Biomedical subjects

Beka Solomon

Publications and source records attributed to Beka Solomon.

18 recordsLinked to original sources

PubMed2006

Intravenous immunoglobulin enhances the clearance of fibrillar amyloid-beta peptide.

Intravenous immunoglobulin (IVIg), a purified immunoglobulin fraction manufactured from the blood of healthy humans, is an FDA-approved treatment for many immune and inflammatory diseases. Recent studies have demonstrated that IVIg therapy has several positive effects on patients with Alzheimer's disease (AD). These include improving cognitive functions and lowering the level of soluble amyloid-beta peptide (AbetaP) in the brain. Nonetheless, the mechanism by which IVIg mediates the clearance of AbetaP from the AD brain currently remains unknown. In this study we investigated the molecular basis for the direct and indirect effects of IVIg on AbetaP clearance using the BV-2 cellular microglia line. Specifically, we show that IVIg dissolves preformed AbetaP fibrils in vitro. Moreover, IVIg increases cellular tolerance to AbetaP, enhances microglial migration toward AbetaP deposits, and mediates phagocytosis of AbetaP. Thus, several mechanisms can be considered when examining the effects of IVIg. Our work supports the hypothesis that IVIg interferes by more than one mechanism in clearing AbetaP from the brains of Alzheimer's patients.

Amyloid beta-Peptides↗

PubMed2006

Alzheimer's disease immunotherapy: from in vitro amyloid immunomodulation to in vivo vaccination.

Site-directed antibodies which modulate conformation of amyloid-beta peptide (Abeta) became the theoretical basis of the immunological approach for treatment of Alzheimer's disease (AD). Indeed, antibodies towards the EFRH sequence, located between amino acids 3-6 of the N-terminal region of Abeta, found to be a key position in modulation of Abeta conformation, prevent formation of fibrillar Abeta and dissolve already formed amyloid plaques. The performance of anti-Abeta antibodies in transgenic mice models of AD showed they are delivered to the central nervous system (CNS), preventing and/or dissolving Abeta. Moreover, these antibodies protected the mice from learning and age-related memory deficits. Development of such antibodies via active and/or passive immunization against Abeta peptide fragments has been proposed for AD immunotherapeutic strategies. Experimental active immunization with fibrillar Abeta 1-42 in hu-mans was stopped in phase II clinical trials due to unexpected neuroinflammatory manifestations. In spite of the fact that it will take considerable effort to establish a suitable immunization procedure, these results clearly strengthen the hypothesis that Abeta plays a central role in AD, stimulating a new area for development of Alzheimer's immunotherapeutics.

Alzheimer Disease↗

PubMed2005

Single chain antibody against the common epitope of mutant p53 restores wild-type activity to mutant p53 protein.

Here, we describe the biological activity of ME1, a mouse single chain Fv fragment (scFv) against the common epitope of mutant p53, which is efficiently expressed in mammalian cells. We found that in vivo interaction of the conformational p53 mutant R175H protein with the scFv resulted in the acquisition of wild-type p53 characteristics, manifested in trans-activation of p21, as well as induction of apoptosis. Moreover, antibody binding leads to abrogation of the mutant p53 mediated "gain of function" as estimated by downregulation of EGR-1, a transcriptional target of mutant p53. These findings suggest that the scFv restores wild-type properties to mutant p53.

Animals↗

PubMed2005

Inhibition of amyloid precursor protein processing by beta-secretase through site-directed antibodies.

Amyloid-beta peptide (AbetaP) that accumulates in the Alzheimer's diseased brain is derived from proteolytic processing of the amyloid precursor protein (APP) by means of beta- and gamma-secretases. The beta-secretase APP cleaving enzyme (BACE), which generates the N terminus of AbetaP, has become a target of intense research aimed at blocking the enzyme activity, thus reducing AbetaP and, subsequently, plaque formation. The search for specific inhibitors of beta-secretase activity as a possible treatment for Alzheimer's disease intensified with the discovery that BACE may be involved in processing other non-APP substrates. The presence of the APP-BACE complex in early endosomes highlights the cell surface as a potential therapeutic target, suggesting that interference in APP-BACE interaction at the cell surface may affect amyloid-beta production. We present here a unique approach to inhibit AbetaP production by means of antibodies against the beta-secretase cleavage site of APP. These antibodies were found to bind human APP overexpressed by CHO cells, and the formed immunocomplex was visualized in the early endosomes. Indeed, blocking of the beta-secretase site by these antibodies interfered with BACE activity and inhibited both intracellular and extracellular AbetaP formation in these cells.

Amyloid Precursor Protein Secretases↗

PubMed2005

Generation of anti-beta-amyloid antibodies via phage display technology towards Alzheimer's disease vaccination.

The pathology of Alzheimer's disease (AD) shows a significant correlation between beta-amyloid peptide (betaAP) deposition and the clinical severity of dementia. The ability of site-directed antibodies towards the N-terminal region of beta-amyloid peptide to suppress in vitro formation of toxic beta-amyloid serves as a factual basis for in vivo investigations. We localized the epitope of these anti-aggregating antibodies, and injection of phage displaying this epitope induced antibodies against the whole anti-beta-amyloid peptide. In Alzheimer's diseased transgenic mice, these antibodies are delivered from the periphery to the CNS preventing beta-amyloid formation and/or dissolving such aggregates. Performance of such antigens opens up possibilities for development of an efficient, long-lasting immunization procedure for treatment of Alzheimer's disease.

Alzheimer Disease↗

PubMed2004

Generation of anti-beta-amyloid antibodies via phage display technology.

