzheimer disease pathology in cognitively healthy elderly: A genome-wide study Neurobiol Aging 2011 32 2113 2122 10.1016/j.neurobiolaging.2010.01.010 20452100 PMC2990809 · DOI · Paper page
  3. Lue LF Kuo YM Roher AE Brachova L Shen Y Sue L Beach T Kurth JH Rydel RE Rogers J Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease Am J Pathol 1999 155 853 862 10.1016/S0002-9440(10)65184-X 10487842 PMC1866907 · DOI · Paper page
  4. Erten-Lyons D Woltjer RL Dodge H Nixon R Vorobik R Calvert JF Leahy M Montine T Kaye J Factors associated with resistance to dementia despite high Alzheimer disease pathology Neurology 2009 72 354 360 10.1212/01.wnl.0000341273.18141.64 19171833 PMC2677499 · DOI
  5. Riudavets MA Iacono D Resnick SM O’Brien R Zonderman AB Martin LJ Rudow G Pletnikova O Troncoso JC Resistance to Alzheimer’s pathology is associated with nuclear hypertrophy in neurons Neurobiol Aging 2007 28 1484 1492 10.1016/j.neurobiolaging.2007.05.005 17599696 PMC2694127 · DOI · Paper page
  6. Cleary JP Walsh DM Hofmeister JJ Shankar GM Kuskowski MA Selkoe DJ Ashe KH Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function Nat Neurosci 2005 8 79 84 10.1038/nn1372 15608634 · DOI
  7. Reese LC Zhang W Dineley KT Kayed R Taglialatela G Selective induction of calcineurin activity and signaling by oligomeric amyloid beta Aging Cell 2008 7 824 835 10.1111/j.1474-9726.2008.00434.x 18782350 PMC2954114 · DOI
  8. Demuro A Mina E Kayed R Milton SC Parker I Glabe CG Calcium Dysregulation and Membrane Disruption as a Ubiquitous Neurotoxic Mechanism of Soluble Amyloid Oligomers J Biol Chem 2005 280 17294 17300 10.1074/jbc.M500997200 15722360 · DOI
  9. Poling A Morgan-Paisley K Panos John J Kim E-M O’Hare E Cleary James P Lesne S Ashe Karen H Porritt M Baker Lisa E Oligomers of the amyloid-beta protein disrupt working memory: confirmation with two behavioral procedures Behavioural brain research 2008 193 230 234 10.1016/j.bbr.2008.06.001 18585407 PMC2786170 · DOI
  10. O’Shea SD Smith IM McCabe OM Cronin MM Walsh DM O’Connor WT Intracerebroventricular administration of amyloid β-protein oligomers selectively increases dorsal hippocampal dialysate glutamate levels in the awake rat Sensors 2008 8 7428 7437 10.3390/s8117428 PMC3787453 27873937 · DOI
  11. Dineley KT Kayed R Neugebauer V Fu Y Zhang W Reese LC Taglialatela G Amyloid-β oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice J Neurosci Res 2010 88 2923 2932 20544830 PMC2919647
  12. Koffie RM Meyer-Luehmann M Hashimoto T Adams KW Mielke ML Garcia-Alloza M Micheva KD Smith SJ Kim ML Lee VM Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques Proc Natl Acad Sci U S A 2009 106 4012 4017 10.1073/pnas.0811698106 19228947 PMC2656196 · DOI · Paper page
  13. Grabrucker AM Schmeisser MJ Udvardi PT Arons M Schoen M Woodling NS Andreasson KI Hof PR Buxbaum JD Garner CC Boeckers TM Amyloid beta protein-induced zinc sequestration leads to synaptic loss via dysregulation of the ProSAP2/Shank3 scaffold Mol Neurodegener 2011 6 65 10.1186/1750-1326-6-65 21939532 PMC3189132 · DOI
  14. Shankar GM Li S Mehta TH Garcia-Munoz A Shepardson NE Smith I Brett FM Farrell MA Rowan MJ Lemere CA Amyloid-β protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory Nat Med 2008 14 837 842 10.1038/nm1782 18568035 PMC2772133 · DOI · Paper page
  15. Abdul HM Sama MA Furman JL Mathis DM Beckett TL Weidner AM Patel ES Baig I Murphy MP LeVine H et al: Cognitive decline in Alzheimer’s disease is associated with selective changes in calcineurin/NFAT signaling J Neurosci 2009 29 12957 12969 10.1523/JNEUROSCI.1064-09.2009 19828810 PMC2782445 · DOI
