An Attenuated Immune Response Is Sufficient to Enhance Cognition in an Alzheimer's Disease Mouse Model Immunized with Amyloid-β Derivatives

Sigurdsson, Einar M.; Knudsen, Elin; Asuni, Ayodeji A.; Fitzer‐Attas, Cheryl; Sage, Daniel; Quartermain, David; Goñi, Fernando; Frangione, Blas; Wısnıewskı, Thomas

doi:10.1523/jneurosci.1344-04.2004

Cited by 148 publications

(176 citation statements)

References 34 publications

(52 reference statements)

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“…Recently, several groups have demonstrated that active immunization of amyloid precursor protein (APP) transgenic (Tg) mice with fibrillar Aβ, as well as passive transfer of anti-Aβ antibodies, significantly reduced Aβ plaque deposition, neuritic dystrophy, and astrogliosis in the brains of these mice (Schenk et al, 1999;Bard et al, 2000;Morgan et al, 2000;Wilcock et al, 2004a). Improvements in learning and memory were also observed after either active or passive immunization of APP/Tg mice (Janus et al, 2000;Morgan et al, 2000;Dodart et al, 2002;Sigurdsson et al, 2004;Wilcock et al, 2004a;2004b).…”

Section: Introductionmentioning

confidence: 99%

Aβ-Immunotherapy for Alzheimer's Disease Using Mannan–Amyloid-Beta Peptide Immunoconjugates

Ghochikyan

Petrushina

Lees³

et al. 2006

DNA and Cell Biology

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In Alzheimer's disease (AD) the accumulation of pathological forms of the beta-amyloid (Aβ) peptide are believed to be causal factors in the neurodegeneration that results in the loss of cognitive function in patients. Anti-Aβ antibodies have been shown to reduce Aβ levels in transgenic mouse models of AD and in AN-1792 clinical trial on AD patients; however, the clinical trial was halted when some patients developed meningoencephalitis. Theories on the cause of the adverse events include proinflammatory "primed patients," a Th1-inducing adjuvant, and Aβ autoreactive T cells. New immunotherapy approaches are being developed to eliminate these putative risk factors. Mannan, which is recognized by pattern recognition receptors of the innate immune system, can be utilized as a molecular adjuvant to promote a Th2-mediated immune response to conjugated B cell epitopes. The N-terminus of Aβ was conjugated to mannan, and used to immunize mice with low concentrations of immunoconjugate, without a conventional adjuvant. Mannan induced a significant and highly polarized toward Th2 phenotype anti-Aβ antibody response not only in BALB/c, but also in B6SJL F1 mice. New preclinical trials in AD mouse models may help to develop novel immunogen-adjuvant configurations with the potential to avoid the adverse immune response that occurred in the first clinical trial.

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Section: Introductionmentioning

confidence: 99%

Aβ-Immunotherapy for Alzheimer's Disease Using Mannan–Amyloid-Beta Peptide Immunoconjugates

Ghochikyan

Petrushina

Lees³

et al. 2006

DNA and Cell Biology

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“…Evidence demonstrated the ability of the immune system to generate Abs after immunization against A␤ that may promote removal of A␤ from the brain (7)(8)(9)(10)(11). Besides the Ab-mediated systemic adaptive response, increasing studies suggest that the T cell immune response may be involved in the inflammation process of AD (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

