P4-357 Modest immune response elicited by Aβ derivatives in TG2576 mice improves cognition

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

doi:10.1016/s0197-4580(04)81915-8

Cited by 5 publications

(11 citation statements)

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“…A␤1-40, A␤12-28, and A␤12-28P peptides were custom-synthesized at the W. M. Keck Facility at Yale University (New Haven, CT) by using solid-phase support, and they were purified as described (11,12,19). A␤12-28P used for in vitro assays was derived from the same batch administered to Tg animals.…”

Section: Methodsmentioning

confidence: 99%

“…Before the aggregation studies A␤1-40 was treated with 1,1,1,3,3,3-hexafluoro-2-propanol to assure complete disaggregation and monomerization (12). The amount of A␤1-40 fibrils formed over time was determined by a standard Thioflavin-T assay performed according to previously published protocols (11,12,19).…”

Section: Methodsmentioning

confidence: 99%

“…Sera collected before and after the treatment were diluted 1:200 and 1:500 and added to ELISA plates coated with synthetic A␤1-40 50 ng per well (19). The plates were washed and incubated with specific antimouse IgG or IgM mAbs conjugated with HRP (Amersham Biosciences, Piscataway, NJ) at a 1:5,000 dilution, followed by adding 3,3,5,5-tetramethybenzidine substrate.…”

Section: Methodsmentioning

confidence: 99%

“…The color reaction was stopped with 2 M sulfuric acid, and the absorbance was read at 450-nm wavelength. Sera from animals vaccinated with the peptide K6A␤1-30 (19), which is known to induce an immune response against A␤, and wells coated with purified murine IgG and IgM were used as positive controls, whereas sera from WT age-matched mice and uncoated wells were used as a negative controls. Each sample was tested in quadruplicate.…”

Section: Methodsmentioning

confidence: 99%

“…Behavioral Studies. APP SWE mice were subjected to behavioral testing with the radial arm maze, which assesses the working memory based on an animal's exploratory behavior (19). The testing was performed during the last month of the experiment (between ages 17 and 18 months) while animals were still receiving A␤12-28P or vehicle.…”

Section: Treatment Of Tg Mice With A␤12-28p: Monitoring the Immune Rementioning

confidence: 99%

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Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease

Sadowski¹,

Pankiewicz²,

Scholtzova³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The amyloid-␤ (A␤) cascade hypothesis of Alzheimer's disease (AD) maintains that accumulation of A␤ peptide constitutes a critical event in the early disease pathogenesis. The direct binding between A␤ and apolipoprotein E (apoE) is an important factor implicated in both A␤ clearance and its deposition in the brain's parenchyma and the walls of meningoencephalic vessels as cerebral amyloid angiopathy. With the aim of testing the effect of blocking the apoE/A␤ interaction in vivo as a potential novel therapeutic target for AD pharmacotherapy, we have developed A␤12-28P, which is a blood-brain-barrier-permeable nontoxic, and nonfibrillogenic synthetic peptide homologous to the apoE binding site on the full-length A␤. A␤12-28P binds with high affinity to apoE, preventing its binding to A␤, but has no direct effect on A␤ aggregation. A␤12-28P shows a strong pharmacological effect in vivo. Its systemic administration resulted in a significant reduction of A␤ plaques and cerebral amyloid angiopathy burden and a reduction of the total brain level of A␤ in two AD transgenic mice models. The treatment did not affect the levels of soluble A␤ fraction or A␤ oligomers, indicating that inhibition of the apoE/A␤ interaction in vivo has a net effect of increasing A␤ clearance over deposition and at the same time does not create conditions favoring formation of toxic oligomers. Furthermore, behavioral studies demonstrated that treatment with A␤12-28P prevents a memory deficit in transgenic animals. These findings provide evidence of another therapeutic approach for AD.Alzheimer's pathology ͉ memory loss prevention ͉ peptide ͉ transgenic mice ͉ treatment A lzheimer's disease (AD) is the most common neurodegenerative disease worldwide, characterized by a progressive dysfunction in multiple cognitive domains and complex neuropathological features that include accumulation of amyloid-␤ (A␤) followed by synaptic dysfunction, formation of neurofibrillary tangles, and neuronal loss. With the expected increase in AD prevalence, as a function of the population aging, effective treatment for AD is critically needed. Multiple lines of evidence indicate that a disturbance of A␤ homeostasis is a paramount event in early disease pathogenesis (1). A␤ is a hydrophobic 39-to 43-aa peptide, which is derived from cleavage of a larger, synaptic transmembrane protein, the amyloid precursor protein (APP) (2). The accumulation of A␤ in the brain is determined by the rate of its generation versus in situ proteolytic degradation and clearance across the blood-brain-barrier [BBB; for review see Tanzi et al. (3)]. In the setting of increased concentration, A␤ monomers assemble into oligomers and fibrils and eventually become deposited, forming parenchymal plaques and cerebral amyloid angiopathy (CAA).Inheritance of the apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor identified so far. ApoE isotype inheritance modulates the prevalence, age of onset, and the burden of pathology in sporadic AD (4, 5). ApoE binds A␤ with high affinity a...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Treatment Of Tg Mice With A␤12-28p: Monitoring the Immune Rementioning

confidence: 99%

See 3 more Smart Citations

Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease

Sadowski¹,

Pankiewicz²,

Scholtzova³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

150

149

View full text Add to dashboard Cite

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Autoantibody-catalyzed Hydrolysis of Amyloid β Peptide

Taguchi

Planque

Nishiyama

et al. 2008

Journal of Biological Chemistry

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Treatment Strategies Targeting Amyloid -Protein

Schenk¹,

Basi²,

Pangalos

2012

Cold Spring Harbor Perspectives in Medicine

108

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With the advent of the key discovery in the mid-1980s that the amyloid b-protein (Ab) is the core constituent of the amyloid plaque pathology found in Alzheimer disease (AD), an intensive effort has been underway to attempt to mitigate its role in the hope of treating the disease. This effort fully matured when it was clarified that the Ab is a normal product of cleavage of the amyloid precursor protein, and well-defined proteases for this process were identified. Further therapeutic options have been developed around the concept of anti-Ab aggregation inhibitors and the surprising finding that immunization with Ab itself leads to reduction of pathology in animal models of the disease. Here we review the progress in this field toward the goal of targeting Ab for treatment and prevention of AD and identify some of the major challenges for the future of this area of medicine.

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P4-357 Modest immune response elicited by Aβ derivatives in TG2576 mice improves cognition

Cited by 5 publications

References 0 publications

Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease

Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease

Autoantibody-catalyzed Hydrolysis of Amyloid β Peptide

Treatment Strategies Targeting Amyloid -Protein

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