The EFRH sequence, found to be the main anti-aggregating epitope corresponding to amino acids 3-6 of beta-amyloid peptide (AbetaP), was displayed on a phage and used as an antigen for immunization of mice, guinea pigs and rabbits. The generated antibodies recognize the full-length AbetaP (1-40) and exhibit similar biological properties to antibodies raised against whole soluble peptide and/or fibrillar beta-amyloid. EFRH-phage immunization of a transgenic mouse model of Alzheimer's disease evokes antibodies able to dissolve already formed beta-amyloid plaques, suggesting that they could become a therapeutic approach in treatment of the disease.

Alzheimer Disease↗

PubMed2004

EFRH-phage immunization of Alzheimer's disease animal model improves behavioral performance in Morris water maze trials.

We have developed an immunization procedure for the production of effective anti-beta-amyloid (anti-Abeta) antibodies, using filamentous phage displaying only 4 amino acids. The EFRH sequence, encompassing amino acids 3-6 of the 42 residues of Abeta peptide, was found previously to be the main regulatory site for amyloid modulation and the epitope of anti-aggregating antibodies. Engineered filamentous phage enable the display of various numbers of EFRH copies on the phage and serve as potent carriers of antigens. In the present study we have found that phage displaying high EFRH copy number are effective in eliciting humoral response against the EFRH sequence, which in turn relieves the amyloid burden in the brains of amyloid precursor protein Tg mice and improves their ability to perform cognitive tasks.

Alzheimer Disease↗

PubMed2004

Alzheimer's disease and immunotherapy.

Site-directed antibodies which modulate conformation of beta-amyloid peptide became the theoretical basis of the immunological approach for treatment of Alzheimer's disease (AD). Indeed, antibodies towards the EFRH sequence, located between amino acids 3-6 of the N-terminal region of Alzheimer's AbetaP, found to be a key position in protein conformation modulation, suppress formation of beta-amyloid and dissolve already formed fibrillar amyloid. The performance of anti-beta-amyloid antibodies in transgenic mice models of AD showed they are delivered to the central nervous system (CNS), preventing and dissolving beta-amyloid plaques. Moreover, these antibodies protected the mice from learning and age-related memory deficits. Naturally occurring anti-AbetaP antibodies have been found in human CSF and in the plasma of healthy individuals, but were significantly lower in AD patients, suggesting that AD may be an immunodeficient disorder. Active and/or passive immunization against beta-amyloid peptide has been proposed as a method for preventing and/or treating Alzheimer's disease. Experimental active immunization with Abeta 1-42 in humans was stopped in phase II clinical trials due to unexpected neuroinflammatory manifestations. Antibodies generated with this first-generation vaccine might not have the desired therapeutic properties to target the "correct" mechanism, however, new clinical approaches are now under consideration. Immunotherapy represents fascinating ways to test the amyloid hypothesis and offers genuine opportunities for AD treatment, but requires careful antigen and antibody selection to maximize efficacy and minimize adverse events.

Alzheimer Disease↗

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↗

PubMed2003

Generation of antibodies against prion protein in wild-type mice via helix 1 peptide immunization.

We present here the development of antibodies against prion protein in BALB/C mice using as antigen human helix 1 of PrP. This sequence is suggested to be involved in protein pathological conformational changes, and is distinguished from that of mice by one amino acid. The immune tolerance to an 'almost-self' epitope and the poor immunogenicity of short peptides was overcome by using Multiple Antigen Peptide displaying eight copies of helix 1. The generated antibodies recognize the whole prion protein with a high binding constant and the established protocol may lead to an active immunization towards therapeutics of prion disease.

Animals↗

PubMed2003

Immunological approach for the treatment of Alzheimer's disease.

Formation of amyloid beta (Abeta) is a complex kinetic and thermodynamic process, dependent on peptidepeptide interactions that may be modulated by other proteins. We found that site-directed antibodies toward peptide (glutamic acid, phenyl alanine, arginine, histidine) EFRH sequences 3-6 of the N-terminal region of beta-amyloid peptide (AbetaP) suppress in vitro formation of Abeta and dissolve already formed fibrillar amyloid. These so-called chaperone-like properties of monoclonal antibodies led to the development of a new immunological approach toward Alzheimer's disease (AD) treatment. Production and performance of anti-Abeta antibodies into the transgenic mouse model of AD showed that these antibodies may be delivered from the periphery to the central nervous system, preventing the formation of Abeta and dissolving amyloid plaques. Moreover, immunization with Abeta protects transgenic mice from the learning and age-related memory deficits that occur in AD. These data support the hypotheses that AbetaP plays a central role in AD, and site-directed antibodies that modulate AbetaP conformation might lead toward immunotherapy of the disease.

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↗

PubMedDate not supplied

Deglycosylation of anti-beta amyloid antibodies inhibits microglia activation in BV-2 cellular model.

Immunotherapy has become a strategy for treatment of Alzheimer's disease, by inducing antibody response to amyloid-beta peptide (AbetaP) or by passive administration of anti-AbetaP antibodies. Clearance of amyloid plaques involves interaction of immunoglobulin Fc receptor (FcR)-expressing microglia and antibodyopsonized Abeta deposits, stimulating phagocytosis but may promote neuroinflammation. Carbohydrate moiety of Fc of the immunoglobulin G molecule plays a significant role in modulating binding to FcR and its effector functions. Here, we enzymatically removed Fc glycan from monoclonal antibody 196 raised against AbetaP Antigen binding ability and in vitro stability of deglycosylated antibody were unaffected by deglycosylation. Moreover, the deglycosylated antibody exhibits low affinity to FcR on microglial BV-2 cells and has limited ability to mediate microglial chemotaxis and antibodydependent cytotoxicity compared to native antibody. These data suggest that deglycosylation of anti-Abeta antibodies before in vivo administration might prevent microglial overactivation, thus reducing the risk of neuroinflammatory response during passive immunization.

Alzheimer Disease↗