mentioning

confidence: 99%

Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier

Shang²,

Zhao³

et al. 2009

The Journal of Immunology

103

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How circulating T cells infiltrate into the brain in Alzheimer disease (AD) remains unclear. We previously reported that amyloid β (Aβ)-dependent CCR5 expression in brain endothelial cells is involved in T cell transendothelial migration. In this study, we explored the signaling pathway of CCR5 up-regulation by Aβ. We showed that inhibitors of JNK, ERK, and PI3K significantly decreased Aβ-induced CCR5 expression in human brain microvascular endothelial cells (HBMECs). Chromatin immunoprecipitation assay revealed that Aβ-activated JNK, ERK, and PI3K promoted brain endothelial CCR5 expression via transcription factor Egr-1. Furthermore, neutralization Ab of receptor for advanced glycation end products (RAGE; an Aβ receptor) effectively blocked Aβ-induced JNK, ERK, and PI3K activation, contributing to CCR5 expression in HBMECs. Aβ fails to induce CCR5 expression when truncated RAGE was overexpressed in HBMECs. Transendothelial migration assay showed that the migration of MIP-1α (a CCR5 ligand)-expressing AD patients’ T cells through in vitro blood-brain barrier model was effectively blocked by anti-RAGE Ab, overexpression of truncated RAGE, and dominant-negative PI3K, JNK/ERK, or Egr-1 RNA interference in HBMECs, respectively. Importantly, blockage of intracerebral RAGE abolished the up-regulation of CCR5 on brain endothelial cells and the increased T cell infiltration in the brain induced by Aβ injection in rat hippocampus. Our results suggest that intracerebral Aβ interaction with RAGE at BBB up-regulates endothelial CCR5 expression and causes circulating T cell infiltration in the brain in AD. This study may provide a new insight into the understanding of inflammation in the progress of AD.

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“…We designed these homologous peptides so that they still have a high binding affinity to wild-type A␤ peptides and also have a similar BBB permeability. In prior studies we have shown that these A␤ homologous peptides do not self-assemble or promote the fibrillization of endogenous A␤ peptides (Asuni et al, 2006;Sigurdsson et al, 2001Sigurdsson et al, , 2004a). In the current study we used K6-A␤1-30 chelated to gadolinium via incorporation of DPTA at the amino terminus.…”

Section: Discussionmentioning

confidence: 94%

“…Hence, we developed a compound, Gd-DTPA-K6A␤1-30, that does not form amyloid aggregates and is non-toxic while maintaining high affinity for A␤. We have previously used K6A␤1-30 and related derivatives as experimental vaccines against AD (Sigurdsson et al, 2001(Sigurdsson et al, , 2004a. In this report we have evaluated the utility of this A␤ homologous peptide, which has therapeutic potential as a vaccine, for a dual use as a MRI contrast agent, when coupled with gadolinium.…”

Section: Introductionmentioning

confidence: 99%

A non-toxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice

Sigurdsson

Wadghiri

Mosconi

et al. 2008

Neurobiology of Aging

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Amyloid plaques are a characteristic feature in Alzheimer's disease (AD). A novel non-toxic contrast agent is presented, Gd-DTPA-K6A␤1-30, which is homologous to A␤, and allows plaque detection in vivo. MRI was performed on AD model mice and controls prior to and following intracarotid injection with Gd-DTPA-K6A␤1-30 in mannitol solution, to transiently open the blood-brain barrier. A gradient echo T2 * -weighted sequence was used to provide 100 m isotropic resolution with imaging times of 115 min. The scans were examined with voxel-based analysis (VBA) using statistical parametric mapping, for un-biased quantitative comparison of ligand-injected mice and controls. The results indicate that: (1) Gd-DTPA-K6A␤1-30 is an effective, non-toxic, ligand for plaque detection when combined with VBA (p ≤ 0.01-0.001), comparing pre and post-ligand injection scans. (2) Large plaques can be detected without the use of a contrast agent and this detection co-localizes with iron deposition. (3) Smaller, earlier plaques require contrast ligand for MRI visualization. Our ligand when combined with VBA may be useful for following therapeutic approaches targeting amyloid in transgenic mouse models.

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An Attenuated Immune Response Is Sufficient to Enhance Cognition in an Alzheimer's Disease Mouse Model Immunized with Amyloid-β Derivatives

Cited by 148 publications

References 34 publications

Aβ-Immunotherapy for Alzheimer's Disease Using Mannan–Amyloid-Beta Peptide Immunoconjugates

Aβ-Immunotherapy for Alzheimer's Disease Using Mannan–Amyloid-Beta Peptide Immunoconjugates

Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier

A non-toxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice

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