  16. Moore AN Waxham MN Dash PK Neuronal activity increases the phosphorylation of the transcription factor cAMP response element-binding protein (CREB) in rat hippocampus and cortex J Biol Chem 1996 271 14214 14220 10.1074/jbc.271.24.14214 8662977 · DOI
  17. Noy D Solomonov I Sinkevich O Arad T Kjaer K Sagi I Zinc-Amyloid β Interactions on a Millisecond Time-Scale Stabilize Non-fibrillar Alzheimer-Related Species J Am Chem Soc 2008 130 1376 1383 10.1021/ja076282l 18179213 · DOI
  18. Deshpande A Kawai H Metherate R Glabe CG Busciglio J A role for synaptic zinc in activity-dependent Aβ oligomer formation and accumulation at excitatory synapses J Neurosci 2009 29 4004 4015 10.1523/JNEUROSCI.5980-08.2009 19339596 PMC6665357 · DOI · Paper page
  19. Danscher G Jensen KB Frederickson CJ Kemp K Andreasen A Juhl S Stoltenberg M Ravid R Increased amount of zinc in the hippocampus and amygdala of Alzheimer’s diseased brains: a proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material J Neurosci Methods 1997 76 53 59 10.1016/S0165-0270(97)00079-4 9334939 · DOI
  20. Deibel MA Ehmann WD Markesbery WR Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer’s disease: Possible relation to oxidative stress J Neurol Sci 1996 143 137 142 10.1016/S0022-510X(96)00203-1 8981312 · DOI · Paper page
  21. Religa D Strozyk D Cherny RA Volitakis I Haroutunian V Winblad B Naslund J Bush AI Elevated cortical zinc in Alzheimer disease Neurology 2006 67 69 75 10.1212/01.wnl.0000223644.08653.b5 16832080 · DOI
  22. Beyer N Coulson DT Heggarty S Ravid R Irvine GB Hellemans J Johnston JA ZnT3 mRNA levels are reduced in Alzheimer’s disease post-mortem brain Mol Neurodegener 2009 4 53 10.1186/1750-1326-4-53 20030848 PMC2806356 · DOI
  23. Uchida Y Takio K Titani K Ihara Y Tomonaga M The growth inhibitory factor that is deficient in the Alzheimer’s disease brain is a 68 amino acid metallothionein-like protein Neuron 1991 7 337 347 10.1016/0896-6273(91)90272-2 1873033 · DOI
  24. Adlard PA Parncutt JM Finkelstein DI Bush AI Cognitive loss in zinc transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of Alzheimer’s disease? J Neurosci 2010 30 1631 1636 10.1523/JNEUROSCI.5255-09.2010 20130173 PMC6633978 · DOI
  25. Yu WH Lukiw WJ Bergeron C Niznik HB Fraser PE Metallothionein III is reduced in Alzheimer’s disease Brain Res 2001 894 37 45 10.1016/S0006-8993(00)03196-6 11245813 · DOI
  26. Cousins RJ Liuzzi JP Lichten LA Mammalian zinc transport, trafficking, and signals J Biol Chem 2006 281 24085 24089 10.1074/jbc.R600011200 16793761 · DOI
  27. Assaf SY Chung SH Release of endogenous Zn2+ from brain tissue during activity Nature 1984 308 734 736 10.1038/308734a0 6717566 · DOI
  28. Colvin RA Davis N Nipper RW Carter PA Zinc transport in the brain: routes of zinc influx and efflux in neurons J Nutr 2000 130 1484S 1487S 10801963
  29. Amico-Ruvio SA Murthy SE Smith TP Popescu GK Zinc Effects on NMDA Receptor Gating Kinetics Biophys J 2011 100 1910 1918 10.1016/j.bpj.2011.02.042 21504727 PMC3077707 · DOI
  30. Harrison NL Gibbons SJ Zn2+: an endogenous modulator of ligand- and voltage-gated ion channels Neuropharmacology 1994 33 935 952 10.1016/0028-3908(94)90152-X 7845550 · DOI
  31. Mathie A Sutton GL Clarke CE Veale EL Zinc and copper: pharmacological probes and endogenous modulators of neuronal excitability Pharmacol Ther 2006 111 567 583 10.1016/j.pharmthera.2005.11.004 16410023 · DOI
