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PMID: 19523517 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Soluble fibrillar oligomer levels are elevated in Alzheimer's disease brain and correlate with cognitive dysfunction.

Neurobiology of disease ·Vol. 35 ·No. 3 ·2009-09-00 ·Pages 352-8

Tomic JL, Pensalfini A, Head E, Glabe CG

Abstract

Recent evidence has suggested a role for soluble oligomeric Abeta species in the pathology of Alzheimer's disease (AD). Fibrillar plaque deposits are present in non-demented individuals and levels of soluble Abeta correlate better with cognitive dysfunction in AD and transgenic mouse models. We have previously reported that there are at least two conformationally distinct types of Abeta oligomers: prefibrillar oligomers that are kinetic intermediates in fibril assembly reactions and are specifically recognized by A11 antibody and fibrillar oligomers that may represent fibril seeds or small pieces of fibrils and are recognized by a fibril specific antibody, OC. We have examined the levels of these two types of oligomers in the PBS soluble fraction of brain tissue from control cases, cases with senile degenerative changes (SDC) and AD patients. We found that the levels of soluble fibrillar oligomers detected by OC antibody are significantly elevated in multiple brain regions of AD patients. The elevated fibrillar oligomer levels were found not to be an artifact of tissue homogenization, nor a result of increased Abeta or APP levels. The concentration of fibrillar oligomers in adjacent brain regions of the same patient can vary widely and were not detected in post-mortem cerebrospinal fluid. In contrast, the level of prefibrillar oligomers are variable in both AD and age matched controls, indicating that they are not correlated with cognitive dysfunction and suggesting that they precede dementia in AD. Significant correlations were found between the levels of fibrillar oligomers and cognitive decline (MMSE scores) as well as the neuropathological hallmarks of AD. These results indicate that fibrillar oligomers may play a key role in the pathology of AD and may be a new target for diagnostic and therapeutic development.

