Seubert, Peter

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AMEYLOID VACCINE, AMYLOID REMOVAL MECHANISMS AND SYNAPTI

Cole, Greg M

30 September 2001 - 31 August 2007
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Total Funding: $ 1,285,000

Published data show that beta amyloid vaccination can markedly reduce amyloid burdens, apparently by activating microglia to degrade amyloid. Vaccinations may also prevent certain behavioral deficits. The overall impact on the AD phenotype remains vague. Vaccination might be expected to reduce amyloid but activate microglial inflammatory cytokine production, NADPH oxidase and reactive oxygen species. This may lead to a net decrease or possibly even an increase in oxidative damage and synapse loss. In this proposal, Aim 1 will address unanswered questions about the impact of vaccination at different timepoints on aspects of inflammation while aim 2 will investigate the impact on oxidative damage and synaptic pathology that we have documented in aging APP transgenic mice. Present data suggests that vaccination may not reduce Abeta 40 and vascular amyloid. There is also a real danger that vaccination may induce vascular damage and possibly even hemorrhage. Aim 3 will assess the impact of vaccination on amyloid and soluble Abeta in different compartments, vascular amyloid and vessel damage. Finally, there are unanswered questions about the mechanisms of amyloid reduction induced by vaccination. Available data strongly support an increase in amyloid phagocytosis by microglia, but data on enhanced degradation are inconsistent with some reports showing increases and some showing no change in amyloid degradation. Aim 4 will investigate hypotheses about the mechanisms involved in vaccine induced amyloid reductions. If successful, these experiments would be expected to lead to small molecule approaches to mitigate potential harmful effects of vaccination and to conceivably enhance amyloid removal.

11 Resulting Publications

• 1.

  2008

  Jeffrey A Fein; Sophie Sokolow; Carol A Miller; Harry V Vinters; Fusheng Yang; Gregory M Cole; Karen Hoppens Gylys

  Co-localization of amyloid beta and tau pathology in Alzheimer's disease synaptosomes.

  The American journal of pathology 2008;172(6):1683-92.

• 2.

  2007

  Qiu-Lan Ma; Marni E Harris-White; Oliver J Ubeda; Mychica Simmons; Walter Beech; Giselle P Lim; Bruce Teter; Sally A Frautschy; Greg M Cole

  Evidence of Abeta- and transgene-dependent defects in ERK-CREB signaling in Alzheimer's models.

  Journal of neurochemistry 2007;103(4):1594-607.

• 3.

  2006

  Qiu-Lan Ma; Giselle P Lim; Marni E Harris-White; Fusheng Yang; Surendra S Ambegaokar; Oliver J Ubeda; Charles G Glabe; Bruce Teter; Sally A Frautschy; Greg M Cole

  Antibodies against beta-amyloid reduce Abeta oligomers, glycogen synthase kinase-3beta activation and tau phosphorylation in vivo and in vitro.

  Journal of neuroscience research 2006;83(3):374-84.

• 4.

  2006

  Lixia Zhao; Qiu-Lan Ma; Frédéric Calon; Marni E Harris-White; Fusheng Yang; Giselle P Lim; Takashi Morihara; Oliver J Ubeda; Surendra Ambegaokar; James E Hansen; et al.

  Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease.

  Nature neuroscience 2006;9(2):234-42.

• 5.

  2005

  Greg M Cole; Giselle P Lim; Fusheng Yang; Bruce Teter; Aynun Begum; Qiulan Ma; Marni E Harris-White; Sally A Frautschy

  Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions.

  Neurobiology of aging 2005;26 Suppl 1():133-6.

• 6.

  2005

  Frédéric Calon; Giselle P Lim; Takashi Morihara; Fusheng Yang; Oliver Ubeda; Norman Salem; Sally A Frautschy; Greg M Cole

  Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer's disease.

  The European journal of neuroscience 2005;22(3):617-26.

• 7.

  2005

  Takashi Morihara; Bruce Teter; Fusheng Yang; Giselle P Lim; Sally Boudinot; F Douglas Boudinot; Sally A Frautschy; Greg M Cole

  Ibuprofen suppresses interleukin-1beta induction of pro-amyloidogenic alpha1-antichymotrypsin to ameliorate beta-amyloid (Abeta) pathology in Alzheimer's models.

  Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2005;30(6):1111-20.

• 8.

  2005

  John M Ringman; Sally A Frautschy; Gregory M Cole; Donna L Masterman; Jeffrey L Cummings

  A potential role of the curry spice curcumin in Alzheimer's disease.

  Current Alzheimer research 2005;2(2):131-6.

• 9.

  2005

  Fusheng Yang; Giselle P Lim; Aynun N Begum; Oliver J Ubeda; Mychica R Simmons; Surendra S Ambegaokar; Pingping P Chen; Rakez Kayed; Charles G Glabe; Sally A Frautschy; et al.

  Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo.

  The Journal of biological chemistry 2005;280(7):5892-901.

• 10.

  2004

  Greg M Cole; Takashi Morihara; Giselle P Lim; Fusheng Yang; Aynun Begum; Sally A Frautschy

  NSAID and antioxidant prevention of Alzheimer's disease: lessons from in vitro and animal models.

  Annals of the New York Academy of Sciences 2004;1035():68-84.

• 11.

  2004

  Frédéric Calon; Giselle P Lim; Fusheng Yang; Takashi Morihara; Bruce Teter; Oliver Ubeda; Phillippe Rostaing; Antoine Triller; Norman Salem; Karen H Ashe; et al.

  Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model.

  Neuron 2004;43(5):633-45.

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