  32. Curtain CC Ali F Volitakis I Cherny RA Norton RS Beyreuther K Barrow CJ Masters CL Bush AI Barnham KJ Alzheimer’s disease amyloid-β binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits J Biol Chem 2001 276 20466 20473 10.1074/jbc.M100175200 11274207 · DOI
  33. Karr JW Akintoye H Kaupp LJ Szalai VA N-Terminal Deletions Modify the Cu2+ Binding Site in Amyloid-β Biochemistry 2005 44 5478 5487 10.1021/bi047611e 15807541 · DOI
  34. Liu S-T Howlett G Barrow CJ Histidine-13 Is a Crucial Residue in the Zinc Ion-Induced Aggregation of the Aβ Peptide of Alzheimer’s Disease Biochemistry 1999 38 9373 9378 10.1021/bi990205o 10413512 · DOI
  35. Lim KH Kim YK Chang Y-T Investigations of the Molecular Mechanism of Metal-Induced Aβ (1–40) Amyloidogenesis Biochemistry 2007 46 13523 13532 10.1021/bi701112z 17973493 · DOI
  36. Bush AI Pettingell WH Paradis Md, Tanzi RE: Modulation of Aβ adhesiveness and secretase site cleavage by zinc J Biol Chem 1994 269 12152 12158 8163520
  37. Green MS Kaye JA Ball MJ The Oregon brain aging study: neuropathology accompanying healthy aging in the oldest old Neurology 2000 54 105 113 10.1212/WNL.54.1.105 10636134 · DOI
  38. McLean CA Cherny RA Fraser FW Fuller SJ Smith MJ Beyreuther K Bush AI Masters CL Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease Ann Neurol 1999 46 860 866 10.1002/1531-8249(199912)46:6<860::AID-ANA8>3.0.CO;2-M 10589538 · DOI
  39. Naslund J Schierhorn A Hellman U Lannfelt L Roses AD Tjernberg LO Silberring J Gandy SE Winblad B Greengard P Relative abundance of Alzheimer A beta amyloid peptide variants in Alzheimer disease and normal aging Proc Natl Acad Sci U S A 1994 91 8378 8382 10.1073/pnas.91.18.8378 8078890 PMC44609 · DOI · Paper page
  40. Selkoe DJ Alzheimer’s Disease Is a Synaptic Failure Science 2002 298 789 791 10.1126/science.1074069 12399581 · DOI · Paper page
  41. Phillips GR Huang JK Wang Y Tanaka H Shapiro L Zhang W Shan W-S Arndt K Frank M Gordon RE The presynaptic particle web: ultrastructure, composition, dissolution, and reconstitution Neuron 2001 32 63 77 10.1016/S0896-6273(01)00450-0 11604139 · DOI
  42. Lambert MP Velasco PT Chang L Viola KL Fernandez S Lacor PN Khuon D Gong Y Bigio EH Shaw P Monoclonal antibodies that target pathological assemblies of Aβ J Neurochem 2007 100 23 35 10.1111/j.1471-4159.2006.04157.x 17116235 · DOI · Paper page
  43. Bito H Takemoto-Kimura S Ca2+/CREB/CBP-dependent gene regulation: a shared mechanism critical in long-term synaptic plasticity and neuronal survival Cell Calcium 2003 34 425 430 10.1016/S0143-4160(03)00140-4 12909086 · DOI · Paper page
  44. Bitanihirwe BKY Cunningham MG Zinc: the brain’s dark horse Synapse 2009 63 1029 1049 10.1002/syn.20683 19623531 · DOI
  45. Frederickson CJ Suh SW Silva D Thompson RB Importance of zinc in the central nervous system: the zinc-containing neuron J Nutr 2000 130 1471S 1483S 10801962
  46. Townsend M Shankar GM Mehta T Walsh DM Selkoe DJ Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers J Physiol 2006 572 477 492 10.1113/jphysiol.2005.103754 16469784 PMC1779683 · DOI · Paper page
  47. Silva AJ Kogan JH Frankland PW Kida S CREB and memory Annu Rev Neurosci 1998 21 127 148 10.1146/annurev.neuro.21.1.127 9530494 · DOI · Paper page
  48. Stoltenberg M Bruhn M Sondergaard C Doering P West MJ Larsen A Troncoso JC Danscher G Immersion autometallographic tracing of zinc ions in Alzheimer beta-amyloid plaques Histochem Cell Biol 2005 123 605 611 10.1007/s00418-005-0787-0 15981003 · DOI
  49. Suh SW Jensen KB Jensen MS Silva DS Kesslak PJ Danscher G Frederickson CJ Histochemically-reactive zinc in amyloid plaques, angiopathy, and degenerating neurons of Alzheimer’s diseased brains Brain Res 2000 852 274 278 10.1016/S0006-8993(99)02096-X 10678753 · DOI