MeSH Terms
Aged Aged, 80 and over Alzheimer Disease/cerebrospinal fluid,metabolism,pathology Amyloid beta-Peptides/metabolism Amyloid beta-Protein Precursor/metabolism Brain/metabolism,pathology Cognition Disorders/cerebrospinal fluid,metabolism,pathology Female Fibrillar Collagens/cerebrospinal fluid,metabolism Humans Immunoblotting Male Protease Nexins Psychiatric Status Rating Scales Receptors, Cell Surface/metabolism
Chemicals
APP protein, human Amyloid beta-Peptides Amyloid beta-Protein Precursor Fibrillar Collagens Protease Nexins Receptors, Cell Surface
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Tomic Jennifer L
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697-3900, USA.
Pensalfini Anna
Head Elizabeth
Glabe Charles G
References (36)
36 references, click to expand
  1. Image analysis of beta-amyloid load in Alzheimer's disease and relation to dementia severity.
    Lancet. 1995 Dec 9;346(8989):1524-8 PMID: 7491048
  2. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins.
    Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53 PMID: 9600986
  3. Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers.
    Mol Neurodegener. 2007 Sep 26;2:18 PMID: 17897471
  4. The levels of soluble versus insoluble brain Abeta distinguish Alzheimer's disease from normal and pathologic aging.
    Exp Neurol. 1999 Aug;158(2):328-37 PMID: 10415140
  5. A specific amyloid-beta protein assembly in the brain impairs memory.
    Nature. 2006 Mar 16;440(7082):352-7 PMID: 16541076
  6. Differences between recognition memory and remote memory for olfactory and visual stimuli in nondemented elderly individuals genetically at risk for Alzheimer's disease.
    Exp Gerontol. 2004 Mar;39(3):433-41 PMID: 15036403
  7. Annular protofibrils are a structurally and functionally distinct type of amyloid oligomer.
    J Biol Chem. 2009 Feb 13;284(7):4230-7 PMID: 19098006
  8. Identification of normal and pathological aging in prospectively studied nondemented elderly humans.
    Neurobiol Aging. 1992 Jan-Feb;13(1):179-89 PMID: 1311804
  9. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.
    Science. 2003 Apr 18;300(5618):486-9 PMID: 12702875
  10. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers.
    J Biol Chem. 2005 Apr 29;280(17):17294-300 PMID: 15722360
  11. Phases of A beta-deposition in the human brain and its relevance for the development of AD.
    Neurology. 2002 Jun 25;58(12):1791-800 PMID: 12084879
  12. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment.
    Ann Neurol. 1991 Oct;30(4):572-80 PMID: 1789684
  13. Neuropathological staging of Alzheimer lesions and intellectual status in Alzheimer's and Parkinson's disease patients.
    Neurosci Lett. 1993 Nov 12;162(1-2):179-82 PMID: 8121624
  14. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician.
    J Psychiatr Res. 1975 Nov;12(3):189-98 PMID: 1202204
  15. Neuropathological stageing of Alzheimer-related changes.
    Acta Neuropathol. 1991;82(4):239-59 PMID: 1759558
  16. Altered expression of synaptic proteins occurs early during progression of Alzheimer's disease.
    Neurology. 2001 Jan 9;56(1):127-9 PMID: 11148253
  17. Olfactory bulb lesions in Alzheimer's disease.
    Neurobiol Aging. 1992 Jul-Aug;13(4):469-73 PMID: 1508297
  18. Pathological changes in frontal cortex from biopsy to autopsy in Alzheimer's disease.
    Neurobiol Aging. 1993 Nov-Dec;14(6):589-96 PMID: 8295661
  19. Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability.
    J Biol Chem. 2002 Aug 30;277(35):32046-53 PMID: 12058030
  20. Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques.
    Ann Neurol. 1988 Feb;23(2):138-44 PMID: 2897823
  21. Alzheimer's disease: amyloid plaques in the cerebellum.
    J Neurol Sci. 1989 Nov;93(2-3):277-87 PMID: 2556503
  22. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
    Nat Med. 2008 Aug;14(8):837-42 PMID: 18568035
  23. Olfactory identification and incidence of mild cognitive impairment in older age.
    Arch Gen Psychiatry. 2007 Jul;64(7):802-8 PMID: 17606814
  24. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective.
    Cell. 2005 Feb 25;120(4):545-55 PMID: 15734686
  25. Taste and smell losses in normal aging and disease.
    JAMA. 1997 Oct 22-29;278(16):1357-62 PMID: 9343468
  26. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease.
    Am J Pathol. 1999 Sep;155(3):853-62 PMID: 10487842
  27. Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons.
    J Neurosci. 1999 Oct 15;19(20):8876-84 PMID: 10516307
  28. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease.
    Ann Neurol. 1999 Dec;46(6):860-6 PMID: 10589538
  29. Has the amyloid cascade hypothesis for Alzheimer's disease been proved?
    Curr Alzheimer Res. 2006 Feb;3(1):71-3 PMID: 16472206
  30. Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss.
    Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10417-22 PMID: 12925731
  31. Synaptic targeting by Alzheimer's-related amyloid beta oligomers.
    J Neurosci. 2004 Nov 10;24(45):10191-200 PMID: 15537891
  32. The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects.
    Br J Psychiatry. 1968 Jul;114(512):797-811 PMID: 5662937
  33. Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies.
    J Neurochem. 2001 Nov;79(3):595-605 PMID: 11701763
  34. Globular amyloid beta-peptide oligomer - a homogenous and stable neuropathological protein in Alzheimer's disease.
    J Neurochem. 2005 Nov;95(3):834-47 PMID: 16135089
  35. Neuritic pathology and dementia in Alzheimer's disease.
    Ann Neurol. 1991 Aug;30(2):156-65 PMID: 1910274
  36. Amyloid beta protein-induced neuronal cell death: neurotoxic properties of aggregated amyloid beta protein.
    Brain Res. 1994 Mar 14;639(2):240-4 PMID: 7515762
Article Info
Journal
Neurobiology of disease
Abbr.
Neurobiol Dis
ISSN
1095-953X
DOI
10.1016/j.nbd.2009.05.024
Published
2009-09-00
Epub
2009-00-10
Pages
352-8
Language
English
Region
United States
NLM ID
9500169
PMCID
PMC2725199
Subset
IM
Grants
NIA NIH HHS · P01 AG000538 · United States
NIA NIH HHS · P01 AG000538-300022 · United States
NIA NIH HHS · AG00538 · United States
External Links
PubMed source DOI: 10.1016/j.nbd.2009.05.024 PMC Full Text View journal details
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