Biomedical subjects

Beka Solomon

Publications and source records attributed to Beka Solomon.

7 recordsLinked to original sources

PubMed2003

Reduction of beta-amyloid plaques in brain of transgenic mouse model of Alzheimer's disease by EFRH-phage immunization.

Antibodies to the epitope EFRH, representing residues 3-6 within the beta-amyloid (Abeta) sequence, were previously shown to affect the solubility and disaggregation of Abeta fibrils in vitro. Here, we describe a novel method of immunization, using as antigen the EFRH peptide displayed on the surface of the filamentous phage. The EFRH phage evoked effective auto-immune antibodies in amyloid precursor protein [V717I] (APP[V717I]) transgenic mice that recapitulate the amyloid plaques and vascular pathology of Alzheimer's disease (AD). The immunization provoked a considerable reduction in the number of Abeta amyloid plaques in the brain of the transgenic mice and may serve as the basis for anti-Abeta vaccine.

Alzheimer Disease↗

PubMed2002

Filamentous phage as vector-mediated antibody delivery to the brain.

Early diagnosis of Alzheimer's disease is prevented by lack of means to visualize and target beta amyloid plaques in the brains of affected people. There are many methods of detecting amyloid plaques by staining postmortem brain tissue, but none are available for monitoring in living patients. We propose anti-beta amyloid antibodies as a highly specific probe to monitor amyloid plaque formation in living patients. Intranasal administration of filamentous phage as delivery vector of anti-beta amyloid antibody fragment into Alzheimer's APP transgenic mice enables in vivo targeting of beta amyloid plaques. The plaques were co-visualized both by thioflavin-S and fluorescent-labeled anti-phage antibodies in the olfactory bulb and the hippocampus region. The genetically engineered filamentous bacteriophage proved to be an efficient and nontoxic viral delivery vector to the brain, offering an obvious advantage over other mammalian vectors. The ability to image A beta deposits in vivo would arguably provide the most useful diagnostic and monitoring test for early diagnosis of Alzheimer's disease.

Alzheimer Disease↗

PubMed2002

Antibodies to beta-amyloid decrease the blood-to-brain transfer of beta-amyloid peptide.

Amyloid-beta peptides (Abeta) play an important role in the pathophysiology of dementia of the Alzheimer's type and in amyloid angiopathy. Abeta outside the CNS could contribute to plaque formation in the brain where its entry would involve interactions with the blood-brain barrier (BBB). Effective antibodies to Abeta have been developed in an effort to vaccinate against Alzheimer's disease. These antibodies could interact with Abeta in the peripheral blood, block the passage of Abeta across the BBB, or prevent Abeta deposition within the CNS. To determine whether the blocking antibodies act at the BBB level, we examined the influx of radiolabeled Abeta (125I-Abeta(1-40)) into the brain after ex-vivo incubation with the antibodies. Antibody mAb3D6 (élan Company) reduced the blood-to-brain influx of Abeta after iv bolus injection. It also significantly decreased the accumulation of Abeta in brain parenchyma. To confirm the in-vivo study and examine the specificity of mAb3D6, in-situ brain perfusion in serum-free buffer was performed after incubation of 125I-Abeta(1-40) with another antibody mAbmc1 (DAKO Company). The presence of mAbmc1 also caused significant reduction of the influx of Abeta into the brain after perfusion. Therefore, effective antibodies to Abeta can reduce the influx of Abeta(1-40) into the brain.

Amino Acid Sequence↗

PubMed2002

Protective Molecules in Alzheimer's Disease: Therapeutic Antibodies.

Treatment of Alzheimer's disease by recruiting an immune response against beta-amyloid was suggested by the findings that monoclonal antibodies against beta-amyloid peptide can keep the peptides from aggregating into neurotoxic fibrils and dissolve already formed amyloid. Subsequent beta-amyloid vaccination studies in transgenic mice models of Alzheimer's disease have shown a significant reduction in the number of amyloid plaques and overall amyloid burden and even some improvement in cognitive performance. It is not yet clear if immunization with soluble or fibrillar forms of beta-amyloid peptide will end up being a treatment to prevent or treat Alzheimer's disease. However, various strategies for mobilizing the immune system may be effective toward treatment and prevention of Alzheimer's disease in humans. (c) 2002 Prous Science. All rights reserved.

Journal Article↗

PubMed2002

Immunological approaches as therapy for Alzheimer's disease.

The pathology of Alzheimer's disease (AD) shows a significant correlation between beta-amyloid peptide (AbetaP) conformation and the clinical severity of dementia. For many years, efforts have been focused on the development of inhibitors of beta-amyloid (Abeta) formation and its related neurotoxic effects. The author has developed a new concept showing that site-directed antibodies may modulate formation of Abeta. The performance of anti-Abeta antibodies in transgenic mice models of AD showed that they are delivered to the central nervous system (CNS), preventing in vivo formation of Abeta. Moreover, these antibodies dissolve Abeta plaques and protect the mice from learning difficulties and age-related memory deficits. Experimental active immunisation with Abeta (1-42) in humans has been stopped in Phase II of their clinical trials. However, several new preparations, able to provide antibodies against Abeta by either active or passive routes, have been formulated and at least one of these is likely to reach clinical testing. These data support the hypothesis that AbetaP plays a central role in AD and antibodies which modulate Abeta conformation may lead to immunotherapy of the disease.

Alzheimer Disease↗

PubMed2002

Anti-aggregating antibodies, a new approach towards treatment of conformational diseases.

More and more evidence shows that Alzheimer's and prion-related diseases belong to the family of conformational diseases characterized by protein self-association and tissue deposition as amyloid fibrils. Regardless of the nature of the protein constituent, all forms of amyloid are stable assemblies based on noncovalent interactions between subunits of crossed beta-sheet structure. Understanding the mechanism and molecular details of the pathological conformational conversion of amyloidogenic proteins may be of importance to the development of approaches towards prevention and treatment of such diseases. We previously found that monoclonal antibodies (mAbs) interact at strategic sites where protein unfolding is initiated, thereby stabilizing the protein and preventing further precipitation. Indeed, site-directed mAbs raised against the N-terminal region of Alzheimer's beta-peptide (A beta P) disaggregate A beta P fibrils, restore peptide solubility and prevent its neurotoxic effects. Similarly, selected mAbs raised against the human prion peptide 106-126 modulate conformational changes occurring in the prion peptide exposed to aggregating conditions, preventing its aggregation and related neurotoxicity on cultivated neural-like cells. All these data and related procedures bring more attention to the immunological concept in the treatment of conformational diseases, and the recent performance of such antibodies in transgenic mice, as a model for human diseases, suggests the development of vaccination approaches against such diseases.

Alzheimer Disease↗

PubMed2002

Towards Alzheimer's disease vaccination.

Active and passive immunization against fibrillar beta-amyloid of various mice models of Alzheimer's disease leads to the disaggregation and inhibition of plaque formation. Preliminary results showing improved behaviour and memory function obtained after administration of anti-beta-amyloid vaccines to transgenic mice encourage these and related approaches for testing in the treatment and prevention of Alzheimer's disease.

Alzheimer Disease↗