  50. Mirra SS Heyman A McKeel D Sumi SM Crain BJ Brownlee LM Vogel FS Hughes JP van Belle G Berg L The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease Neurology 1991 41 479 486 10.1212/WNL.41.4.479 2011243 · DOI · Paper page
  51. Folstein MF Folstein SE McHugh PR “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician J Psychiatr Res 1975 12 189 198 10.1016/0022-3956(75)90026-6 1202204 · DOI · Paper page
  52. Romijn HJ van Uum JF Breedijk I Emmering J Radu I Pool CW Double immunolabeling of neuropeptides in the human hypothalamus as analyzed by confocal laser scanning fluorescence microscopy J Histochem Cytochem 1999 47 229 236 10.1177/002215549904700211 9889258 · DOI
  53. Bjorklund NL Sadagoparamanujam VM Taglialatela G Selective, quantitative measurement of releasable synaptic zinc in human autopsy hippocampal brain tissue from Alzheimer’s disease patients J Neurosci Methods 2012 203 146 151 10.1016/j.jneumeth.2011.09.008 21945000 PMC3221793 · DOI
  54. Henriques AG Vieira SI da Cruz E Silva EF da Cruz E Silva OA Aβ promotes Alzheimer’s disease-like cytoskeleton abnormalities with consequences to APP processing in neurons J Neurochem 2010 113 761 771 10.1111/j.1471-4159.2010.06643.x 20345756 · DOI
  55. Wang Q Woltjer RL Cimino PJ Pan C Montine KS Zhang J Montine TJ Proteomic analysis of neurofibrillary tangles in Alzheimer disease identifies GAPDH as a detergent-insoluble paired helical filament tau binding protein FASEB J 2005 19 869 871 810.1096/fj.1004-3210fje 15746184 · DOI
  56. Aldridge GM Podrebarac DM Greenough WT Weiler IJ The use of total protein stains as loading controls: An alternative to high-abundance single-protein controls in semi-quantitative immunoblotting J Neurosci Methods 2008 172 250 254 10.1016/j.jneumeth.2008.05.003 18571732 PMC2567873 · DOI · Paper page
  57. Alcock NW A hydrogen-peroxide digestion system for tissue trace-metal analysis Biol Trace Elem Res 1987 13 363 370 10.1007/BF02796647 24254691 · DOI

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Authors
Bjorklund, N. L., Reese, L. C., Sadagoparamanujam, V.-M., Ghirardi, V., Woltjer, R. L., & Taglialatela, G.
Affiliations
  • The University of Texas Medical Branch at Galveston (US)
  • Oregon Health & Science University (US)
Corresponding author
Taglialatela, Giulio
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2012-05-28
Volume
7
Issue
1
Pages
23-23
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/1750-1326-7-23
PMC
PMC3403985
OpenAlex
W2139892536
Cited by
98
References
12
Citations by year
2026: 2 · 2025: 8 · 2024: 7 · 2023: 8 · 2022: 9 · 2021: 6 · 2020: 8 · 2019: 2 · 2018: 5 · 2017: 6 · 2016: 10 · 2015: 11 · 2014: 11 · 2013: 4 · 2012: 1
FWCI
5.79
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Alzheimer's Association (IIRG-90755)
  • Northwestern University
  • National Institute on Aging (P30AG008017)
  • National Institute of Neurological Disorders and Stroke (F31NS062558, R01NS059901)
  • National Institute of Environmental Health Sciences (T32ES007254)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Alzheimer's disease, amyloid-beta oligomers, postsynaptic localization, zinc, ZnT3, synaptic vesicles, hippocampus, CREB phosphorylation, synaptic plasticity, cognitive resistance
MeSH terms
Aged, 80 and over, Alzheimer Disease, Cognition Disorders, Female, Hippocampus, Humans, Immunohistochemistry, Male, Synapses, Zinc, Blotting, Western, Amyloid beta-Peptides

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